PEMETREXED

1 INDICATIONS AND USAGE Pemetrexed Injection is a folate analog metabolic inhibitor indicated: • In combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous, non-small cell lung cancer (NSCLC). ( 1.1 ) • As a single agent for the maintenance treatment of patients with locally advanced or metastatic, non -squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. ( 1.1 ) • As a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy. ( 1.1 ) • Limitations of Use : Pemetrexed Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer. ( 1.1 ) • Initial treatment, in combination with cisplatin, of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. ( 1.2 ) 1.1 Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Pemetrexed Injection is indicated: • In combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous, non-small cell lung cancer (NSCLC). • As a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. • As a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy. Limitations of Use: Pemetrexed Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer [see Clinical Studies 14.1 ]. 1.2 Mesothelioma Pemetrexed Injection is indicated, in combination with cisplatin, for the initial treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.

2 DOSAGE AND ADMINISTRATION • The recommended dose of Pemetrexed Injection, administered as a single agent or with cisplatin, in patients with creatinine clearance of 45 mL/minute or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. ( 2.1 , 2.2 ) • Initiate folic acid 400 mcg to 1000 mcg orally, once daily, beginning 7 days prior to the first dose of Pemetrexed Injection and continue until 21 days after the last dose of Pemetrexed Injection. ( 2.4 ) • Administer vitamin B 12 , 1 mg intramuscularly, 1 week prior to the first dose of Pemetrexed Injection and every 3 cycles. ( 2.4 ) • Administer dexamethasone 4 mg orally, twice daily the day before, the day of, and the day after Pemetrexed Injection administration. ( 2.4 ) 2.1 Recommended Dosage for Non-Squamous NSCLC • The recommended dose of Pemetrexed Injection when administered with cisplatin for initial treatment of locally advanced or metastatic non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes administered prior to cisplatin on Day 1 of each 21-day cycle for up to six cycles in the absence of disease progression or unacceptable toxicity. • The recommended dose of Pemetrexed Injection for maintenance treatment of non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity after four cycles of platinum-based first-line chemotherapy. • The recommended dose of Pemetrexed Injection for treatment of recurrent non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. 2.2 Recommended Dosage for Mesothelioma The recommended dose of Pemetrexed Injection when administered with cisplatin in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. 2.3 Renal Impairment Pemetrexed Injection dosing recommendations are provided for patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater [see Dosage and Administration (2.1 , 2.2) ] . There is no recommended dose for patients whose creatinine clearance is less than 45 mL/min [see Use in Specific Populations (8.6) ] . 2.4 Premedication and Concomitant Medications to Mitigate Toxicity Vitamin Supplementation • Initiate folic acid 400 mcg to 1000 mcg orally once daily, beginning 7 days before the first dose of Pemetrexed Injection and continuing until 21 days after the last dose of Pemetrexed Injection [see Warnings and Precautions (5.1) ] . • Administer vitamin B 12 , 1 mg intramuscularly, 1 week prior to the first dose of Pemetrexed Injection and every 3 cycles thereafter. Subsequent vitamin B 12 injections may be given the same day as treatment with Pemetrexed Injection [see Warnings and Precautions (5.1) ] . Do not substitute oral vitamin B 12 for intramuscular vitamin B 12 . Corticosteroids • Administer dexamethasone 4 mg orally twice daily for three consecutive days, beginning the day before each Pemetrexed Injection administration. 2.5 Dosage Modification of Ibuprofen in Patients with Mild to Moderate Renal Impairment Receiving Pemetrexed Injection In patients with creatinine clearances between 45 mL/min and 79 mL/min, modify administration of ibuprofen as follows [see Warnings and Precautions (5.6) , Drug Interactions (7) and Clinical Pharmacology (12.3) ] : • Avoid administration of ibuprofen for 2 days before, the day of, and 2 days fol …

3 DOSAGE FORMS AND STRENGTHS Pemetrexed Injection is a clear colorless to pale yellow ready-to-dilute solution available in single-dose vials as follows: • 100 mg/4 mL (25 mg/mL) • 500 mg/20 mL (25 mg/mL) • 1 g/40 mL (25 mg/mL) Injection: 100 mg/4 mL (25 mg/mL) in a single-dose vial ( 3 ) Injection: 500 mg/20 mL (25 mg/mL) in a single-dose vial ( 3 ) Injection: 1 g/40 mL (25 mg/mL) in a single-dose vial. ( 3 )

4 CONTRAINDICATIONS Pemetrexed Injection is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed [see Adverse Reactions (6.1) ] . History of severe hypersensitivity reaction to pemetrexed. ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Myelosuppression [see Warnings and Precautions (5.1) ] • Renal failure [see Warnings and Precautions (5.2) ] • Bullous and exfoliative skin toxicity [see Warnings and Precautions (5.3) ] • Interstitial pneumonitis [see Warnings and Precautions (5.4) ] • Radiation recall [see Warnings and Precautions (5.5) ] • The most common adverse reactions (incidence ≥20%) of pemetrexed when administered as a single agent are fatigue, nausea, and anorexia. ( 6.1 ) • The most common adverse reactions (incidence ≥20%) of pemetrexed when administered with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc., at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. In clinical trials, the most common adverse reactions (incidence ≥20%) of pemetrexed, when administered as a single agent, are fatigue, nausea, and anorexia. The most common adverse reactions (incidence ≥20%) of pemetrexed, when administered in combination with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. Non-Squamous NSCLC Initial Treatment in Combination with Cisplatin The safety of pemetrexed was evaluated in Study JMDB, a randomized (1:1), open-label, multicenter trial conducted in chemotherapy-naive patients with locally advanced or metastatic NSCLC. Patients received either pemetrexed 500 mg/m 2 intravenously and cisplatin 75 mg/m 2 intravenously on Day 1 of each 21-day cycle (n=839) or gemcitabine 1250 mg/m 2 intravenously on Days 1 and 8 and cisplatin 75 mg/m 2 intravenously on Day 1 of each 21-day cycle (n=830). All patients were fully supplemented with folic acid and vitamin B 12 . Study JMDB excluded patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS of 2 or greater), uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B 12 or corticosteroids were also excluded from the study. The data described below reflect exposure to pemetrexed plus cisplatin in 839 patients in Study JMDB. Median age was 61 years (range 26–83 years); 70% of patients were men; 78% were White,16% were Asian, 2.9% were Hispanic or Latino, 2.1% were Black or African American, and <1% were other ethnicities; 36% had an ECOG PS 0. Patients received a median of 5 cycles of pemetrexed. Table 2 provides the frequency and severity of adverse reactions that occurred in ≥5% of 839 patients receiving pemetrexed in combination with cisplatin in Study JMDB. Study JMDB was not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed, as compared to the control arm, for any specified adverse reaction listed in Table 2. Table 2: Adverse Reactions Occurring in ≥5% of Fully Vitamin-Supplemented Patients Receiving Pemetrexed in Combination with Cisplatin Chemotherapy in Study JMDB Adverse Reaction NCI CTCAE version 2.0 Pemetrexed/Cisplatin (N=839) Gemcitabine/Cisplatin (N=830) All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%) All adverse reactions 90 37 91 53 Laboratory Hematologic Anemia 33 6 46 10 Neutropenia 29 15 38 27 Thrombocytopenia 10 4 27 13 Renal Elevated creatinine 10 1 7 1 Clinical Constitutional symptoms Fatigue 43 7 45 5 Gastrointestinal Nausea 56 7 53 4 Vomiting 40 6 36 6 Anorexia 27 2 24 1 Constipation 21 1 20 0 Stomatitis/pharyngitis 14 1 12 0 Diarrhea 12 1 …

7 DRUG INTERACTIONS Ibuprofen increased risk of Pemetrexed Injection toxicity in patients with mild to moderate renal impairment. Modify the ibuprofen dosage as recommended for patients with a creatinine clearance between 45 mL/min and 79 mL/min. ( 2.5 , 5.6 , 7 ) Effects of Ibuprofen on Pemetrexed Ibuprofen increases exposure (AUC) of pemetrexed [see Clinical Pharmacology (12.3) ] . In patients with creatinine clearance between 45 mL/min and 79 mL/min: • Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of Pemetrexed Injection [see Dosage and Administration (2.5) ] . • Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, Pemetrexed Injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on Pemetrexed Injection use in pregnant women. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and malformations at doses lower than the recommended human dose of 500 mg/m 2 [see Data ] . Advise pregnant women of the potential risk to a fetus [see Use in Special Populations (8.3) ] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Pemetrexed was teratogenic in mice. Daily dosing of pemetrexed by intravenous injection to pregnant mice during the period of organogenesis increased the incidence of fetal malformations (cleft palate; protruding tongue; enlarged or misshaped kidney; and fused lumbar vertebra) at doses (based on BSA) 0.03 times the human dose of 500 mg/m 2 . At doses, based on BSA, greater than or equal to 0.0012 times the 500 mg/m 2 human dose, pemetrexed administration resulted in dose-dependent increases in developmental delays (incomplete ossification of talus and skull bone; and decreased fetal weight). 8.2 Lactation Risk Summary There is no information regarding the presence of pemetrexed or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from Pemetrexed Injection, advise women not to breastfeed during treatment with Pemetrexed Injection and for one week after last dose. 8.3 Females and Males of Reproductive Potential Based on animal data, pemetrexed can cause malformations and developmental delays when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating Pemetrexed Injection [see Use in Specific Populations (8.1) ] . Contraception Females Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 6 months after the last dose of Pemetrexed Injection. Males Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 3 months after the last dose [see Nonclinical Toxicology (13.1) ] . Infertility Males Pemetrexed Injection may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use The safety and effectiveness of Pemetrexed Injection in pediatric patients have not been established. The safety and pharmacokinetics of pemetrexed were evaluated in two clinical studies conducted in pediatric patients with recurrent solid tumors (NCT00070473, N=32 and NCT00520936, N=72). Patients in both studies received concomitant vitamin B 12 and folic acid supplementation and dexamethasone. No tumor responses were observed. Adverse reactions observed in pediatric patients were similar to those observed in adults. Pharmacokinetics of pemetrexed in 22 patients age 4 to 18 years enrolled in NCT00070473 were within range of values in adults. 8.5 Geriatric Use Of the 3,946 patients enrolled in clinical studies of pemetrexed, 34% were 65 and over and 4% were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. The incidences of Grade 3–4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were h …

12.1 Mechanism of Action Pemetrexed Injection is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic processes essential for cell replication. In vitro studies show that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT.

11 DESCRIPTION Pemetrexed is a folate analog metabolic inhibitor. The drug substance, pemetrexed disodium (2.5 H 2 O), has the chemical name N -[[4-[2-(2-Amino-4-oxo-4,7-dihydro-1 H -pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]phenyl]carbonyl]-L-glutamic acid disodium, hemipentahydrate with a molecular formula of C 20 H 19 N 5 Na 2 O 6 ∙2.5H 2 O and a molecular weight of 516.41. The structural formula is as follows: Pemetrexed Injection, 100 mg/4 mL, 500 mg/20 mL, and 1 g/40 mL are supplied as a sterile, preservative-free, clear, colorless to pale yellow ready-to-dilute solution in a single-dose vial for intravenous infusion. Each milliliter (mL) contains 25 mg pemetrexed (equivalent to 27.57 mg pemetrexed disodium), 1.2 mg monothioglycerol, water for injection and may contain sodium hydroxide for pH adjustment. Chemical Structure

10 OVERDOSAGE No drugs are approved for the treatment of Pemetrexed Injection overdose. Based on animal studies, administration of leucovorin may mitigate the toxicities of Pemetrexed Injection overdosage. It is not known whether pemetrexed is dialyzable.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Pemetrexed Injection is a clear, colorless to pale yellow ready-to-dilute solution in a single-dose vial for intravenous infusion. NDC 0409-0020-02: Carton containing one (1) single-dose vial, 100 mg/4 mL (25 mg/mL). NDC 0409-0021-03: Carton containing one (1) single-dose vial, 500 mg/20 mL (25 mg/mL). NDC 0409-0004-04: Carton containing one (1) single-dose vial, 1 g/40 mL (25 mg/mL). Storage and Handling Store Pemetrexed Injection at controlled refrigerated temperature, 2°C to 8°C (36°F to 46°F). Pemetrexed Injection is a hazardous drug. Follow applicable special handling and disposal procedures. [see References (15) ]