DOSAGE FORMS AND STRENGTHS HIGHLIGHTS OF PRESCRIBING INFORMATION

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1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use ALIMTA sfely nd effectively. See full prescribing informtion for ALIMTA. ALIMTA (pemetrexed disodium) Injection, Powder, Lyophilized, For Solution for Intrvenous Use Initil U.S. Approvl: RECENT MAJOR CHANGES Indictions nd Usge, Loclly Advnced or Metsttic Nonsqumous Non-Smll Cell Lung Cncer - Combintion with Cispltin (1.1) 09/2008 Indictions nd Usge, Loclly Advnced or Metsttic Nonsqumous Non-Smll Cell Lung Cncer - Mintennce (1.2) 07/2009 Indictions nd Usge, Loclly Advnced or Metsttic Nonsqumous Non-Smll Cell Lung Cncer - After Prior Chemotherpy (1.3) 09/2008 Dosge nd Administrtion, Combintion Use with Cispltin (2.1) 09/ INDICATIONS AND USAGE ALIMTA is folte nlog metbolic inhibitor indicted for: Loclly Advnced or Metsttic Nonsqumous Non-Smll Cell Lung Cncer: Initil tretment in combintion with cispltin. (1.1) Mintennce tretment of ptients whose disese hs not progressed fter four cycles of pltinum-bsed first-line chemotherpy. (1.2) After prior chemotherpy s single-gent. (1.3) Mesotheliom: in combintion with cispltin. (1.4) Limittions of Use: ALIMTA is not indicted for the tretment of ptients with squmous cell non-smll cell lung cncer. (1.5) DOSAGE AND ADMINISTRATION Combintion use in Non-Smll Cell Lung Cncer nd Mesotheliom: Recommended dose of ALIMTA is 500 mg/m 2 i.v. on Dy 1 of ech 21-dy cycle in combintion with cispltin 75 mg/m 2 i.v. beginning 30 minutes fter ALIMTA dministrtion. (2.1) Single-Agent use in Non-Smll Cell Lung Cncer: Recommended dose of ALIMTA is 500 mg/m 2 i.v. on Dy 1 of ech 21-dy cycle. (2.2) Dose Reductions: Dose reductions or discontinution my be needed bsed on toxicities from the preceding cycle of therpy. (2.4) DOSAGE FORMS AND STRENGTHS mg vil for injection (3) 500 mg vil for injection (3) CONTRAINDICATIONS History of severe hypersensitivity rection to pemetrexed. (4) WARNINGS AND PRECAUTIONS Premediction regimen: Instruct ptients to tke folic cid nd vitmin B 12. Pretretment with dexmethsone or equivlent reduces cutneous rection. (5.1) Bone mrrow suppression: Reduce doses for subsequent cycles bsed on hemtologic nd nonhemtologic toxicities. (5.2) Renl function: Do not dminister when CrCl <45 ml/min. (2.4, 5.3) NSAIDs with renl insufficiency: Use cution in ptients with mild to moderte renl insufficiency (CrCl ml/min). (5.4) Lb monitoring: Do not begin next cycle unless ANC 1500 cells/mm 3, pltelets 100,000 cells/mm 3, nd CrCl 45 ml/min. (5.5) Pregnncy: Fetl hrm cn occur when dministered to pregnnt womn. Women should be dvised to use effective contrception mesures to prevent pregnncy during tretment with ALIMTA. (5.6) ADVERSE REACTIONS The most common dverse rections (incidence 20%) with single-gent use re ftigue, nuse, nd norexi. Additionl common dverse rections when used in combintion with cispltin include vomiting, neutropeni, leukopeni, nemi, stomtitis/phryngitis, thrombocytopeni, nd constiption. (6.1) To report SUSPECTED ADVERSE REACTIONS, contct Eli Lilly nd Compny t LillyRx ( ) or FDA t FDA-1088 or DRUG INTERACTIONS NSAIDs: Use cution with ibuprofen or other NSAIDs. (7.1) Nephrotoxic drugs: Concomitnt use of these drugs nd/or substnces which re tubulrly secreted my result in delyed clernce. (7.2) See 17 for PATIENT COUNSELING INFORMATION nd FDA-pproved ptient lbeling Revised: 07/ FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Nonsqumous Non-Smll Cell Lung Cncer Combintion with Cispltin 1.2 Nonsqumous Non-Smll Cell Lung Cncer Mintennce 1.3 Nonsqumous Non-Smll Cell Lung Cncer After Prior Chemotherpy 1.4 Mesotheliom 1.5 Limittions of Use 2 DOSAGE AND ADMINISTRATION 2.1 Combintion Use with Cispltin 2.2 Single-Agent Use 2.3 Premediction Regimen 2.4 Lbortory Monitoring nd Dose Reduction/Discontinution Recommendtions 2.5 Preprtion nd Administrtion Precutions 2.6 Preprtion for Intrvenous Infusion Administrtion 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Premediction Regimen 5.2 Bone Mrrow Suppression 5.3 Decresed Renl Function 5.4 Use with Non-Steroidl Anti-Inflmmtory Drugs with Mild to Moderte Renl Insufficiency 5.5 Required Lbortory Monitoring 5.6 Pregnncy Ctegory D 5.7 Third Spce Fluid 6 ADVERSE REACTIONS 6.1 Clinicl Trils Experience 6.2 Post-Mrketing Experience 7 DRUG INTERACTIONS 7.1 Non-Steroidl Anti-Inflmmtory Drugs (NSAIDs) 7.2 Nephrotoxic Drugs 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.3 Nursing Mothers 8.4 Peditric Use 8.5 Geritric Use 8.6 Ptients with Heptic Impirment 8.7 Ptients with Renl Impirment 8.8 Gender 8.9 Rce 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.2 Phrmcodynmics 12.3 Phrmcokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 14 CLINICAL STUDIES 14.1 Non-Smll Cell Lung Cncer (NSCLC) Combintion with Cispltin 14.2 Non-Smll Cell Lung Cncer Mintennce 14.3 Non-Smll Cell Lung Cncer After Prior Chemotherpy 14.4 Mlignnt Pleurl Mesotheliom

2 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storge nd Hndling 17 PATIENT COUNSELING INFORMATION 17.1 Need for Folic Acid nd Vitmin B Low Blood Cell Counts 17.3 Gstrointestinl Effects 17.4 Concomitnt Medictions *Sections or subsections omitted from the full prescribing informtion re not listed 2 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Nonsqumous Non-Smll Cell Lung Cncer - Combintion with Cispltin ALIMTA is indicted in combintion with cispltin therpy for the initil tretment of ptients with loclly dvnced or metsttic nonsqumous non-smll cell lung cncer. 1.2 Nonsqumous Non-Smll Cell Lung Cncer - Mintennce ALIMTA is indicted for the mintennce tretment of ptients with loclly dvnced or metsttic nonsqumous non-smll cell lung cncer whose disese hs not progressed fter four cycles of pltinum-bsed first-line chemotherpy. 1.3 Nonsqumous Non-Smll Cell Lung Cncer - After Prior Chemotherpy ALIMTA is indicted s single-gent for the tretment of ptients with loclly dvnced or metsttic nonsqumous non-smll cell lung cncer fter prior chemotherpy. 1.4 Mesotheliom ALIMTA in combintion with cispltin is indicted for the tretment of ptients with mlignnt pleurl mesotheliom whose disese is unresectble or who re otherwise not cndidtes for curtive surgery. 1.5 Limittions of Use ALIMTA is not indicted for the tretment of ptients with squmous cell non smll cell lung cncer. [see Clinicl Studies (14.1, 14.2, 14.3)] 2 DOSAGE AND ADMINISTRATION 2.1 Combintion Use with Cispltin Nonsqumous Non-Smll Cell Lung Cncer nd Mlignnt Pleurl Mesotheliom The recommended dose of ALIMTA is 500 mg/m 2 dministered s n intrvenous infusion over 10 minutes on Dy 1 of ech 21-dy cycle. The recommended dose of cispltin is 75 mg/m 2 infused over 2 hours beginning pproximtely 30 minutes fter the end of ALIMTA dministrtion. Ptients should receive pproprite hydrtion prior to nd/or fter receiving cispltin. See cispltin pckge insert for more informtion. 2.2 Single-Agent Use Nonsqumous Non-Smll Cell Lung Cncer The recommended dose of ALIMTA is 500 mg/m 2 dministered s n intrvenous infusion over 10 minutes on Dy 1 of ech 21-dy cycle. 2.3 Premediction Regimen Vitmin Supplementtion To reduce toxicity, ptients treted with ALIMTA must be instructed to tke low-dose orl folic cid preprtion or multivitmin with folic cid on dily bsis. At lest 5 dily doses of folic cid must be tken during the 7-dy period preceding the first dose of ALIMTA; nd dosing should continue during the full course of therpy nd for 21 dys fter the lst dose of ALIMTA. Ptients must lso receive one (1) intrmusculr injection of vitmin B 12 during the week preceding the first dose of ALIMTA nd every 3 cycles therefter. Subsequent vitmin B 12 injections my be given the sme dy s ALIMTA. In clinicl trils, the dose of folic cid studied rnged from 350 to 1000 mcg, nd the dose of vitmin B 12 ws 1000 mcg. The most commonly used dose of orl folic cid in clinicl trils ws 400 mcg [see Wrnings nd Precutions (5.1)]. Corticosteroid Skin rsh hs been reported more frequently in ptients not pretreted with corticosteroid. Pretretment with dexmethsone (or equivlent) reduces the incidence nd severity of cutneous rection. In clinicl trils, dexmethsone 4 mg ws given by mouth twice dily the dy before, the dy of, nd the dy fter ALIMTA dministrtion [see Wrnings nd Precutions (5.1)]. 2.4 Lbortory Monitoring nd Dose Reduction/Discontinution Recommendtions Monitoring Complete blood cell counts, including pltelet counts, should be performed on ll ptients receiving ALIMTA. Ptients should be monitored for ndir nd recovery, which were tested in the clinicl study before ech dose nd on dys 8 nd 15 of ech cycle. Ptients should not begin new cycle of tretment unless the ANC is 1500 cells/mm 3, the pltelet count is 100,000 cells/mm 3, nd cretinine clernce is 45 ml/min. Periodic chemistry tests should be performed to evlute renl nd heptic function [see Wrnings nd Precutions (5.5)]. Dose Reduction Recommendtions Dose djustments t the strt of subsequent cycle should be bsed on ndir hemtologic counts or mximum nonhemtologic toxicity from the preceding cycle of therpy. Tretment my be delyed to llow sufficient time for recovery. Upon recovery, ptients

3 3 should be retreted using the guidelines in Tbles 1-3, which re suitble for using ALIMTA s single-gent or in combintion with cispltin. Tble 1: Dose Reduction for ALIMTA (single-gent or in combintion) nd Cispltin - Hemtologic Toxicities Ndir ANC <500/mm 3 nd ndir pltelets 50,000/mm 3. 75% of previous dose (pemetrexed nd cispltin). Ndir pltelets <50,000/mm 3 without bleeding regrdless of ndir ANC. 75% of previous dose (pemetrexed nd cispltin). Ndir pltelets <50,000/mm 3 with bleeding, regrdless of ndir ANC. 50% of previous dose (pemetrexed nd cispltin). These criteri meet the CTC version 2.0 (NCI 1998) definition of CTC Grde 2 bleeding. If ptients develop nonhemtologic toxicities (excluding neurotoxicity) Grde 3, tretment should be withheld until resolution to less thn or equl to the ptient s pre-therpy vlue. Tretment should be resumed ccording to guidelines in Tble 2. Tble 2: Dose Reduction for ALIMTA (single-gent or in combintion) nd Cispltin - Nonhemtologic Toxicities,b Dose of ALIMTA (mg/m 2 ) Dose of Cispltin (mg/m 2 ) Any Grde 3 or 4 toxicities except mucositis 75% of previous dose 75% of previous dose Any dirrhe requiring hospitliztion (irrespective of Grde) or Grde 3 or 75% of previous dose 75% of previous dose 4 dirrhe Grde 3 or 4 mucositis 50% of previous dose 100% of previous dose NCI Common Toxicity Criteri (CTC). b Excluding neurotoxicity (see Tble 3). In the event of neurotoxicity, the recommended dose djustments for ALIMTA nd cispltin re described in Tble 3. Ptients should discontinue therpy if Grde 3 or 4 neurotoxicity is experienced. Tble 3: Dose Reduction for ALIMTA (single-gent or in combintion) nd Cispltin - Neurotoxicity CTC Grde Dose of ALIMTA (mg/m 2 ) Dose of Cispltin (mg/m 2 ) % of previous dose 100% of previous dose 2 100% of previous dose 50% of previous dose Discontinution Recommendtion ALIMTA therpy should be discontinued if ptient experiences ny hemtologic or nonhemtologic Grde 3 or 4 toxicity fter 2 dose reductions or immeditely if Grde 3 or 4 neurotoxicity is observed. Renlly Impired Ptients In clinicl studies, ptients with cretinine clernce 45 ml/min required no dose djustments other thn those recommended for ll ptients. Insufficient numbers of ptients with cretinine clernce below 45 ml/min hve been treted to mke dosge recommendtions for this group of ptients [see Clinicl Phrmcology (12.3)]. Therefore, ALIMTA should not be dministered to ptients whose cretinine clernce is <45 ml/min using the stndrd Cockcroft nd Gult formul (below) or GFR mesured by Tc99m-DPTA serum clernce method: Mles: [140 - Age in yers] Actul Body Weight (kg) 72 Serum Cretinine (mg/dl) Femles: Estimted cretinine clernce for mles 0.85 = ml/min Cution should be exercised when dministering ALIMTA concurrently with NSAIDs to ptients whose cretinine clernce is <80 ml/min [see Drug Interctions (7.1)]. 2.5 Preprtion nd Administrtion Precutions As with other potentilly toxic nticncer gents, cre should be exercised in the hndling nd preprtion of infusion solutions of ALIMTA. The use of gloves is recommended. If solution of ALIMTA contcts the skin, wsh the skin immeditely nd thoroughly with sop nd wter. If ALIMTA contcts the mucous membrnes, flush thoroughly with wter. Severl published guidelines for hndling nd disposl of nticncer gents re vilble [see References (15)]. ALIMTA is not vesicnt. There is no specific ntidote for extrvstion of ALIMTA. To dte, there hve been few reported cses of ALIMTA extrvstion, which were not ssessed s serious by the investigtor. ALIMTA extrvstion should be mnged with locl stndrd prctice for extrvstion s with other non-vesicnts. 2.6 Preprtion for Intrvenous Infusion Administrtion 1. Use septic technique during the reconstitution nd further dilution of ALIMTA for intrvenous infusion dministrtion. 2. Clculte the dose of ALIMTA nd determine the number of vils needed. Vils contin either 100 mg or 500 mg of ALIMTA. The vils contin n excess of ALIMTA to fcilitte delivery of lbel mount.

4 4 3. Reconstitute ech 100-mg vil with 4.2 ml of 0.9% Sodium Chloride Injection (preservtive free). Reconstitute ech 500-mg vil with 20 ml of 0.9% Sodium Chloride Injection (preservtive free). Reconstitution of either size vil gives solution contining 25 mg/ml ALIMTA. Gently swirl ech vil until the powder is completely dissolved. The resulting solution is cler nd rnges in color from colorless to yellow or green-yellow without dversely ffecting product qulity. The ph of the reconstituted ALIMTA solution is between 6.6 nd 7.8. FURTHER DILUTION IS REQUIRED. 4. Prenterl drug products should be inspected visully for prticulte mtter nd discolortion prior to dministrtion, whenever solution nd continer permit. If prticulte mtter is observed, do not dminister. 5. An pproprite quntity of the reconstituted ALIMTA solution must be further diluted into solution of 0.9% Sodium Chloride Injection (preservtive free), so tht the totl volume of solution is 100 ml. ALIMTA is dministered s n intrvenous infusion over 10 minutes. 6. Chemicl nd physicl stbility of reconstituted nd infusion solutions of ALIMTA were demonstrted for up to 24 hours following initil reconstitution, when stored t refrigerted or mbient room temperture [see USP Controlled Room Temperture] nd lighting. When prepred s directed, reconstitution nd infusion solutions of ALIMTA contin no ntimicrobil preservtives. Discrd ny unused portion. Reconstitution nd further dilution prior to intrvenous infusion is only recommended with 0.9% Sodium Chloride Injection (preservtive free). ALIMTA is physiclly incomptible with diluents contining clcium, including Lctted Ringer s Injection, USP nd Ringer s Injection, USP nd therefore these should not be used. Codministrtion of ALIMTA with other drugs nd diluents hs not been studied, nd therefore is not recommended. ALIMTA is comptible with stndrd polyvinyl chloride (PVC) dministrtion sets nd intrvenous solution bgs. 3 DOSAGE FORMS AND STRENGTHS ALIMTA, pemetrexed for injection, is white to either light-yellow or green-yellow lyophilized powder vilble in sterile single-use vils contining 100 mg or 500 mg pemetrexed. 4 CONTRAINDICATIONS ALIMTA is contrindicted in ptients who hve history of severe hypersensitivity rection to pemetrexed or to ny other ingredient used in the formultion. 5 WARNINGS AND PRECAUTIONS 5.1 Premediction Regimen Need for Folte nd Vitmin B 12 Supplementtion Ptients treted with ALIMTA must be instructed to tke folic cid nd vitmin B 12 s prophylctic mesure to reduce tretment-relted hemtologic nd GI toxicity [see Dosge nd Administrtion (2.3)]. In clinicl studies, less overll toxicity nd reductions in Grde 3/4 hemtologic nd nonhemtologic toxicities such s neutropeni, febrile neutropeni, nd infection with Grde 3/4 neutropeni were reported when pretretment with folic cid nd vitmin B 12 ws dministered. Corticosteroid Supplementtion Skin rsh hs been reported more frequently in ptients not pretreted with corticosteroid in clinicl trils. Pretretment with dexmethsone (or equivlent) reduces the incidence nd severity of cutneous rection [see Dosge nd Administrtion (2.3)]. 5.2 Bone Mrrow Suppression ALIMTA cn suppress bone mrrow function, s mnifested by neutropeni, thrombocytopeni, nd nemi (or pncytopeni) [see Adverse Rections (6.1)]; myelosuppression is usully the dose-limiting toxicity. Dose reductions for subsequent cycles re bsed on ndir ANC, pltelet count, nd mximum nonhemtologic toxicity seen in the previous cycle [see Dosge nd Administrtion (2.4)]. 5.3 Decresed Renl Function ALIMTA is primrily eliminted unchnged by renl excretion. No dosge djustment is needed in ptients with cretinine clernce 45 ml/min. Insufficient numbers of ptients hve been studied with cretinine clernce <45 ml/min to give dose recommendtion. Therefore, ALIMTA should not be dministered to ptients whose cretinine clernce is <45 ml/min [see Dosge nd Administrtion (2.4)]. One ptient with severe renl impirment (cretinine clernce 19 ml/min) who did not receive folic cid nd vitmin B 12 died of drug-relted toxicity following dministrtion of ALIMTA lone. 5.4 Use with Non-Steroidl Anti-Inflmmtory Drugs with Mild to Moderte Renl Insufficiency Cution should be used when dministering ibuprofen concurrently with ALIMTA to ptients with mild to moderte renl insufficiency (cretinine clernce from 45 to 79 ml/min). Other NSAIDs should lso be used with cution [see Drug Interctions (7.1)]. 5.5 Required Lbortory Monitoring Ptients should not begin new cycle of tretment unless the ANC is 1500 cells/mm 3, the pltelet count is 100,000 cells/mm 3, nd cretinine clernce is 45 ml/min [see Dosge nd Administrtion (2.4)]. 5.6 Pregnncy Ctegory D Bsed on its mechnism of ction, ALIMTA cn cuse fetl hrm when dministered to pregnnt womn. Pemetrexed dministered intrperitonelly to mice during orgnogenesis ws embryotoxic, fetotoxic nd tertogenic in mice t greter thn

5 5 1/833rd the recommended humn dose. If ALIMTA is used during pregnncy, or if the ptient becomes pregnnt while tking this drug, the ptient should be pprised of the potentil hzrd to the fetus. Women of childbering potentil should be dvised to void becoming pregnnt. Women should be dvised to use effective contrceptive mesures to prevent pregnncy during tretment with ALIMTA [see Use in Specific Popultions (8.1)]. 5.7 Third Spce Fluid The effect of third spce fluid, such s pleurl effusion nd scites, on ALIMTA is unknown. In ptients with cliniclly significnt third spce fluid, considertion should be given to drining the effusion prior to ALIMTA dministrtion. 6 ADVERSE REACTIONS 6.1 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 20%) during therpy with ALIMTA s single-gent were ftigue, nuse, nd norexi. Additionl common dverse rections (incidence 20%) during therpy with ALIMTA when used in combintion with cispltin included vomiting, neutropeni, leukopeni, nemi, stomtitis/phryngitis, thrombocytopeni, nd constiption. Non-Smll Cell Lung Cncer (NSCLC) - Combintion with Cispltin Tble 4 provides the frequency nd severity of dverse rections tht hve been reported in >5% of 839 ptients with NSCLC who were rndomized to study nd received ALIMTA plus cispltin nd 830 ptients with NSCLC who were rndomized to study nd received gemcitbine plus cispltin. All ptients received study therpy s initil tretment for loclly dvnced or metsttic NSCLC nd ptients in both tretment groups were fully supplemented with folic cid nd vitmin B 12. Tble 4: Adverse Rections in Fully Supplemented Ptients Receiving ALIMTA plus Cispltin in NSCLC ALIMTA/cispltin Gemcitbine/cispltin (N=839) (N=830) Rection b All Grdes Grde 3-4 All Grdes Grde 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) All Adverse Rections Lbortory Hemtologic Anemi Neutropeni Leukopeni Thrombocytopeni Renl Cretinine elevtion Clinicl Constitutionl Symptoms Ftigue Gstrointestinl Nuse Vomiting Anorexi Constiption Stomtitis/Phryngitis Dirrhe Dyspepsi/Hertburn Neurology Neuropthy-sensory Tste disturbnce 8 0 c 9 0 c Dermtology/Skin Alopeci 12 0 c 21 1 c Rsh/Desqumtion For the purpose of this tble cut off of 5% ws used for inclusion of ll events where the reporter considered possible reltionship to ALIMTA. b Refer to NCI CTC Criteri version 2.0 for ech Grde of toxicity. c According to NCI CTC Criteri version 2.0, this dverse event term should only be reported s Grde 1 or 2. No cliniclly relevnt differences in dverse rections were seen in ptients bsed on histology.

6 6 In ddition to the lower incidence of hemtologic toxicity on the ALIMTA nd cispltin rm, use of trnsfusions (RBC nd pltelet) nd hemtopoietic growth fctors ws lower in the ALIMTA nd cispltin rm compred to the gemcitbine nd cispltin rm. The following dditionl dverse rections were observed in ptients with non-smll cell lung cncer rndomly ssigned to receive ALIMTA plus cispltin. Incidence 1% to 5% Body s Whole febrile neutropeni, infection, pyrexi Generl Disorders dehydrtion Metbolism nd Nutrition incresed AST, incresed ALT Renl cretinine clernce decrese, renl filure Specil Senses conjunctivitis Incidence Less thn 1% Crdiovsculr rrhythmi Generl Disorders chest pin Metbolism nd Nutrition incresed GGT Neurology motor neuropthy Non-Smll Cell Lung Cncer (NSCLC) - Mintennce Tble 5 provides the frequency nd severity of dverse rections tht hve been reported in >5% of 438 ptients with NSCLC who received ALIMTA nd 218 ptients with NSCLC who received plcebo. All ptients received study therpy immeditely following 4 cycles of pltinum-bsed tretment for loclly dvnced or metsttic NSCLC. Ptients in both study rms were fully supplemented with folic cid nd vitmin B 12. Tble 5: Adverse Rections in Ptients Receiving ALIMTA versus Plcebo in NSCLC ALIMTA Plcebo (N=438) (N=218) Rection b All Grdes Grde 3-4 All Grdes Grde 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) All Adverse Rections Lbortory Hemtologic Anemi Neutropeni Leukopeni Heptic Incresed ALT Incresed AST Clinicl Constitutionl Symptoms Ftigue Gstrointestinl Nuse Anorexi Vomiting Mucositis/stomtitis Dirrhe Infection Neurology Neuropthy-sensory Dermtology/Skin Rsh/Desqumtion For the purpose of this tble cut off of 5% ws used for inclusion of ll events where the reporter considered possible reltionship to ALIMTA. b Refer to NCI CTCAE Criteri version 3.0 for ech Grde of toxicity. No cliniclly relevnt differences in Grde 3/4 dverse rections were seen in ptients bsed on ge, gender, ethnic origin, or histology except higher incidence of Grde 3/4 ftigue for Cucsin ptients compred to non-cucsin ptients (6.5% versus 0.6%). Sfety ws ssessed by exposure for ptients who received t lest one dose of ALIMTA (N=438). The incidence of dverse rections ws evluted for ptients who received 6 cycles of ALIMTA, nd compred to ptients who received >6 cycles of

7 7 ALIMTA. Increses in dverse rections (ll grdes) were observed with longer exposure; however no cliniclly relevnt differences in Grde 3/4 dverse rections were seen. Consistent with the higher incidence of nemi (ll grdes) on the ALIMTA rm, use of trnsfusions (minly RBC) nd erythropoiesis stimulting gents (ESAs; erythropoietin nd drbepoetin) were higher in the ALIMTA rm compred to the plcebo rm (trnsfusions 9.5% versus 3.2%, ESAs 5.9% versus 1.8%). The following dditionl dverse rections were observed in ptients with non-smll cell lung cncer who received ALIMTA. Incidence 1% to 5% Dermtology/Skin lopeci, pruritis/itching Gstrointestinl constiption Generl Disorders edem, fever (in the bsence of neutropeni) Hemtologic thrombocytopeni Renl decresed cretinine clernce, incresed cretinine, decresed glomerulr filtrtion rte Specil Senses oculr surfce disese (including conjunctivitis), incresed lcrimtion Incidence Less thn 1% Crdiovsculr suprventriculr rrhythmi Dermtology/Skin erythem multiforme Generl Disorders febrile neutropeni, llergic rection/hypersensitivity Neurology motor neuropthy Renl renl filure Non-Smll Cell Lung Cncer (NSCLC) After Prior Chemotherpy Tble 6 provides the frequency nd severity of dverse rections tht hve been reported in >5% of 265 ptients rndomly ssigned to receive single-gent ALIMTA with folic cid nd vitmin B 12 supplementtion nd 276 ptients rndomly ssigned to receive single-gent docetxel. All ptients were dignosed with loclly dvnced or metsttic NSCLC nd received prior chemotherpy. Tble 6: Adverse Rections in Fully Supplemented Ptients Receiving ALIMTA versus Docetxel in NSCLC ALIMTA Docetxel (N=265) (N=276) Rection b All Grdes Grdes 3-4 All Grdes Toxicity (%) Toxicity (%) Toxicity (%) Grdes 3-4 Toxicity (%) Lbortory Hemtologic Anemi Leukopeni Neutropeni Thrombocytopeni Heptic Incresed ALT Incresed AST Clinicl Gstrointestinl Nuse Anorexi Vomiting Stomtitis/Phryngitis Dirrhe Constiption Constitutionl Symptoms Ftigue Fever Dermtology/Skin Rsh/Desqumtion Pruritis Alopeci 6 1 c 38 2 c For the purpose of this tble cut off of 5% ws used for inclusion of ll events where the reporter considered possible reltionship to ALIMTA. b Refer to NCI CTC Criteri for lb vlues for ech Grde of toxicity (version 2.0). c According to NCI CTC Criteri version 2.0, this dverse event term should only be reported s Grde 1 or 2.

8 No cliniclly relevnt differences in dverse rections were seen in ptients bsed on histology. Cliniclly relevnt dverse rections occurring in <5% of ptients tht received ALIMTA tretment but >5% of ptients tht received docetxel include CTC Grde 3/4 febrile neutropeni (1.9% ALIMTA, 12.7% docetxel). The following dditionl dverse rections were observed in ptients with non-smll cell lung cncer rndomly ssigned to receive ALIMTA. Incidence 1% to 5% Body s Whole bdominl pin, llergic rection/hypersensitivity, febrile neutropeni, infection Dermtology/Skin erythem multiforme Neurology motor neuropthy, sensory neuropthy Renl incresed cretinine Incidence Less thn 1% Crdiovsculr suprventriculr rrhythmis Mlignnt Pleurl Mesotheliom (MPM) Tble 7 provides the frequency nd severity of dverse rections tht hve been reported in >5% of 168 ptients with mesotheliom who were rndomly ssigned to receive cispltin nd ALIMTA nd 163 ptients with mesotheliom rndomly ssigned to receive single-gent cispltin. In both tretment rms, these chemonive ptients were fully supplemented with folic cid nd vitmin B 12. Tble 7: Adverse Rections in Fully Supplemented Ptients Receiving ALIMTA plus Cispltin in MPM ALIMTA/cispltin Cispltin (N=168) (N=163) Rection b All Grdes Grde 3-4 All Grdes Toxicity (%) Toxicity (%) Toxicity (%) 8 Grde 3-4 Toxicity (%) Lbortory Hemtologic Neutropeni Leukopeni Anemi Thrombocytopeni Renl Cretinine elevtion Cretinine clernce decresed Clinicl Eye Disorder Conjunctivitis Gstrointestinl Nuse Vomiting Stomtitis/Phryngitis Anorexi Dirrhe Constiption Dyspepsi Constitutionl Symptoms Ftigue Metbolism nd Nutrition Dehydrtion Neurology Neuropthy-sensory Tste Disturbnce 8 0 c 6 0 c Dermtology/Skin Rsh Alopeci 11 0 c 6 0 c b c For the purpose of this tble cut off of 5% ws used for inclusion of ll events where the reporter considered possible reltionship to ALIMTA. Refer to NCI CTC Criteri version 2.0 for ech Grde of toxicity except the term cretinine clernce decresed which is derived from the CTC term renl/genitourinry-other. According to NCI CTC Criteri version 2.0, this dverse event term should only be reported s Grde 1 or 2.

9 The following dditionl dverse rections were observed in ptients with mlignnt pleurl mesotheliom rndomly ssigned to receive ALIMTA plus cispltin. Incidence 1% to 5% 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 Less thn 1% Crdiovsculr rrhythmi Neurology motor neuropthy Effects of Vitmin Supplementtions Tble 8 compres the incidence (percentge of ptients) of CTC Grde 3/4 toxicities in ptients who received vitmin supplementtion with dily folic cid nd vitmin B 12 from the time of enrollment in the study (fully supplemented) with the incidence in ptients who never received vitmin supplementtion (never supplemented) during the study in the ALIMTA plus cispltin rm. Tble 8: Selected Grde 3/4 Adverse Events Compring Fully Supplemented versus Never Supplemented Ptients in the ALIMTA plus Cispltin rm (% incidence) Adverse Event (%) Fully Supplemented Ptients (N=168) Never Supplemented Ptients (N=32) Neutropeni/grnulocytopeni Thrombocytopeni 5 9 Vomiting Febrile neutropeni 1 9 Infection with Grde 3/4 neutropeni 0 6 Dirrhe 4 9 Refer to NCI CTC criteri for lb nd non-lbortory vlues for ech grde of toxicity (Version 2.0). The following dverse events were greter in the fully supplemented group compred to the never supplemented group: hypertension (11%, 3%), chest pin (8%, 6%), nd thrombosis/embolism (6%, 3%). Subpopultions No relevnt effect for ALIMTA sfety due to gender or rce ws identified, except n incresed incidence of rsh in men (24%) compred to women (16%). 6.2 Post-Mrketing 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. These rections hve occurred with ALIMTA when used s single-gent nd in combintion therpies. Gstrointestinl colitis Generl Disorders nd Administrtion Site Conditions edem Injury, poisoning, nd procedurl complictions Rdition recll hs been reported in ptients who hve previously received rdiotherpy. Respirtory interstitil pneumonitis 7 DRUG INTERACTIONS 7.1 Non-Steroidl Anti-Inflmmtory Drugs (NSAIDs) Ibuprofen Although ibuprofen (400 mg four times dy) cn decrese the clernce of pemetrexed, it cn be dministered with ALIMTA in ptients with norml renl function (cretinine clernce 80 ml/min). Cution should be used when dministering ibuprofen concurrently with ALIMTA to ptients with mild to moderte renl insufficiency (cretinine clernce from 45 to 79 ml/min) [see Clinicl Phrmcology (12.3)]. Other NSAIDs Ptients with mild to moderte renl insufficiency should void tking NSAIDs with short elimintion hlf-lives for period of 2 dys before, the dy of, nd 2 dys following dministrtion of ALIMTA. In the bsence of dt regrding potentil interction between ALIMTA nd NSAIDs with longer hlf-lives, ll ptients tking these NSAIDs should interrupt dosing for t lest 5 dys before, the dy of, nd 2 dys following ALIMTA dministrtion. If concomitnt dministrtion of n NSAID is necessry, ptients should be monitored closely for toxicity, especilly myelosuppression, renl, nd gstrointestinl toxicity. 7.2 Nephrotoxic Drugs 9

10 10 ALIMTA is primrily eliminted unchnged renlly s result of glomerulr filtrtion nd tubulr secretion. Concomitnt dministrtion of nephrotoxic drugs could result in delyed clernce of ALIMTA. Concomitnt dministrtion of substnces tht re lso tubulrly secreted (e.g., probenecid) could potentilly result in delyed clernce of ALIMTA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy Tertogenic Effects - Pregnncy Ctegory D [see Wrnings nd Precutions (5.6)] Bsed on its mechnism of ction, ALIMTA cn cuse fetl hrm when dministered to pregnnt womn. There re no dequte nd well controlled studies of ALIMTA in pregnnt women. Pemetrexed ws embryotoxic, fetotoxic, nd tertogenic in mice. In mice, repeted intrperitonel doses of pemetrexed when given during orgnogenesis cused fetl mlformtions (incomplete ossifiction of tlus nd skull bone; bout 1/833rd the recommended intrvenous humn dose on mg/m 2 bsis), nd cleft plte (1/33rd the recommended intrvenous humn dose on mg/m 2 bsis). Embryotoxicity ws chrcterized by incresed embryo-fetl deths nd reduced litter sizes. If ALIMTA is used during pregnncy, or if the ptient becomes pregnnt while tking this drug, the ptient should be pprised of the potentil hzrd to the fetus. Women of childbering potentil should be dvised to use effective contrceptive mesures to prevent pregnncy during the tretment with ALIMTA. 8.3 Nursing Mothers It is not known whether ALIMTA or its metbolites re excreted in humn milk. Becuse mny drugs re excreted in humn milk, nd becuse of the potentil for serious dverse rections in nursing infnts from ALIMTA, decision should be mde to discontinue nursing or discontinue the drug, tking into ccount the importnce of the drug for the mother. 8.4 Peditric Use The sfety nd effectiveness of ALIMTA in peditric ptients hve not been estblished. 8.5 Geritric Use ALIMTA is known to be substntilly excreted by the kidney, nd the risk of dverse rections to this drug my be greter in ptients with impired renl function. Becuse elderly ptients re more likely to hve decresed renl function, cre should be tken in dose selection. Renl function monitoring is recommended with dministrtion of ALIMTA. No dose reductions other thn those recommended for ll ptients re necessry for ptients 65 yers of ge or older [see Dosge nd Administrtion (2.4)]. In the initil tretment non-smll cell lung cncer clinicl tril, 37.7% of ptients treted with ALIMTA plus cispltin were 65 yers nd Grde 3/4 neutropeni ws greter s compred to ptients <65 yers (19.9% versus 12.2%). For ptients <65 yers, the HR for overll survivl ws 0.96 (95% CI: 0.83, 1.10) nd for ptients 65 yers the HR ws 0.88 (95% CI: 0.74, 1.06) in the intent to tret popultion. In the mintennce non-smll cell lung cncer tril 33.3% of ptients treted with ALIMTA were 65 yers nd no differences were seen in Grde 3/4 dverse rections s compred to ptients <65 yers. For ptients <65 yers, the HR for overll survivl ws 0.74 (95% CI: 0.58, 0.93) nd for ptients 65 yers the HR ws 0.88 (95% CI: 0.65, 1.21) in the intent to tret popultion. In the non-smll cell lung cncer tril fter prior chemotherpy, 29.7% ptients treted with ALIMTA were 65 yers nd Grde 3/4 hypertension ws greter s compred to ptients <65 yers. For ptients <65 yers, the HR for overll survivl ws 0.95 (95% CI: 0.76, 1.19), nd for ptients 65 yers the HR ws 1.15 (95% CI: 0.79, 1.68) in the intent to tret popultion. The mesotheliom tril included 36.7% ptients treted with ALIMTA plus cispltin tht were 65 yers, nd Grde 3/4 ftigue, leukopeni, neutropeni, nd thrombocytopeni were greter s compred to ptients <65 yers. For ptients <65 yers, the HR for overll survivl ws 0.71(95% CI: 0.53, 0.96) nd for ptients 65 yers, the HR ws 0.85 (95% CI: 0.59, 1.22) in the intent to tret popultion. 8.6 Ptients with Heptic Impirment There ws no effect of elevted AST, ALT, or totl bilirubin on the phrmcokinetics of pemetrexed [see Clinicl Phrmcology (12.3)]. Dose djustments bsed on heptic impirment experienced during tretment with ALIMTA re provided in Tble 2 [see Dosge nd Administrtion (2.4)]. 8.7 Ptients with Renl Impirment ALIMTA is known to be primrily excreted by the kidneys. Decresed renl function will result in reduced clernce nd greter exposure (AUC) to ALIMTA compred with ptients with norml renl function [see Dosge nd Administrtion (2.4) nd Clinicl Phrmcology (12.3)]. Cispltin codministrtion with ALIMTA hs not been studied in ptients with moderte renl impirment. 8.8 Gender In the initil tretment non-smll cell lung cncer tril, 70% of ptients were mles nd 30% femles. For mles the HR for overll survivl ws 0.97 (95% CI: 0.85, 1.10) nd for femles the HR ws 0.86 (95% CI: 0.70, 1.06) in the intent to tret popultion. In the mintennce non-smll cell lung cncer tril, 73% of ptients were mles nd 27% femles. For mles the HR for overll survivl ws 0.78 (95% CI: 0.63, 0.96) nd for femles the HR ws 0.83 (95% CI: 0.56, 1.21) in the intent to tret popultion. In the non-smll cell lung cncer tril fter prior chemotherpy, 72% of ptients were mles nd 28% femles. For mles the HR for overll survivl ws 0.95 (95% CI: 0.76, 1.19) nd for femles the HR ws 1.28 (95% CI: 0.86, 1.91) in the intent to tret popultion.

11 11 In the mesotheliom tril, 82% of ptients were mles nd 18% femles. For mles the HR for overll survivl ws 0.85 (95% CI: 0.66, 1.09) nd for femles the HR ws 0.48 (95% CI: 0.27, 0.85) in the intent to tret popultion. 8.9 Rce In the initil tretment non-smll cell lung cncer tril, 78% of ptients were Cucsins, 13% Est/Southest Asins, nd 9% others. For Cucsins, the HR for overll survivl ws 0.92 (95% CI: 0.82, 1.04), for Est/Southest Asins the HR ws 0.86 (95% CI: 0.61, 1.21), nd for others the HR ws 1.24 (95% CI: 0.84, 1.84) in the intent to tret popultion. In the mintennce non-smll cell lung cncer tril, 65% of ptients were Cucsins, 23% Est Asin, nd 12% others. For Cucsins the HR for overll survivl ws 0.77 (95% CI: 0.62, 0.97), for Est Asins ws 1.05 (95% CI: 0.70, 1.59) nd for others the HR ws 0.46 (95% CI: 0.26, 0.79) in the intent to tret popultion. In the non-smll cell lung cncer tril fter prior chemotherpy, 71% of ptients were Cucsins nd 29% others. For Cucsins the HR for overll survivl ws 0.91 (95% CI: 0.73, 1.15) nd for others the HR ws 1.27 (95% CI: 0.87, 1.87) in the intent to tret popultion. In the mesotheliom tril, 92% of ptients were Cucsins nd 8% others. For Cucsins, the HR for overll survivl ws 0.77 (95% CI: 0.61, 0.97) nd for others the HR ws 0.86 (95% CI: 0.39, 1.90) in the intent to tret popultion. 10 OVERDOSAGE There hve been few cses of ALIMTA overdose. Reported toxicities included neutropeni, nemi, thrombocytopeni, mucositis, nd rsh. Anticipted complictions of overdose include bone mrrow suppression s mnifested by neutropeni, thrombocytopeni, nd nemi. In ddition, infection with or without fever, dirrhe, nd mucositis my be seen. If n overdose occurs, generl supportive mesures should be instituted s deemed necessry by the treting physicin. In clinicl trils, leucovorin ws permitted for CTC Grde 4 leukopeni lsting 3 dys, CTC Grde 4 neutropeni lsting 3 dys, nd immeditely for CTC Grde 4 thrombocytopeni, bleeding ssocited with Grde 3 thrombocytopeni, or Grde 3 or 4 mucositis. The following intrvenous doses nd schedules of leucovorin were recommended for intrvenous use: 100 mg/m 2, intrvenously once, followed by leucovorin, 50 mg/m 2, intrvenously every 6 hours for 8 dys. The bility of ALIMTA to be dilyzed is unknown. 11 DESCRIPTION Pemetrexed disodium hepthydrte hs the chemicl nme L-Glutmic cid, N-[4-[2-(2-mino-4,7-dihydro-4-oxo-1Hpyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium slt, hepthydrte. It is white to lmost-white solid with moleculr formul of C 20 H 19 N 5 N 2 O 6 7H 2 O nd moleculr weight of The structurl formul is s follows: ALIMTA is supplied s sterile lyophilized powder for intrvenous infusion vilble in single-dose vils. The product is white to either light yellow or green-yellow lyophilized solid. Ech 100-mg or 500-mg vil of ALIMTA contins pemetrexed disodium equivlent to 100 mg pemetrexed nd 106 mg mnnitol or 500 mg pemetrexed nd 500 mg mnnitol, respectively. Hydrochloric cid nd/or sodium hydroxide my hve been dded to djust ph. 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action ALIMTA, pemetrexed for injection, is folte nlog metbolic inhibitor tht exerts its ction by disrupting folte-dependent metbolic processes essentil for cell repliction. In vitro studies hve shown tht pemetrexed inhibits thymidylte synthse (TS), dihydrofolte reductse (DHFR), 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. Polyglutmtion is time- nd concentrtion-dependent process tht occurs in tumor cells nd, is thought to occur to lesser extent, in norml tissues. Polyglutmted metbolites re thought to hve n incresed intrcellulr hlf-life resulting in prolonged drug ction in mlignnt cells Phrmcodynmics Preclinicl studies hve shown tht pemetrexed inhibits the in vitro growth of mesotheliom cell lines (MSTO-211H, NCI-H2052). Studies with the MSTO-211H mesotheliom cell line showed synergistic effects when pemetrexed ws combined concurrently with cispltin.

12 12 Absolute neutrophil counts (ANC) following single-gent dministrtion of ALIMTA to ptients not receiving folic cid nd vitmin B 12 supplementtion were chrcterized using popultion phrmcodynmic nlyses. Severity of hemtologic toxicity, s mesured by the depth of the ANC ndir, correltes with the systemic exposure, or re under the curve (AUC) of pemetrexed. It ws lso observed tht lower ANC ndirs occurred in ptients with elevted bseline cystthionine or homocysteine concentrtions. The levels of these substnces cn be reduced by folic cid nd vitmin B 12 supplementtion. There is no cumultive effect of pemetrexed exposure on ANC ndir over multiple tretment cycles. Time to ANC ndir with pemetrexed systemic exposure (AUC), vried between 8 to 9.6 dys over rnge of exposures from 38.3 to mcg hr/ml. Return to bseline ANC occurred 4.2 to 7.5 dys fter the ndir over the sme rnge of exposures Phrmcokinetics Absorption The phrmcokinetics of ALIMTA dministered s single-gent in doses rnging from 0.2 to 838 mg/m 2 infused over 10-minute period hve been evluted in 426 cncer ptients with vriety of solid tumors. Pemetrexed totl systemic exposure (AUC) nd mximum plsm concentrtion (C mx ) increse proportionlly with dose. The phrmcokinetics of pemetrexed do not chnge over multiple tretment cycles. Distribution Pemetrexed hs stedy-stte volume of distribution of 16.1 liters. In vitro studies indicte tht pemetrexed is pproximtely 81% bound to plsm proteins. Binding is not ffected by degree of renl impirment. Metbolism nd Excretion Pemetrexed is not metbolized to n pprecible extent nd is primrily eliminted in the urine, with 70% to 90% of the dose recovered unchnged within the first 24 hours following dministrtion. The clernce decreses, nd exposure (AUC) increses, s renl function decreses. The totl systemic clernce of pemetrexed is 91.8 ml/min nd the elimintion hlf-life of pemetrexed is 3.5 hours in ptients with norml renl function (cretinine clernce of 90 ml/min). The phrmcokinetics of pemetrexed in specil popultions were exmined in bout 400 ptients in controlled nd single rm studies. Effect of Age No effect of ge on the phrmcokinetics of pemetrexed ws observed over rnge of 26 to 80 yers. Effect of Gender The phrmcokinetics of pemetrexed were not different in mle nd femle ptients. Effect of Rce The phrmcokinetics of pemetrexed were similr in Cucsins nd ptients of Africn descent. Insufficient dt re vilble to compre phrmcokinetics for other ethnic groups. Effect of Heptic Insufficiency There ws no effect of elevted AST, ALT, or totl bilirubin on the phrmcokinetics of pemetrexed. However, studies of hepticlly impired ptients hve not been conducted [see Dosge nd Administrtion (2.4) nd Use in Specific Popultions (8.6)]. Effect of Renl Insufficiency Phrmcokinetic nlyses of pemetrexed included 127 ptients with reduced renl function. Plsm clernce of pemetrexed decreses s renl function decreses, with resultnt increse in systemic exposure. Ptients with cretinine clernces of 45, 50, nd 80 ml/min hd 65%, 54%, nd 13% increses, respectively in pemetrexed totl systemic exposure (AUC) compred to ptients with cretinine clernce of 100 ml/min [see Wrnings nd Precutions (5.4) nd Dosge nd Administrtion (2.4)]. Peditric Peditric ptients were not included in clinicl trils. Effect of Ibuprofen Ibuprofen doses of 400 mg four times dy reduce pemetrexed s clernce by bout 20% (nd increse AUC by 20%) in ptients with norml renl function. The effect of greter doses of ibuprofen on pemetrexed phrmcokinetics is unknown [see Drug Interctions (7.1)]. Effect of Aspirin Aspirin, dministered in low to moderte doses (325 mg every 6 hours), does not ffect the phrmcokinetics of pemetrexed. The effect of greter doses of spirin on pemetrexed phrmcokinetics is unknown. Effect of Cispltin Cispltin does not ffect the phrmcokinetics of pemetrexed nd the phrmcokinetics of totl pltinum re unltered by pemetrexed. Effect of Vitmins Codministrtion of orl folic cid or intrmusculr vitmin B 12 does not ffect the phrmcokinetics of pemetrexed. Drugs Metbolized by Cytochrome P450 Enzymes Results from in vitro studies with humn liver microsomes predict tht pemetrexed would not cuse cliniclly significnt inhibition of metbolic clernce of drugs metbolized by CYP3A, CYP2D6, CYP2C9, nd CYP1A2. 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility No crcinogenicity studies hve been conducted with pemetrexed. Pemetrexed ws clstogenic in the in vivo micronucleus ssy in mouse bone mrrow but ws not mutgenic in multiple in vitro tests (Ames ssy, CHO cell ssy). Pemetrexed dministered

13 13 t i.v. doses of 0.1 mg/kg/dy or greter to mle mice (bout 1/1666 the recommended humn dose on mg/m 2 bsis) resulted in reduced fertility, hypospermi, nd testiculr trophy. 14 CLINICAL STUDIES 14.1 Non-Smll Cell Lung Cncer (NSCLC) - Combintion with Cispltin A multi-center, rndomized, open-lbel study in 1725 chemonive ptients with Stge IIIb/IV NSCLC ws conducted to compre the overll survivl following tretment with ALIMTA in combintion with cispltin (AC) versus gemcitbine in combintion with cispltin (GC). ALIMTA ws dministered intrvenously over 10 minutes t dose of 500 mg/m 2 with cispltin dministered intrvenously t dose of 75 mg/m 2 fter ALIMTA dministrtion, on Dy 1 of ech 21-dy cycle. Gemcitbine ws dministered t dose of 1250 mg/m 2 on Dy 1 nd Dy 8, nd cispltin ws dministered intrvenously t dose of 75 mg/m 2 fter dministrtion of gemcitbine, on Dy 1 of ech 21-dy cycle. Tretment ws dministered up to totl of 6 cycles, nd ptients in both tretment rms received folic cid, vitmin B 12, nd dexmethsone [see Dosge nd Administrtion (2.3)]. Ptient demogrphics of the intent to tret (ITT) popultion re shown in Tble 9. The demogrphics nd disese chrcteristics were well blnced. Tble 9: First-Line Therpy: Summry of Ptient Chrcteristics in Study of NSCLC ALIMTA plus Cispltin (AC) Ptient chrcteristic (N=862) Gemcitbine plus Cispltin (GC) (N=863) Age (yrs) Medin (rnge) 61.1 ( ) 61.0 ( ) Gender Mle/Femle 70.2%/29.8% 70.1%/29.9% Origin Cucsin 669 (77.6%) 680 (78.8%) Hispnic 27 (3.1%) 23 (2.7%) Asin 146 (16.9%) 141 (16.3%) Africn descent 18 (2.1%) 18 (2.1%) Stge t Entry IIIb/IV 23.8%/76.2% 24.3%/75.7% Histology Nonsqumous NSCLC 618 (71.7%) 634 (73.5%) Adenocrcinom 436 (50.6%) 411 (47.6%) Lrge cell 76 (8.8%) 77 (8.9%) Other b 106 (12.3%) 146 (16.9%) Squmous 244 (28.3%) 229 (26.5%) ECOG PS c,d 0/1 35.4%/64.6% 35.6%/64.3% Smoking History e Ever/never smoker 83.1%/16.9% 83.9%/16.1% b c d e Includes denocrcinom, lrge cell, nd other histologies except those with squmous cell type. The subgroup of other represents ptients with primry dignosis of NSCLC whose disese did not clerly qulify s denocrcinom, squmous cell crcinom, or lrge cell crcinom. Estern Coopertive Oncology Group Performnce Sttus. ECOG PS ws not reported for ll rndomized ptients. Percentges re representtive of N=861 for the ALIMTA plus cispltin rm, nd N=861 for the gemcitbine plus cispltin rm. Smoking history ws collected for 88% of rndomized ptients (N=757 for the ALIMTA plus cispltin rm nd N=759 for the gemcitbine plus cispltin rm). Ptients received medin of 5 cycles of tretment in both study rms. Ptients treted with ALIMTA plus cispltin received reltive dose intensity of 94.8% of the protocol-specified ALIMTA dose intensity nd 95.0% of the protocol-specified cispltin dose intensity. Ptients treted with gemcitbine plus cispltin received reltive dose intensity of 85.8% of the protocol-specified gemcitbine dose intensity nd 93.5% of the protocol-specified cispltin dose intensity. The primry endpoint in this study ws overll survivl. The medin survivl time ws 10.3 months in the ALIMTA plus cispltin tretment rm nd 10.3 months in the gemcitbine plus cispltin rm, with n djusted hzrd rtio of Tble 10: First-Line Therpy: Efficcy in NSCLC - ITT Popultion ALIMTA plus Cispltin (N=862) Gemcitbine plus Cispltin (N=863) Medin overll survivl (95% CI) 10.3 mos ( ) 10.3 mos ( )

14 14 Adjusted hzrd rtio (HR),b (95% CI) 0.94 ( ) Medin progression-free survivl (95% CI) 4.8 mos ( ) 5.1 mos ( ) Adjusted hzrd rtio (HR),b (95% CI) 1.04 ( ) Overll response rte (95% CI) 27.1% ( ) 24.7% ( ) Adjusted for gender, stge, bsis of dignosis, nd performnce sttus. b A HR tht is less thn 1.0 indictes tht survivl is better in the AC rm thn in the GC rm. Alterntively, HR tht is greter thn 1.0 indictes survivl is better in the GC rm thn in the AC rm. Survivl Probbility 1.0 Medin (95% CI) 0.9 AC 10.3 (9.8, 11.2) 0.8 GC 10.3 (9.6, 10.9) 0.7 AC vs GC Adjusted HR (95% CI) (0.84, 1.05) Ptients t Risk Survivl Time (months) AC GC Figure 1: Kpln-Meier Curves for Overll Survivl ALIMTA plus Cispltin (AC) versus Gemcitbine plus Cispltin (GC) in NSCLC - ITT Popultion. A pre-specified nlysis of the impct of NSCLC histology on overll survivl ws exmined. Cliniclly relevnt differences in survivl ccording to histology were observed nd re shown in Tble 11. This difference in tretment effect for ALIMTA bsed on histology demonstrting lck of efficcy in squmous cell histology ws lso observed in the single-gent, second-line study nd the mintennce study [see Clinicl Studies (14.2, 14.3)]. b c d e Tble 11: First-Line Therpy: Overll Survivl in NSCLC Histologic Subgroups Medin Overll Survivl in Months Undjusted Adjusted Hzrd Histology Subgroup (95% CI) Hzrd Rtio (HR),b,c ALIMTA plus Cispltin Gemcitbine plus Cispltin Rtio (HR),b (95% CI) (95% CI) Nonsqumous NSCLC d (N=1252) 11.0 ( ) N= ( ) N= ( ) 0.84 ( ) Adenocrcinom (N=847) 12.6 ( ) N= ( ) N= ( ) 0.84 ( ) Lrge Cell (N=153) 10.4 ( ) N= ( ) N= ( ) 0.67 ( ) Other e (N=252) 8.6 ( ) N= ( ) N= ( ) 1.08 ( ) Squmous Cell (N=473) 9.4 ( ) N= ( ) N= ( ) 1.23 ( ) A HR tht is less thn 1.0 indictes tht survivl is better in the AC rm thn in the GC rm. Alterntively, HR tht is greter thn 1.0 indictes survivl is better in the GC rm thn in the AC rm. Undjusted for multiple comprisons. HRs djusted for ECOG PS, gender, disese stge, nd bsis for pthologicl dignosis (histopthologicl/cytopthologicl). Includes denocrcinom, lrge cell, nd other histologies except those with squmous cell type. The subgroup of other represents ptients with primry dignosis of NSCLC whose disese did not clerly qulify s denocrcinom, squmous cell crcinom, or lrge cell crcinom