See 17 for PATIENT COUNSELING INFORMATION and FDAapproved

Transcription

1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use ALIMTA sfely nd effectively. See full prescribing informtion for ALIMTA. ALIMTA (pemetrexed for injection), for intrvenous use Initil U.S. Approvl: INDICATIONS AND USAGE ALIMTA is folte nlog metbolic inhibitor indicted for the: initil tretment of ptients with loclly dvnced or metsttic non-squmous, non-smll cell lung cncer (NSCLC) in combintion with cispltin. (.) mintennce tretment of ptients with loclly dvnced or metsttic, non-squmous NSCLC whose disese hs not progressed fter four cycles of pltinum-bsed first-line chemotherpy, s single gent. (.) tretment of ptients with recurrent, metsttic non-squmous, NSCLC fter prior chemotherpy, s single gent. (.) Limittions of Use: ALIMTA is not indicted for the tretment of ptients with squmous cell NSCLC. (.) initil tretment, in combintion with cispltin, of ptients with mlignnt pleurl mesotheliom whose disese is unresectble or who re otherwise not cndidtes for curtive surgery. (.) DOSAGE AND ADMINISTRATION The recommended dose of ALIMTA, dministered s single gent or with cispltin, in ptients with cretinine clernce of ml/minute or greter is mg/m s n intrvenous infusion over minutes on Dy of ech -dy cycle. (.,.,.3) Initite folic cid mcg to mcg orlly, once dily, beginning 7 dys prior to the first dose of ALIMTA nd continue until dys fter the lst dose of ALIMTA. (.) Administer vitmin B, mg intrmusculrly, week prior to the first dose of ALIMTA nd every 3 cycles. (.) Administer dexmethsone mg orlly, twice dily the dy before, the dy of, nd the dy fter ALIMTA dministrtion. (.) DOSAGE FORMS AND STRENGTHS For Injection: mg or mg lyophilized powder in single-dose vil (3) CONTRAINDICATIONS History of severe hypersensitivity rection to pemetrexed. () WARNINGS AND PRECAUTIONS Myelosuppression: Cn cuse severe bone mrrow suppression resulting in cytopeni nd n incresed risk of infection. Do not FULL PRESCRIBING INFORMATION: CONTENTS* INDICATIONS AND USAGE. Non-Squmous Non-Smll Cell Lung Cncer (NSCLC). Mesotheliom DOSAGE AND ADMINISTRATION. Recommended Dosge nd Schedule for Non-Squmous NSCLC. Recommended Dosge nd Schedule for Mesotheliom.3 Renl Impirment. Premediction nd Concomitnt Medictions to Mitigte Toxicity. Dosge Modifiction of Ibuprofen in Ptients with Mild to Moderte Renl Impirment Receiving ALIMTA. Dosge Modifictions for Adverse Rections.7 Preprtion for Administrtion 3 DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS. Myelosuppression nd Incresed Risk of Myelosuppression without Vitmin Supplementtion. Renl Filure.3 Bullous nd Exfolitive Skin Toxicity. Interstitil Pneumonitis dminister ALIMTA when the bsolute neutrophil count is less thn cells/mm 3 nd pltelets re less thn, cells/mm 3. Initite supplementtion with orl folic cid nd intrmusculr vitmin B to reduce the severity of hemtologic nd gstrointestinl toxicity of ALIMTA. (.,.) Renl Filure: Cn cuse severe, nd sometimes ftl, renl filure. Do not dminister when cretinine clernce is less thn ml/min. (.3,.) Bullous nd Exfolitive Skin Toxicity: Permnently discontinue for severe nd life-thretening bullous, blistering or exfoliting skin toxicity. (.3) Interstitil Pneumonitis: Withhold for cute onset of new or progressive unexplined pulmonry symptoms. Permnently discontinue if pneumonitis is confirmed. (.) Rdition Recll: Cn occur in ptients who received rdition weeks to yers previously; permnently discontinue for signs of rdition recll. (.) Embryo-Fetl Toxicity: Cn cuse fetl hrm. Advise ptients of the potentil risk to fetus nd to use effective contrception. (.7, 8., 8.3) ADVERSE REACTIONS The most common dverse rections (incidence %) of ALIMTA, when dministered s single gent re ftigue, nuse, nd norexi. (.) The most common dverse rections (incidence %) of ALIMTA when dministered with cispltin re vomiting, neutropeni, nemi, stomtitis/phryngitis, thrombocytopeni, nd constiption. (.) To report SUSPECTED ADVERSE REACTIONS, contct Eli Lilly nd Compny t -8-LillyRx ( ) or FDA t -8-FDA-88 or DRUG INTERACTIONS Ibuprofen incresed risk of ALIMTA toxicity in ptients with mild to moderte renl impirment. Modify the ibuprofen dosge s recommended for ptients with cretinine clernce between ml/min nd 79 ml/min. (.,., 7) USE IN SPECIFIC POPULATIONS Lcttion: Advise not to brestfeed. (8.) See 7 for PATIENT COUNSELING INFORMATION nd FDApproved ptient lbeling. Revised: /7. Rdition Recll. Incresed Risk of Toxicity with Ibuprofen in Ptients with Renl Impirment.7 Embryo-Fetl Toxicity ADVERSE REACTIONS. Clinicl Trils Experience. Postmrketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8. Pregnncy 8. Lcttion 8.3 Femles nd Mles of Reproductive Potentil 8. Peditric Use 8. Geritric Use 8. Ptients with Renl Impirment OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY. Mechnism of Action. Phrmcodynmics.3 Phrmcokinetics 3 NONCLINICAL TOXICOLOGY

2 3. Crcinogenesis, Mutgenesis, Impirment of Fertility CLINICAL STUDIES. Non-squmous NSCLC. Mesotheliom REFERENCES HOW SUPPLIED/STORAGE AND HANDLING 7 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing informtion re not listed. FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE. Non-Squmous Non-Smll Cell Lung Cncer (NSCLC) ALIMTA is indicted for: initil tretment of ptients with loclly dvnced or metsttic, non-squmous, non-smll cell lung cncer (NSCLC) in combintion with cispltin. mintennce tretment of ptients with loclly dvnced or metsttic, non-squmous NSCLC whose disese hs not progressed fter four cycles of pltinum-bsed first-line chemotherpy, s single gent. tretment of ptients with recurrent, metsttic non-squmous, NSCLC fter prior chemotherpy, s single gent. Limittions of Use: ALIMTA is not indicted for the tretment of ptients with squmous cell, non-smll cell lung cncer [see Clinicl Studies.].. Mesotheliom ALIMTA is indicted, in combintion with cispltin, for the initil tretment of ptients with mlignnt pleurl mesotheliom whose disese is unresectble or who re otherwise not cndidtes for curtive surgery. DOSAGE AND ADMINISTRATION. Recommended Dosge nd Schedule for Non-Squmous NSCLC The recommended dose of ALIMTA in combintion with cispltin for initil tretment of NSCLC in ptients with cretinine clernce (clculted by Cockcroft-Gult eqution) of ml/min or greter is mg/m s n intrvenous infusion over minutes dministered prior to cispltin on Dy of ech -dy cycle for up to six cycles in the bsence of disese progression or uncceptble toxicity. The recommended dose of ALIMTA for mintennce tretment of NSCLC in ptients with cretinine clernce (clculted by Cockcroft-Gult eqution) of ml/min or greter is mg/m s n intrvenous infusion over minutes on Dy of ech -dy cycle until disese progression or uncceptble toxicity fter four cycles of pltinum-bsed first-line chemotherpy. The recommended dose of ALIMTA for tretment of recurrent NSCLC in ptients with cretinine clernce (clculted by Cockcroft-Gult eqution) of ml/min or greter is mg/m s n intrvenous infusion over minutes on Dy of ech -dy cycle until disese progression or uncceptble toxicity...3. Recommended Dosge nd Schedule for Mesotheliom The recommended dose of ALIMTA, dministered in combintion with cispltin, in ptients with cretinine clernce (clculted by Cockcroft-Gult eqution) of ml/min or greter is mg/m s n intrvenous infusion over minutes on Dy of ech -dy cycle until disese progression or uncceptble toxicity. Renl Impirment ALIMTA dosing recommendtions re provided for ptients with cretinine clernce (clculted by Cockcroft-Gult eqution) of ml/min or greter [see Dosge nd Administrtion (.,.)]. There is no recommended dose for ptients whose cretinine clernce is less thn ml/min [see Use in Specific Popultions (8.)]. Premediction nd Concomitnt Medictions to Mitigte Toxicity Vitmin Supplementtion

3 3 Initite folic cid mcg to mcg orlly once dily, beginning 7 dys before the first dose of ALIMTA nd continuing until 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. Subsequent vitmin B injections my be given the sme dy s tretment with ALIMTA [see Wrnings nd Precutions (.)]. Do not substitute orl vitmin B for intrmusculr vitmin B. Corticosteroids Administer dexmethsone mg orlly twice dily for three consecutive dys, beginning the dy before ech ALIMTA dministrtion.. Dosge Modifiction of Ibuprofen in Ptients with Mild to Moderte Renl Impirment Receiving ALIMTA In ptients with cretinine clernces between ml/min nd 79 ml/min, modify dministrtion of ibuprofen s follows [see Wrnings nd Precutions (.), Drug Interctions (7) nd Clinicl Phrmcology (.3)]: Avoid dministrtion of ibuprofen for dys before, the dy of, nd dys following dministrtion of ALIMTA. Monitor ptients more frequently for myelosuppression, renl, nd gstrointestinl toxicity, if concomitnt dministrtion of ibuprofen cnnot be voided.. Dosge Modifictions for Adverse Rections Obtin complete blood count on Dys, 8, nd of ech cycle. Assess cretinine clernce prior to ech cycle. Do not dminister ALIMTA if the cretinine clernce is less thn ml/min. Dely initition of the next cycle of ALIMTA until: recovery of non-hemtologic toxicity to Grde -, bsolute neutrophil count (ANC) is cells/mm3 or higher, nd pltelet count is, cells/mm3 or higher. Upon recovery, modify the dosge of ALIMTA in the next cycle s specified in Tble. For dosing modifictions for cispltin, refer to the prescribing informtion for cispltin. Tble : Recommended Dosge Modifictions for Adverse Rections Toxicity in Most Recent Tretment Cycle Myelosuppressive toxicity [see Wrnings nd Precutions (.)] ANC less thn /mm3 nd pltelets greter thn or equl to,/mm3 OR Pltelet count less thn,/mm3 without bleeding. Pltelet count less thn,/mm3 with bleeding Recurrent Grde 3 or myelosuppression fter dose reductions Non-hemtologic toxicity Any Grde 3 or toxicities EXCEPT mucositis or neurologic toxicity OR Dirrhe requiring hospitliztion Grde 3 or mucositis 7% of previous dose % of previous dose Discontinue 7% of previous dose % of previous dose Withhold until cretinine Renl toxicity [see Wrnings nd Precutions (.)] clernce is ml/min or greter Grde 3 or neurologic toxicity Permnently discontinue Recurrent Grde 3 or non-hemtologic toxicity fter dose reductions Permnently discontinue Severe nd life-thretening Skin Toxicity [see Wrnings nd Precutions (.3)] Permnently discontinue Interstitil Pneumonitis [see Wrnings nd Precutions (.)] Permnently discontinue Ntionl Cncer Institute Common Toxicity Criteri for Adverse Events version (NCI CTCAE v).7 ALIMTA Dose Modifiction for Next Cycle Preprtion for Administrtion ALIMTA is cytotoxic drug. Follow pplicble specil hndling nd disposl procedures.

4 Clculte the dose of ALIMTA nd determine the number of vils needed. Reconstitute ALIMTA to chieve concentrtion of mg/ml s follows: Reconstitute ech -mg vil with. ml of.9% Sodium Chloride Injection, USP (preservtive-free) Reconstitute ech -mg vil with ml of.9% Sodium Chloride Injection, USP (preservtive-free) Do not use clcium-contining solutions for reconstitution. 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. FURTHER DILUTION IS REQUIRED prior to dministrtion. Store reconstituted, preservtive-free product under refrigerted conditions [-8 C (3- F)] for no longer thn hours from the time of reconstitution. Discrd vil fter hours. Inspect reconstituted product visully for prticulte mtter nd discolortion prior to further dilution. If prticulte mtter is observed, discrd vil. Withdrw the clculted dose of ALIMTA from the vil(s) nd discrd vil with ny unused portion. Further dilute ALIMTA with.9% Sodium Chloride Injection (preservtive-free) to chieve totl volume of ml for intrvenous infusion. Store diluted, reconstituted product under refrigerted conditions [-8 C (3- F)] for no more thn hours from the time of reconstitution. Discrd fter hours. 3 DOSAGE FORMS AND STRENGTHS For injection: mg or mg pemetrexed s white to light-yellow or green-yellow lyophilized powder in single-dose vils for reconstitution. CONTRAINDICATIONS ALIMTA is contrindicted in ptients with history of severe hypersensitivity rection to pemetrexed [see Adverse Rections (.)]. WARNINGS AND PRECAUTIONS. Myelosuppression nd Incresed Risk of Myelosuppression without Vitmin Supplementtion ALIMTA cn cuse severe myelosuppression resulting in requirement for trnsfusions nd which my led to neutropenic infection. The risk of myelosuppression is incresed in ptients who do not receive vitmin supplementtion. In Study JMCH, incidences of Grde 3- neutropeni (38% versus 3%), thrombocytopeni (9% versus %), febrile neutropeni (9% versus.%), nd neutropenic infection (% versus ) were higher in ptients who received ALIMTA plus cispltin without vitmin supplementtion s compred to ptients who were fully supplemented with folic cid nd vitmin B prior to nd throughout ALIMTA plus cispltin tretment. Initite supplementtion with orl folic cid nd intrmusculr vitmin B prior to the first dose of ALIMTA; continue vitmin supplementtion during tretment nd for dys fter the lst dose of ALIMTA to reduce the severity of hemtologic nd gstrointestinl toxicity of ALIMTA [see Dosge nd Administrtion (.)]. Obtin complete blood count t the beginning of ech cycle. Do not dminister ALIMTA until the ANC is t lest cells/mm3 nd pltelet count is t lest, cells/mm3. Permnently reduce ALIMTA in ptients with n ANC of less thn cells/mm3 or pltelet count 3 of less thn, cells/mm in previous cycles [see Dosge nd Administrtion (.)]. In Studies JMDB nd JMCH, mong ptients who received vitmin supplementtion, incidence of Grde 3- neutropeni ws % nd 3%, the incidence of Grde 3- nemi ws % nd %, nd incidence of Grde 3- thrombocytopeni ws % nd %, respectively. In Study JMCH, 8% of ptients in the ALIMTA rm required red blood cell trnsfusions compred to 7% of ptients in the cispltin rm [see Adverse Rections (.)]. In Studies JMEN, PARAMOUNT, nd JMEI, where ll ptients received vitmin supplementtion, incidence of Grde 3- neutropeni rnged from 3% to %, nd incidence of Grde 3- nemi rnged from 3% to %.. Renl Filure

5 ALIMTA cn cuse severe, nd sometimes ftl, renl toxicity. The incidences of renl filure in clinicl studies in which ptients received ALIMTA with cispltin were:.% in Study JMDB nd.% in Study JMCH. The incidence of renl filure in clinicl studies in which ptients received ALIMTA s single gent rnged from.% to.% (Studies JMEN, PARAMOUNT, nd JMEI [see Adverse Rections (.)]. Determine cretinine clernce before ech dose nd periodiclly monitor renl function during tretment with ALIMTA. Withhold ALIMTA in ptients with cretinine clernce of less thn ml/minute [see Dosge nd Administrtion (.3)]..3 Bullous nd Exfolitive Skin Toxicity Serious nd sometimes ftl, bullous, blistering nd exfolitive skin toxicity, including cses suggestive of StevensJohnson Syndrome/Toxic epiderml necrolysis cn occur with ALIMTA. Permnently discontinue ALIMTA for severe nd life-thretening bullous, blistering or exfoliting skin toxicity.. Interstitil Pneumonitis Serious interstitil pneumonitis, including ftl cses, cn occur with ALIMTA tretment. Withhold ALIMTA for cute onset of new or progressive unexplined pulmonry symptoms such s dyspne, cough, or fever pending dignostic evlution. If pneumonitis is confirmed, permnently discontinue ALIMTA.. Rdition Recll Rdition recll cn occur with ALIMTA in ptients who hve received rdition weeks to yers previously. Monitor ptients for inflmmtion or blistering in res of previous rdition tretment. Permnently discontinue ALIMTA for signs of rdition recll.. Incresed Risk of Toxicity with Ibuprofen in Ptients with Renl Impirment Exposure to ALIMTA is incresed in ptients with mild to moderte renl impirment who tke concomitnt ibuprofen, incresing the risks of dverse rections of ALIMTA. In ptients with cretinine clernces between ml/min nd 79 ml/min, void dministrtion of ibuprofen for dys before, the dy of, nd dys following dministrtion of ALIMTA. If concomitnt ibuprofen use cnnot be voided, monitor ptients more frequently for ALIMTA dverse rections, including myelosuppression, renl, nd gstrointestinl toxicity [see Dosge nd Administrtion (.), Drug Interctions (7), nd Clinicl Phrmcology (.3)]..7 Embryo-Fetl Toxicity Bsed on findings from niml studies nd its mechnism of ction, ALIMTA cn cuse fetl hrm when dministered to pregnnt womn. In niml reproduction studies, intrvenous dministrtion of pemetrexed to pregnnt mice during the period of orgnogenesis ws tertogenic, resulting in developmentl delys nd incresed mlformtions t doses lower thn the recommended humn dose of mg/m. Advise pregnnt women of the potentil risk to the fetus. Advise femles of reproductive potentil to use effective contrception during tretment with ALIMTA nd for months fter the finl dose. Advise mles with femle prtners of reproductive potentil to use effective contrception during tretment with ALIMTA nd for 3 months fter the finl dose [see Use in Specific Popultions (8., 8.3) nd Clinicl Phrmcology (.)]. ADVERSE REACTIONS The following dverse rections re discussed in greter detil in other sections of the lbeling: Myelosuppression [see Wrnings nd Precutions (.)] Renl filure [see Wrnings nd Precutions (.)] Bullous nd exfolitive skin toxicity [see Wrning nd Precutions (.3)] Interstitil pneumonitis [see Wrnings nd Precutions (.)] Rdition recll [see Wrnings nd Precutions (.)]. Clinicl Trils Experience Becuse clinicl trils re conducted under widely vrying conditions, dverse rections rtes cnnot be directly compred to rtes in other clinicl trils nd my not reflect the rtes observed in clinicl prctice. In clinicl trils, the most common dverse rections (incidence %) of ALIMTA, when dministered s single gent, re ftigue, nuse, nd norexi. The most common dverse rections (incidence %) of ALIMTA, when dministered in combintion with cispltin re vomiting, neutropeni, nemi, stomtitis/phryngitis, thrombocytopeni, nd constiption.

6 Non-Squmous NSCLC Initil Tretment in Combintion with Cispltin The sfety of ALIMTA ws evluted in Study JMDB, rndomized (:), open-lbel, multicenter tril conducted in chemotherpy-nive ptients with loclly dvnced or metsttic NSCLC. Ptients received either ALIMTA mg/m intrvenously nd cispltin 7 mg/m intrvenously on Dy of ech -dy cycle (n=839) or gemcitbine mg/m intrvenously on Dys nd 8 nd cispltin 7 mg/m intrvenously on Dy of ech -dy cycle (n=83). All ptients were fully supplemented with folic cid nd vitmin B. Study JMDB excluded ptients with n Estern Coopertive Oncology Group Performnce Sttus (ECOG PS of or greter), uncontrolled third-spce fluid retention, indequte bone mrrow reserve nd orgn function, or clculted cretinine clernce less thn ml/min. Ptients unble to stop using spirin or other non-steroidl nti-inflmmtory drugs or unble to tke folic cid, vitmin B or corticosteroids were lso excluded from the study. The dt described below reflect exposure to ALIMTA plus cispltin in 839 ptients in Study JMDB. Medin ge ws yers (rnge -83 yers); 7% of ptients were men; 78% were White,% were Asin,.9% were Hispnic or Ltino,.% were Blck or Africn Americn, nd <% were other ethnicities; 3% hd n ECOG PS. Ptients received medin of cycles of ALIMTA. Tble provides the frequency nd severity of dverse rections tht occurred in % of 839 ptients receiving ALIMTA in combintion with cispltin in Study JMDB. Study JMDB ws not designed to demonstrte sttisticlly significnt reduction in dverse rection rtes for ALIMTA, s compred to the control rm, for ny specified dverse rection listed in Tble. Tble : Adverse Rections Occurring in % of Fully Vitmin-Supplemented Ptients Receiving ALIMTA in Combintion with Cispltin Chemotherpy in Study JMDB Adverse Rection All dverse rections Lbortory Hemtologic Anemi Neutropeni Thrombocytopeni Renl Elevted cretinine Clinicl Constitutionl symptoms Ftigue Gstrointestinl Nuse Vomiting Anorexi Constiption Stomtitis/phryngitis Dirrhe Dyspepsi/hertburn Neurology Sensory neuropthy Tste disturbnce Dermtology/Skin Alopeci Rsh/Desqumtion NCI CTCAE version.. ALIMTA/Cispltin (N=839) All Grdes Grde Gemcitbine/Cispltin (N=83) All Grdes Grde The following dditionl dverse rections of ALIMTA were observed.

7 7 Incidence % to <% Body s Whole febrile neutropeni, infection, pyrexi Generl Disorders dehydrtion Metbolism nd Nutrition incresed AST, incresed ALT Renl renl filure Eye Disorder conjunctivitis Incidence <% Crdiovsculr rrhythmi Generl Disorders chest pin Metbolism nd Nutrition incresed GGT Neurology motor neuropthy Mintennce Tretment Following First-line Non-ALIMTA Contining Pltinum-Bsed Chemotherpy In Study JMEN, the sfety of ALIMTA ws evluted in rndomized (:), plcebo-controlled, multicenter tril conducted in ptients with non-progressive loclly dvnced or metsttic NSCLC following four cycles of first-line, pltinum-bsed chemotherpy regimen. Ptients received either ALIMTA mg/m or mtching plcebo intrvenously every dys until disese progression or uncceptble toxicity. Ptients in both study rms were fully supplemented with folic cid nd vitmin B. Study JMEN excluded ptients with n ECOG PS of or greter, uncontrolled third-spce fluid retention, indequte bone mrrow reserve nd orgn function, or clculted cretinine clernce less thn ml/min. Ptients unble to stop using spirin or other non-steroidl nti-inflmmtory drugs or unble to tke folic cid, vitmin B or corticosteroids were lso excluded from the study. The dt described below reflect exposure to ALIMTA in 38 ptients in Study JMEN. Medin ge ws yers (rnge -83 yers), 73% of ptients were men; % were White, 3% were Asin,.9% were Hispnic or Ltino, nd <% were other ethnicities; 39% hd n ECOG PS. Ptients received medin of cycles of ALIMTA nd reltive dose intensity of ALIMTA of 9%. Approximtely hlf the ptients (8%) completed t lest six, -dy cycles nd 3% completed ten or more -dy cycles of ALIMTA. Tble 3 provides the frequency nd severity of dverse rections reported in % of the 38 ALIMTA-treted ptients in Study JMEN. Tble 3: Adverse Rections Occurring in % of Ptients Receiving ALIMTA in Study JMEN Adverse Rection All dverse rections Lbortory Hemtologic Anemi Neutropeni Heptic Incresed ALT Incresed AST Clinicl Constitutionl symptoms Ftigue Gstrointestinl Nuse Anorexi Vomiting Mucositis/stomtitis Dirrhe Infection Neurology ALIMTA (N=38) All Grdes Grde 3- Plcebo (N=8) All Grdes Grde

8 8 Sensory neuropthy Dermtology/Skin Rsh/desqumtion NCI CTCAE version The requirement for trnsfusions (9.% versus 3.%), primrily red blood cell trnsfusions, nd for erythropoiesis stimulting gents (.9% versus.8%) were higher in the ALIMTA rm compred to the plcebo rm. The following dditionl dverse rections were observed in ptients who received ALIMTA. Incidence % to<% Dermtology/Skin lopeci, pruritus/itching Gstrointestinl constiption Generl Disorders edem, fever Hemtologic thrombocytopeni Eye Disorder oculr surfce disese (including conjunctivitis), incresed lcrimtion Incidence <% Crdiovsculr suprventriculr rrhythmi Dermtology/Skin erythem multiforme Generl Disorders febrile neutropeni, llergic rection/hypersensitivity Neurology motor neuropthy Renl renl filure Mintennce Tretment Following First-line ALIMTA Plus Pltinum Chemotherpy The sfety of ALIMTA ws evluted in PARAMOUNT, rndomized (:), plcebo-controlled study conducted in ptients with non-squmous NSCLC with non-progressive (stble or responding disese) loclly dvnced or metsttic NSCLC following four cycles of ALIMTA in combintion with cispltin s first-line therpy for NSCLC. Ptients were rndomized to receive ALIMTA mg/m or mtching plcebo intrvenously on Dy of ech -dy cycle until disese progression or uncceptble toxicity. Ptients in both study rms received folic cid nd vitmin B supplementtion. PARAMOUNT excluded ptients with n ECOG PS of or greter, uncontrolled third-spce fluid retention, indequte bone mrrow reserve nd orgn function, or clculted cretinine clernce less thn ml/min. Ptients unble to stop using spirin or other non-steroidl nti-inflmmtory drugs or unble to tke folic cid, vitmin B or corticosteroids were lso excluded from the study. The dt described below reflect exposure to ALIMTA in 333 ptients in PARAMOUNT. Medin ge ws yers (rnge 3 to 83 yers); 8% of ptients were men; 9% were White,.8% were Asin, nd <% were Blck or Africn Americn; 3% hd n ECOG PS. The medin number of mintennce cycles ws for ALIMTA nd plcebo rms. Dose reductions for dverse rections occurred in 3.3% of ptients in the ALIMTA rm nd.% in the plcebo rm. Dose delys for dverse rections occurred in % of ptients in the ALIMTA rm nd % in the plcebo rm. Tble provides the frequency nd severity of dverse rections reported in % of the 333 ALIMTA-treted ptients in PARAMOUNT. Tble : Adverse Rections Occurring in % of Ptients Receiving ALIMTA in PARAMOUNT Adverse Rection All dverse rections Lbortory Hemtologic Anemi Neutropeni Clinicl Constitutionl symptoms Ftigue Gstrointestinl ALIMTA (N=333) Plcebo (N=7) All Grdes 3 Grde 3-7 All Grdes 3 Grdes

9 9 Nuse Vomiting Mucositis/stomtitis Generl disorders Edem NCI CTCAE version The requirement for red blood cell (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 plcebo rm. The following dditionl Grde 3 or dverse rections were observed more frequently in the ALIMTA rm. Incidence % to <% Blood/Bone Mrrow thrombocytopeni Generl Disorders febrile neutropeni Incidence <% Crdiovsculr ventriculr tchycrdi, syncope Generl Disorders pin Gstrointestinl gstrointestinl obstruction Neurologic depression Renl renl filure Vsculr pulmonry embolism Tretment of Recurrent Disese After Prior Chemotherpy The sfety of ALIMTA ws evluted in Study JMEI, rndomized (:), open-lbel, ctive-controlled tril conducted in ptients who hd progressed following pltinum-bsed chemotherpy. Ptients received ALIMTA mg/m intrvenously or docetxel 7 mg/m intrvenously on Dy of ech -dy cycle. All ptients on the ALIMTA rm received folic cid nd vitmin B supplementtion. Study JMEI excluded ptients with n ECOG PS of 3 or greter, uncontrolled third-spce fluid retention, indequte bone mrrow reserve nd orgn function, or clculted cretinine clernce less thn ml/min. Ptients unble to discontinue spirin or other non-steroidl nti-inflmmtory drugs or unble to tke folic cid, vitmin B or corticosteroids were lso excluded from the study. The dt described below reflect exposure to ALIMTA in ptients in Study JMEI. Medin ge ws 8 yers (rnge to 87 yers); 73% of ptients were men; 7% were White, % were Asin,.% were Blck or Africn Americn,.8% were Hispnic or Ltino, nd <% were other ethnicities; 9% hd n ECOG PS. Tble provides the frequency nd severity of dverse rections reported in % of the ALIMTA-treted ptients in Study JMEI. Study JMEI is not designed to demonstrte sttisticlly significnt reduction in dverse rection rtes for ALIMTA, s compred to the control rm, for ny specified dverse rection listed in the Tble below. Tble : Adverse Rections Occurring in % of Fully Supplemented Ptients Receiving ALIMTA in Study JMEI Adverse Rection Lbortory Hemtologic Anemi Neutropeni Thrombocytopeni Heptic Incresed ALT Incresed AST Clinicl Gstrointestinl ALIMTA (N=) All Grdes Grdes 3- Docetxel (N=7) All Grde Grdes

10 Nuse Anorexi Vomiting Stomtitis/phryngitis Dirrhe Constiption Constitutionl symptoms Ftigue Fever Dermtology/Skin Rsh/desqumtion Pruritus Alopeci NCI CTCAE version The following dditionl dverse rections were observed in ptients ssigned to receive ALIMTA. Incidence % to <% Body s Whole bdominl pin, llergic rection/hypersensitivity, febrile neutropeni, infection Dermtology/Skin erythem multiforme Neurology motor neuropthy, sensory neuropthy Incidence <% Crdiovsculr suprventriculr rrhythmis Renl renl filure Mesotheliom The sfety of ALIMTA ws evluted in Study JMCH, rndomized (:), single-blind study conducted in ptients with MPM who hd received no prior chemotherpy for MPM. Ptients received ALIMTA mg/m intrvenously in combintion with cispltin 7 mg/m intrvenously on Dy of ech -dy cycle or cispltin 7 mg/m intrvenously on Dy of ech -dy cycle dministered until disese progression or uncceptble toxicity. Sfety ws ssessed in ptients who received t lest one dose of ALIMTA in combintion with cispltin nd ptients who received t lest one dose of cispltin lone. Among ptients who received ALIMTA in combintion with cispltin, 7% (n=8) received full supplementtion with folic cid nd vitmin B during study therpy, % (n=3) were never supplemented, nd % (n=) were prtilly supplemented. Study JMCH excluded ptients with Krnofsky Performnce Scle (KPS) of less thn 7, indequte bone mrrow reserve nd orgn function, or clculted cretinine clernce less thn ml/min. Ptients unble to stop using spirin or other non-steroidl nti-inflmmtory drugs were lso excluded from the study. The dt described below reflect exposure to ALIMTA in 8 ptients tht were fully supplemented with folic cid nd vitmin B. Medin ge ws yers (rnge 9 to 8 yers); 8% were men; 9% were White, % were Hispnic or Ltino, 3.% were Asin, nd <% were other ethnicities; % hd KPS of 9-. The medin number of tretment cycles dministered ws in the ALIMTA/cispltin fully supplemented group nd in the ALIMTA/cispltin never supplemented group. Ptients receiving ALIMTA in the fully supplemented group hd reltive dose intensity of 93% of the protocol-specified ALIMTA dose intensity. The most common dverse rection resulting in dose dely ws neutropeni. Tble provides the frequency nd severity of dverse rections % in the subgroup of ALIMTA-treted ptients who were fully vitmin supplemented in Study JMCH. Study JMCH ws not designed to demonstrte sttisticlly significnt reduction in dverse rection rtes for ALIMTA, s compred to the control rm, for ny specified dverse rection listed in the tble below. Tble : Adverse Rections Occurring in % of Fully Supplemented Subgroup of Ptients Receiving ALIMTA/Cispltin in Study JMCH b Adverse Rection ALIMTA/cispltin (N=8) All Grdes Grde 3- Cispltin (N=3) All Grdes Grde 3-

11 Lbortory Hemtologic Neutropeni Anemi Thrombocytopeni 3 9 Renl Elevted cretinine Decresed cretinine clernce 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 Metbolism nd Nutrition Dehydrtion 7 Neurology Sensory neuropthy Tste disturbnce 8 Dermtology/Skin Rsh Alopeci In Study JMCH, ptients received t lest one dose of ALIMTA in combintion with cispltin nd ptients received t lest one dose of cispltin. Tble provides the ADRs for subgroup of ptients treted with ALIMTA in combintion with cispltin (8 ptients) or cispltin lone (3 ptients) who received full supplementtion with folic cid nd vitmin B during study therpy. b NCI CTCAE version. The following dditionl dverse rections were observed in ptients receiving ALIMTA plus cispltin: Incidence % to <% Body s Whole febrile neutropeni, infection, pyrexi Dermtology/Skin urticri Generl Disorders chest pin Metbolism nd Nutrition incresed AST, incresed ALT, incresed GGT Renl renl filure Incidence <% Crdiovsculr rrhythmi Neurology motor neuropthy Explortory Subgroup Anlyses bsed on Vitmin Supplementtion Tble 7 provides the results of explortory nlyses of the frequency nd severity of NCI CTCAE Grde 3 or dverse rections reported in more ALIMTA-treted ptients who did not receive vitmin supplementtion (never supplemented) s compred with those who received vitmin supplementtion with dily folic cid nd vitmin B from the time of enrollment in Study JMCH (fully-supplemented). Tble 7: Explortory Subgroup Anlysis of Selected Grde 3/ Adverse Rections Occurring in Ptients Receiving ALIMTA in Combintion with Cispltin with or without Full Vitmin Supplementtion in Study JMCH

12 Grde 3- Adverse Rections Neutropeni Thrombocytopeni Vomiting Febrile neutropeni Infection with Grde 3/ neutropeni Dirrhe NCI CTCAE version. Fully Supplemented Ptients N=8 3 Never Supplemented Ptients N= The following dverse rections occurred more frequently in ptients who were fully vitmin supplemented thn in ptients who were never supplemented: hypertension (% versus 3%), chest pin (8% versus %), thrombosis/embolism (% versus 3%). Additionl Experience Across Clinicl Trils Sepsis, with or without neutropeni, including ftl cses: % Severe esophgitis, resulting in hospitliztion: <%. Postmrketing Experience The following dverse rections hve been identified during post-pprovl use of ALIMTA. Becuse these rections re reported voluntrily from popultion of uncertin size, it is not lwys possible to relibly estimte their frequency or estblish cusl reltionship to drug exposure. Blood nd Lymphtic System immune-medited hemolytic nemi Gstrointestinl colitis, pncretitis Generl Disorders nd Administrtion Site Conditions edem Injury, poisoning, nd procedurl complictions rdition recll Respirtory interstitil pneumonitis Skin Serious nd ftl bullous skin conditions, Stevens-Johnson syndrome, nd toxic epiderml necrolysis 7 DRUG INTERACTIONS Effects of Ibuprofen on Pemetrexed Ibuprofen increses exposure (AUC) of pemetrexed [see Clinicl Phrmcology (.3)]. In ptients with cretinine clernce between ml/min nd 79 ml/min: Avoid dministrtion of ibuprofen for dys before, the dy of, nd dys following dministrtion of ALIMTA [see Dosge nd Administrtion (.)]. Monitor ptients more frequently for myelosuppression, renl, nd gstrointestinl toxicity, if concomitnt dministrtion of ibuprofen cnnot be voided. 8 USE IN SPECIFIC POPULATIONS 8. Pregnncy Risk Summry Bsed on findings from niml studies nd its mechnism of ction, ALIMTA cn cuse fetl hrm when dministered to pregnnt womn [see Clinicl Phrmcology (.)]. There re no vilble dt on ALIMTA use in pregnnt women. In niml reproduction studies, intrvenous dministrtion of pemetrexed to pregnnt mice during the period of orgnogenesis ws tertogenic, resulting in developmentl delys nd mlformtions t doses lower thn the recommended humn dose of mg/m [see Dt]. Advise pregnnt women of the potentil risk to fetus [see Use in Specil Popultions (8.3)]. In the U.S. generl popultion, the estimted bckground risk of mjor birth defects nd miscrrige in cliniclly recognized pregnncies is to % nd to %, respectively. Dt Animl Dt

13 3 Pemetrexed ws tertogenic in mice. Dily dosing of pemetrexed by intrvenous injection to pregnnt mice during the period of orgnogenesis incresed the incidence of fetl mlformtions (cleft plte; protruding tongue; enlrged or misshped kidney; nd fused lumbr vertebr) t doses (bsed on BSA).3 times the humn dose of mg/m. At doses, bsed on BSA, greter thn or equl to. times the mg/m humn dose, pemetrexed dministrtion resulted in dose-dependent increses in developmentl delys (incomplete ossifiction of tlus nd skull bone; nd decresed fetl weight). 8. Lcttion Risk Summry There is no informtion regrding the presence of pemetrexed or its metbolites in humn milk, the effects on the brestfed infnt, or the effects on milk production. Becuse of the potentil for serious dverse rections in brestfed infnts from ALIMTA, dvise women not to brestfeed during tretment with ALIMTA nd for one week fter lst dose. 8.3 Femles nd Mles of Reproductive Potentil Contrception Femles ALIMTA cn cuse fetl hrm when dministered to pregnnt womn [see Use in Specific Popultions (8.)]. Becuse of the potentil for genotoxicity, dvise femles of reproductive potentil to use effective contrception during tretment with ALIMTA for t lest months fter the finl dose of ALIMTA. Mles Becuse of the potentil for genotoxicity, dvise mles with femle prtners of reproductive potentil to use effective contrception during tretment with ALIMTA nd for 3 months fter the finl dose [see Nonclinicl Toxicology (3.)]. Infertility Mles ALIMTA my impir fertility in mles of reproductive potentil. It is not known whether these effects on fertility re reversible [see Nonclinicl Toxicology (3.)]. 8. Peditric Use The sfety nd effectiveness of ALIMTA in peditric ptients hve not been estblished. The sfety nd phrmcokinetics of ALIMTA were evluted in two clinicl studies conducted in peditric ptients with recurrent solid tumors. ALIMTA ws dministered t doses rnging from to 8 mg/m intrvenously over minutes on Dy of -dy cycle to 3 peditric ptients with recurrent solid tumors in dose-finding study. The mximum tolerted dose (MTD) ws determined to be 9 mg/m ( mg/kg for ptients < months old). ALIMTA ws dministered t the MTD every dys in n ctivity-estimting study enrolling 7 ptients with relpsed or refrctory osteosrcom, Ewing srcom/peripherl primitive neurl ectoderml tumor (PNET), rhbdomyosrcom, neuroblstom, ependymom, medulloblstom/suprtentoril PNET, or non-brinstem high grde gliom. Ptients in both studies received concomitnt vitmin B nd folic cid supplementtion nd dexmethsone. No tumor responses were observed. Adverse rections observed in peditric ptients were similr to those observed in dults. Single-dose phrmcokinetics of ALIMTA dministered t doses rnging from to 8 mg/m were evluted in ptients (3 mles nd 9 femles) ge to 8 yers (verge ge yers). Pemetrexed exposure (AUC nd Cmx) ppered to increse proportionlly with dose. Averge clernce (.3 L/h/m) nd hlf-life (.3 hours) were similr in peditric ptients compred to dults. 8. Geritric Use Of the 3,9 ptients enrolled in clinicl studies of ALIMTA, 3% were nd over nd % were 7 nd over. No overll differences in effectiveness were observed between these ptients nd younger ptients. The incidences of Grde 3- nemi, ftigue, thrombocytopeni, hypertension, nd neutropeni were higher in ptients yers of ge nd older s compred to younger ptients: in t lest one of five rndomized clinicl trils. [see Adverse Rections (.) nd Clinicl Studies (.,.)]. 8. Ptients with Renl Impirment ALIMTA is primrily excreted by the kidneys. Decresed renl function results in reduced clernce nd greter exposure (AUC) to ALIMTA compred with ptients with norml renl function [Wrnings nd Precutions (.,.) nd Clinicl

14 Phrmcology (.3)]. No dose is recommended for ptients with cretinine clernce less thn ml/min [see Dosge nd Administrtion (.3)]. OVERDOSAGE No drugs re pproved for the tretment of ALIMTA overdose. Bsed on niml studies, dministrtion of leucovorin my mitigte the toxicities of ALIMTA overdosge. It is not known whether pemetrexed is dilyzble. DESCRIPTION ALIMTA (pemetrexed for injection) is folte nlog metbolic inhibitor. The drug substnce, pemetrexed disodium hepthydrte, hs the chemicl nme L-glutmic cid, N-[-[-(-mino-,7-dihydro--oxo-H-pyrrolo[,3-d]pyrimidin-yl)ethyl]benzoyl]-, disodium slt, hepthydrte with moleculr formul of CH9NNO7HO nd moleculr weight of The structurl formul is s follows: ALIMTA is sterile white-to-light yellow or green-yellow lyophilized powder in single-dose vils to be reconstituted for intrvenous infusion. Ech -mg vil of ALIMTA contins mg pemetrexed (equivlent to 39.8 mg pemetrexed disodium hepthydrte) nd mg mnnitol. Ech -mg vil of ALIMTA contins mg pemetrexed (equivlent to 99 mg pemetrexed disodium hepthydrte) nd mg mnnitol. Hydrochloric cid nd/or sodium hydroxide my hve been dded to djust ph. CLINICAL PHARMACOLOGY. Mechnism of Action ALIMTA is folte nlog metbolic inhibitor tht disrupts folte-dependent metbolic processes essentil for cell repliction. In vitro studies show tht pemetrexed inhibits thymidylte synthse (TS), dihydrofolte reductse, nd glycinmide ribonucleotide formyltrnsferse (GARFT), which re folte-dependent enzymes involved in the de novo biosynthesis of thymidine nd purine nucleotides. Pemetrexed is tken into cells by membrne crriers such s the reduced folte crrier nd membrne folte binding protein trnsport systems. Once in the cell, pemetrexed is converted to polyglutmte forms by the enzyme folylpolyglutmte synthetse. The polyglutmte forms re retined in cells nd re inhibitors of TS nd GARFT.. Phrmcodynmics Pemetrexed inhibited the in vitro growth of mesotheliom cell lines (MSTO-H, NCI-H) nd showed synergistic effects when combined with cispltin. Bsed on popultion phrmcodynmic nlyses, the depth of the bsolute neutrophil counts (ANC) ndir correltes with the systemic exposure to pemetrexed nd supplementtion with folic cid nd vitmin B. There is no cumultive effect of pemetrexed exposure on ANC ndir over multiple tretment cycles..3 Phrmcokinetics Absorption The phrmcokinetics of pemetrexed when ALIMTA ws dministered s single gent in doses rnging from. to 838 mg/m infused over -minute period hve been evluted in cncer ptients with vriety of solid tumors. Pemetrexed totl systemic exposure (AUC) nd mximum plsm concentrtion (Cmx) incresed proportionlly with increse of dose. The phrmcokinetics of pemetrexed did not chnge over multiple tretment cycles. Distribution Pemetrexed hs stedy-stte volume of distribution of. liters. In vitro studies indicted tht pemetrexed is 8% bound to plsm proteins.

15 Elimintion 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). As renl function decreses, the clernce of pemetrexed decreses nd exposure (AUC) of pemetrexed increses. Metbolism Pemetrexed is not metbolized to n pprecible extent. Excretion Pemetrexed is primrily eliminted in the urine, with 7% to 9% of the dose recovered unchnged within the first hours following dministrtion. In vitro studies indicted tht pemetrexed is substrte of OAT3 (orgnic nion trnsporter 3), trnsporter tht is involved in the ctive secretion of pemetrexed. Specific Popultions Age ( to 8 yers) nd sex hd no cliniclly meningful effect on the systemic exposure of pemetrexed bsed on popultion phrmcokinetic nlyses. Rcil Groups The phrmcokinetics of pemetrexed were similr in Whites nd Blcks or Africn Americns. Insufficient dt re vilble for other ethnic groups. Ptients with Heptic Impirment Pemetrexed hs not been formlly studied in ptients with heptic impirment. No effect of elevted AST, ALT, or totl bilirubin on the PK of pemetrexed ws observed in clinicl studies. Ptients with Renl Impirment Phrmcokinetic nlyses of pemetrexed included 7 ptients with impired 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 systemic exposure (AUC) compred to ptients with cretinine clernce of ml/min [see Dosge nd Administrtion (.3) nd Wrnings nd Precutions (.)]. Third-Spce Fluid The pemetrexed plsm concentrtions in ptients with vrious solid tumors with stble, mild to moderte third-spce fluid were comprble to those observed in ptients without third spce fluid collections. The effect of severe third spce fluid on phrmcokinetics is not known. Drug Interction Studies Drugs Inhibiting OAT3 Trnsporter Ibuprofen, n OAT3 inhibitor, dministered t mg four times dy decresed the clernce of pemetrexed nd incresed its exposure (AUC) by pproximtely % in ptients with norml renl function (cretinine clernce >8 ml/min). In Vitro Studies Pemetrexed is substrte for OAT3. Ibuprofen, n OAT3 inhibitor inhibited the uptke of pemetrexed in OAT3-expressing cell cultures with n verge [I u ]/IC rtio of.38. In vitro dt predict tht t cliniclly relevnt concentrtions, other NSAIDs (nproxen, diclofenc, celocoxib) would not inhibit the uptke of pemetrexed by OAT3 nd would not increse the AUC of pemetrexed to cliniclly significnt extent. [see Drug Interctions (7)]. Pemetrexed is substrte for OAT. In vitro, ibuprofen nd other NSAIDs (nproxen, diclofenc, celocoxib) re not inhibitors of OAT t cliniclly relevnt concentrtions. Aspirin Aspirin, dministered in low to moderte doses (3 mg every hours), does not ffect the phrmcokinetics of pemetrexed. Cispltin Cispltin does not ffect the phrmcokinetics of pemetrexed nd the phrmcokinetics of totl pltinum re unltered by pemetrexed.

16 Vitmins Neither folic cid nor vitmin B ffect the phrmcokinetics of pemetrexed. Drugs Metbolized by Cytochrome P Enzymes In vitro studies suggest tht pemetrexed does not inhibit the clernce of drugs metbolized by CYP3A, CYPD, CYPC9, nd CYPA. 3 NONCLINICAL TOXICOLOGY 3. Crcinogenesis, Mutgenesis, Impirment of Fertility No crcinogenicity studies hve been conducted with pemetrexed. Pemetrexed ws clstogenic in n in vivo micronucleus ssy in mouse bone mrrow but ws not mutgenic in multiple in vitro tests (Ames ssy, Chinese Hmster Ovry cell ssy). Pemetrexed dministered intrperitonelly t doses of. mg/kg/dy to mle mice (pproximtely. times the recommended humn dose bsed on BSA) resulted in reduced fertility, hypospermi, nd testiculr trophy. CLINICAL STUDIES. Non-Squmous NSCLC Initil Tretment in Combintion with Cispltin The efficcy of ALIMTA ws evluted in Study JMDB (NCT877), multi-center, rndomized (:), open-lbel study conducted in 7 chemotherpy-nive ptients with Stge IIIb/IV NSCLC. Ptients were rndomized to receive ALIMTA with cispltin or gemcitbine with cispltin. Rndomiztion ws strtified by Estern Coopertive Oncology Group Performnce Sttus (ECOG PS versus ), gender, disese stge, bsis for pthologicl dignosis (histopthologicl/cytopthologicl), history of brin metstses, nd investigtive center. ALIMTA ws dministered intrvenously over minutes t dose of mg/m on Dy of ech -dy cycle. Cispltin ws dministered intrvenously t dose of 7 mg/m pproximtely 3 minutes fter ALIMTA dministrtion on Dy of ech cycle, gemcitbine ws dministered t dose of mg/m on Dy nd Dy 8, nd cispltin ws dministered intrvenously t dose of 7 mg/m pproximtely 3 minutes fter dministrtion of gemcitbine, on Dy of ech dy cycle. Tretment ws dministered up to totl of cycles; ptients in both rms received folic cid, vitmin B, nd dexmethsone [see Dosge nd Administrtion (.)]. The primry efficcy outcome mesure ws overll survivl. A totl of 7 ptients were enrolled with 8 ptients rndomized to ALIMTA in combintion with cispltin nd 83 ptients to gemcitbine in combintion with cispltin. The medin ge ws yers (rnge -83 yers), 7% were mle, 78% were White, 7% were Asin,.9% were Hispnic or Ltino, nd.% were Blck or Africn Americn, nd <% were other ethnicities. Among ptients for whom ECOG PS (n=7) nd smoking history (n=) were collected, % hd n ECOG PS of, 3% hd n ECOG PS of, nd 8% were smokers. For tumor chrcteristics, 73% hd non-squmous NSCLC nd 7% hd squmous NSCLC; 7% hd Stge IV disese. Among ptients with nonsqumous NSCLC histology, 8% hd dignosis of denocrcinom, % hd lrge cell histology nd % hd other histologic subtypes. Efficcy results in Study JMDB re presented in Tble 8 nd Figure. Tble 8: Efficcy Results in Study JMDB Efficcy Prmeter Overll Survivl,b Hzrd rtio (HR) Progression-Free Survivl ALIMTA plus Cispltin (N=8) Gemcitbine plus Cispltin (N=83).3 (9.8-.).3 (9.-.9).9 (.8-.).8 (.-.3). (.-.)

17 Hzrd rtio (HR),b Overll Response Rte 7.% (.-3.) Undjusted for multiple comprisons. b Adjusted for gender, stge, bsis of dignosis, nd performnce sttus. 7. (.9-.).7% (.8-7.) Figure : Kpln-Meier Curves for Overll Survivl in Study JMDB In pre-specified nlyses ssessing the impct of NSCLC histology on overll survivl, cliniclly relevnt differences in survivl ccording to histology were observed. These subgroup nlyses re shown in Tble 9 nd Figures nd 3. This difference in tretment effect for ALIMTA bsed on histology demonstrting lck of efficcy in squmous cell histology ws lso observed in Studies JMEN nd JMEI. Tble 9: Overll Survivl in NSCLC Histologic Subgroups in Study JMDB Histologic Subgroups Non-squmous NSCLC (N=) HR,b Adenocrcinom (N=87) HR,b Lrge Cell (N=3) HR,b Otherc (N=) ALIMTA plus Cispltin (N=8) Gemcitbine plus Cispltin (N=83). (.-.). (9.3-.9).8 (.7-.9). (.7-3.).9 (.-.9).8 (.7-.99). (8.-.).7 (.-9.).7 (.8-.9)

18 (.8-.) (8.-.) HR,b.8 (.8-.) Squmous Cellc (N=73) 9..8 (8.-.) (9.-.) HR,b.3 (.-.) Undjusted for multiple comprisons. b Adjusted for ECOG PS, gender, disese stge, nd bsis for pthologicl dignosis (histopthologicl/cytopthologicl). c Includes denocrcinom, lrge cell, nd other histologies except those with squmous cell type. Figure : Kpln-Meier Curves for Overll Survivl in Non-squmous NSCLC in Study JMDB

19 9 Figure 3: Kpln-Meier Curves for Overll Survivl in Squmous NSCLC in Study JMDB Mintennce Tretment Following First-line Non-ALIMTA Contining Pltinum-Bsed Chemotherpy The efficcy of ALIMTA s mintennce therpy following first-line pltinum-bsed chemotherpy ws evluted in Study JMEN (NCT8), multicenter, rndomized (:), double-blind, plcebo-controlled study conducted in 3 ptients with Stge IIIb/IV NSCLC who did not progress fter four cycles of pltinum-bsed chemotherpy. Ptients were rndomized to receive ALIMTA mg/m intrvenously every dys or plcebo until disese progression or intolerble toxicity. Ptients in both study rms received folic cid, vitmin B, nd dexmethsone [see Dosge nd Administrtion (.)]. Rndomiztion ws crried out using minimiztion pproch [Pocock nd Simon (97)] using the following fctors: gender, ECOG PS ( versus ), response to prior chemotherpy (complete or prtil response versus stble disese), history of brin metstses (yes versus no), non-pltinum component of induction therpy (docetxel versus gemcitbine versus pclitxel), nd disese stge (IIIb versus IV). The mjor efficcy outcome mesures were progression-free survivl bsed on ssessment by independent review nd overll survivl; both were mesured from the dte of rndomiztion in Study JMEN. A totl of 3 ptients were enrolled with ptients rndomized to ALIMTA nd ptients rndomized to plcebo. The medin ge ws yers (rnge -83 yers); 73% were mle; % were White, 3% were Asin,.9% were Hispnic or Ltino, nd <% were other ethnicities; % hd n ECOG PS of ; nd 73% were current or former smokers. Medin time from initition of pltinum-bsed chemotherpy to rndomiztion ws 3.3 months (rnge. to. months) nd 9% of the popultion chieved prtil or complete response to first-line, pltinum-bsed chemotherpy. With regrd to tumor chrcteristics, 8% hd Stge IV disese, 73% hd non-squmous NSCLC nd 7% hd squmous NSCLC. Among the 8 ptients with non-squmous NSCLC, 8% hd denocrcinom, % hd lrge cell, nd 8% hd other histologies. Efficcy results re presented in Tble nd Figure. Tble : Efficcy Results in Study JMEN Efficcy Prmeter Overll survivl Hzrd rtio ALIMTA N= 3. (.9-.9) Plcebo N=. (8.7-.).79 (.-.9)