ADVERSE REACTIONS SECTION.

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 Warning and Precautions (5.3 )] Interstitial pneumonitis [see Warnings and Precautions (5.4)] Radiation recall [see Warnings and Precautions (5.5)] o The most common adverse reactions (incidence >=20%) of pemetrexed for injection, when administered as single agent are fatigue, nausea, and anorexia. (6.1) The most common adverse reactions (incidence >=20%) of pemetrexed for injection when administered with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. (6.1) The most common adverse reactions (incidence >=20%) of pemetrexed for injection when administered in combination with pembrolizumab and platinum chemotherapy are fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, and pyrexia. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Dr. REDDYS LABORATORIES Inc., at 1-888-375-3784 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 for injection, when administered as single agent, are fatigue, nausea, and anorexia. The most common adverse reactions (incidence >=20%) of pemetrexed for injection, when administered in combination with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. The most common adverse reactions (incidence >=20%) of pemetrexed for injection, when administered in combination with pembrolizumab and platinum chemotherapy, are fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, and pyrexia.Non-Squamous NSCLCFirst-line Treatment of Metastatic Non-squamous NSCLC with Pembrolizumab and Platinum ChemotherapyThe safety of pemetrexed for injection, in combination with pembrolizumab and investigators choice of platinum (either carboplatin or cisplatin), was investigated in Study KEYNOTE-189, multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated, metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations.A total of 607 patients received pemetrexed for injection, pembrolizumab, and platinum every weeks for cycles followed by pemetrexed for injection and pembrolizumab (n=405), or placebo, pemetrexed for injection, and platinum every weeks for cycles followed by placebo and pemetrexed for injection (n=202). Patients with autoimmune disease that required systemic therapy within years of treatment; medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible [see Clinical Studies (14.1)].The median duration of exposure to pemetrexed for injection was 7.2 months (range: day to 1.7 years). Seventy-two percent of patients received carboplatin. The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 years or older, 59% male, 94% White and 3% Asian, and 18% with history of brain metastases at baseline.Pemetrexed for injection was discontinued for adverse reactions in 23% of patients in the pemetrexed for injection, pembrolizumab, and platinum arm. The most common adverse reactions resulting in discontinuation of pemetrexed for injection in this arm were acute kidney injury (3%) and pneumonitis (2%). Adverse reactions leading to interruption of pemetrexed for injection occurred in 49% of patients in the pemetrexed for injection, pembrolizumab, and platinum arm. The most common adverse reactions or laboratory abnormalities leading to interruption of pemetrexed for injection in this arm (>=2%) were neutropenia (12%), anemia (7%), asthenia (4%), pneumonia (4%), thrombocytopenia (4%), increased blood creatinine (3%), diarrhea (3%), and fatigue (3%).Table summarizes the adverse reactions that occurred in >=20% of patients treated with pemetrexed for injection, pembrolizumab, and platinumTable 2: Adverse Reactions Occurring in >=20% of Patients in KEYNOTE-189Pemetrexed for injection Pembrolizumab Platinum Chemotherapy n=405Placebo pemetrexed for injectionPlatinum Chemotherapy n=202Adverse ReactionAll Gradesa (%)Grade 3-4 (%)All Grades (%)Grade 3-4 (%)Gastrointestinal DisordersNausea563.5523.5Constipation351.0320.5Diarrhea315213.0Vomiting243.7233.0General Disorders and Administration Site ConditionsFatigueb5612586Pyrexia200.2150Metabolism and Nutrition DisordersDecreased appetite281.5300.5Skin and Subcutaneous Tissue DisordersRashc252.0172.5Respiratory, Thoracic and Mediastinal DisordersCough210280Dyspnea213.7265 Graded per NCI CTCAE version 4.03.b Includes asthenia and fatigue.c Includes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular.Table summarizes the laboratory abnormalities that worsened from baseline in at least 20% of patients treated with pemetrexed for injection, pembrolizumab, and platinum.Table 3: Laboratory Abnormalities Worsened from Baseline in >=20% of Patients in KEYNOTE-189Pemetrexed for Injection PembrolizumabPlatinum ChemotherapyPlacebo Pemetrexed for InjectionPlatinum ChemotherapyLaboratory TestaAll Gradesb%Grades 3-4%All Grades%Grades 3-4%ChemistryHyperglycemia639607Increased ALT473.8422.6Increased AST472.8401.0Hypoalbuminemia392.8391.1Increased creatinine374.2251.0Hyponatremia327236Hypophosphatemia30102814Increased alkaline phosphatase261.8292.1Hypocalcemia242.8170.5Hyperkalemia242.8193.1Hypokalemia215205HematologyAnemia85178118Lymphopenia64226425Neutropenia48204119Thrombocytopenia3012298 Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: pemetrexed for injection /pembrolizumab/platinum chemotherapy (range: 381 to 401 patients) and placebo/pemetrexed for injection /platinum chemotherapy (range: 184 to 197 patients).b Graded per NCI CTCAE version 4.03.Initial Treatment in Combination with Cisplatin The safety of pemetrexed for injection was evaluated in Study JMDB, randomized (1:1), open-label, multicenter trial conducted in chemotherapy-naive patients with locally advanced or metastatic NSCLC. Patients received either pemetrexed for injection 500 mg/m2 intravenously and cisplatin 75 mg/m2 intravenously on Day of each 21 day cycle (n=839) or gemcitabine 1,250 mg/m2 intravenously on Days and and cisplatin 75 mg/m2 intravenously on Day of each 21 day cycle (n=830). All patients were fully supplemented with folic acid and vitamin B12.Study JMDB excluded patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS of or greater), uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or 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 B12 or corticosteroids were also excluded from the study. The data described below reflect exposure to pemetrexed for injection plus cisplatin in 839 patients in Study JMDB. Median age was 61 years (range 26 to 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 median of cycles of pemetrexed. Table provides the frequency and severity of adverse reactions that occurred in >=5% of 839 patients receiving pemetrexed for injection in combination with cisplatin in Study JMDB. Study JMDB was not designed to demonstrate statistically significant reduction in adverse reaction rates for pemetrexed for injection as compared to the control arm, for any specified adverse reaction listed in Table 4.Table 4: Adverse Reactions Occurring in >=5% of Fully Vitamin-Supplemented Patients Receiving Pemetrexed in Combination with Cisplatin Chemotherapy in Study JMDB Pemetrexed for injection/ Cisplatin (N=839)Gemcitabine/ Cisplatin (N=830)Adverse ReactionaAll Grades (%)Grade to (%)All Grades (%)Grade to (%)All adverse reactions 90 37 91 53 LaboratoryHematologic Anemia 33 46 10 Neutropenia 29 15 38 27 Thrombocytopenia 10 27 13 Renal Elevated creatinine 10 7 ClinicalConstitutional symptoms Fatigue 43 45 Gastrointestinal Nausea 56 53 Vomiting 40 36 Anorexia 27 24 Constipation 21 20 Stomatitis/pharyngitis 14 12 Diarrhea 12 13 Dyspepsia/heartburn 0 0 Neurology Sensory neuropathy 0 12 Taste disturbance 0 0 Dermatology/Skin Alopecia 12 21 Rash/Desquamation 0 1 NCI CTCAE version 2.0.The following additional adverse reactions of pemetrexed were observed. Incidence 1% to <5% Body as Whole -- febrile neutropenia, infection, pyrexia General Disorders -- dehydration Metabolism and Nutrition -- increased AST, increased ALT Renal -- creatinine clearance decrease, renal failure Eye Disorder -- conjunctivitisIncidence 1% Cardiovascular -- arrhythmia General Disorders -- chest pain Metabolism and Nutrition -- increased GGT Neurology -- motor neuropathy Maintenance Treatment Following First-line Non-Pemetrexed for injection Containing Platinum-Based Chemotherapy In Study JMEN, the safety of pemetrexed for injection was evaluated in randomized (2:1), placebo-controlled, multicenter trial conducted in patients with non-progressive locally advanced or metastatic NSCLC following four cycles of first-line, platinum-based chemotherapy regimen. Patients received either pemetrexed for injection 500 mg/m2 or matching placebo intravenously every 21 days until disease progression or unacceptable toxicity. Patients in both study arms were fully supplemented with folic acid and vitamin B12. Study JMEN excluded patients with an ECOG PS of or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or 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 B12 or corticosteroids were also excluded from the study. The data described below reflect exposure to pemetrexed for injection in 438 patients in Study JMEN. Median age was 61 years (range 26-83 years), 73% of patients were men; 65% were White, 31% were Asian, 2.9% were Hispanic or Latino, and <2% were other ethnicities; 39% had an ECOG PS 0. Patients received median of cycles of pemetrexed for injection and relative dose intensity of pemetrexed for injection of 96%. Approximately half the patients (48%) completed at least six, 21-day cycles and 23% completed ten or more 21-day cycles of pemetrexed for injection. Table provides the frequency and severity of adverse reactions reported in >=5% of the 438 pemetrexed for injection -treated patients in Study JMEN. Table 5: Adverse Reactions Occurring in >=5% of Patients Receiving Pemetrexed for injection in Study JMEN Pemetrexed for Injection (N=438)Placebo (N=218)Adverse ReactionaAll Grades (%) Grade to (%)All Grades (%)Grade to (%)All adverse reactions 66 16 37 LaboratoryHematologic Anemia 15 6 Neutropenia 3 0 Hepatic Increased ALT 10 4 Increased AST 0 0 ClinicalConstitutional symptoms Fatigue 25 11 Gastrointestinal Nausea 19 6 Anorexia 19 5 Vomiting 0 0 Mucositis/stomatitis 1 0 Diarrhea 1 0 Infection 2 0 Neurology Sensory neuropathy 1 0 Dermatology/Skin Rash/desquamation 10 3 a NCI CTCAE version 3.0.The requirement for transfusions (9.5% versus 3.2%), primarily red blood cell transfusions, and for erythropoiesis stimulating agents (5.9% versus 1.8%) were higher in the pemetrexed for injection arm compared to the placebo arm. The following additional adverse reactions were observed in patients who received pemetrexed. Incidence 1% to <5% Dermatology/Skin -- alopecia, pruritis/itching Gastrointestinal -- constipation General Disorders -- edema, fever Hematologic -- thrombocytopenia Eye Disorder -- ocular surface disease (including conjunctivitis), increased lacrimation Incidence 1% Cardiovascular -- supraventricular arrhythmia Dermatology/Skin -- erythema multiforme General Disorders -- febrile neutropenia, allergic reaction/hypersensitivity Neurology -- motor neuropathy Renal -- renal failure Maintenance Treatment Following First-line pemetrexed Plus Platinum Chemotherapy The safety of pemetrexedwas evaluated in PARAMOUNT, randomized (2:1), placebo-controlled study conducted in patients with non-squamous NSCLC with non-progressive (stable or responding disease) locally advanced or metastatic NSCLC following four cycles of pemetrexedin combination with cisplatin as first-line therapy for NSCLC. Patients were randomized to receive pemetrexed 500 mg/m2 or matching placebo intravenously on Day of each 21 day cycle until disease progression or unacceptable toxicity. PARAMOUNT excluded patients with an ECOG PS of or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or 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 corticosteroids were also excluded from the study. The data described below reflect exposure to pemetrexed in 333 patients in PARAMOUNT. Median age was 61 years (range 32 to 83 years); 58% of patients were men; 94% were White, 4.8% were Asian, and <1% were Black or African American; 36% had an ECOG PS 0. The median number of maintenance cycles was for pemetrexed and placebo arms.Dose reductions for adverse reactions occurred in 3.3% of patients in the pemetrexed arm and 0.6% in the placebo arm. Dose delays for adverse reactions occurred in 22% of patients in the pemetrexed arm and 16% in the placebo arm. Table provides the frequency and severity of adverse reactions reported in >=5% of the 333 pemetrexed-treated patients in PARAMOUNT. Table 6: Adverse Reactions Occurring in >=5% of Patients Receiving Pemetrexed in PARAMOUNT Pemetrexed (N=333)Placebo (N=167)Adverse ReactionaAll Grades (%)Grade to (%)All Grades (%)Grades to (%)All adverse reactions 53 17 34 4.8 LaboratoryHematologic Anemia 15 4.8 4.8 0.6 Neutropenia 3.9 0.6 ClinicalConstitutional symptoms Fatigue 18 4.5 11 0.6 Gastrointestinal Nausea 12 0.3 2.4 Vomiting 0 1.8 Mucositis/stomatitis 0.3 2.4 General disorders Edema 0 3.6 a NCI CTCAE version 3.0.The requirement for red blood cell (13% versus 4.8%) and platelet (1.5% versus 0.6%) transfusions, erythropoiesis stimulating agents (12% versus 7%), and granulocyte colony stimulating factors (6% versus 0%) were higher in the pemetrexed arm compared to the placebo arm. The following additional Grade or adverse reactions were observed more frequently in the pemetrexed arm. Incidence 1% to 5% Blood/Bone Marrow -- thrombocytopenia General Disorders -- febrile neutropenia Incidence Less than 1% Cardiovascular -- ventricular tachycardia, syncope General Disorders -- pain Gastrointestinal -- gastrointestinal obstruction Neurologic -- depression Renal -- renal failure Vascular -- pulmonary embolism Treatment of Recurrent Disease After Prior Chemotherapy The safety of pemetrexed for injection was evaluated in Study JMEI, randomized (1:1), open-label, active-controlled trial conducted in patients who had progressed following platinum-based chemotherapy. Patients received pemetrexed 500 mg/m2 intravenously or docetaxel 75 mg/m2 intravenously on Day of each 21 day cycle. All patients on the pemetrexed for injection arm received folic acid and vitamin B12 supplementation. Study JMEI excluded patients with an ECOG PS of or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or calculated creatinine clearance less than 45 mL/min. Patients unable to discontinue aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 orcorticosteroids were also excluded from the study. The data described below reflect exposure to pemetrexed for injection in 265 patients in Study JMEI. Median age was 58 years (range 22 to 87 years); 73% of patients were men; 70% were White, 24% were Asian, 2.6% were Black or African American, 1.8% were Hispanic or Latino, and <2% were other ethnicities; 19% had an ECOG PS 0. Table provides the frequency and severity of adverse reactions reported in >=5% of the 265 pemetrexed for injection -treated patients in Study JMEI. Study JMEI is not designed to demonstrate statistically significant reduction in adverse reaction rates for pemetrexed, as compared to the control arm, for any specified adverse reaction listed in the Table7 below. Table 7: Adverse Reactions Occurring in >=5% of Fully Supplemented Patients Receiving Pemetrexed forInjection in Study JMEI Pemetrexed for Injection (N=265)Docetaxel (N=276)Adverse ReactionaAll Grades (%)Grades to (%)All Grade (%)Grades to (%)LaboratoryHematologicAnemia194224Neutropenia1154540Thrombocytopenia8210HepaticIncreased ALT8210Increased AST7110ClinicalGastrointestinalNausea313172Anorexia222243Vomiting162121Stomatitis/pharyngitis151171Diarrhea130243Constipation6040Constitutional symptomsFatigue345365Fever8080Dermatology/SkinRash/desquamation14060Pruritus7020Alopecia61382a NCI CTCAE version 2.0.The following additional adverse reactions were observed in patients assigned to receive pemetrexed.Incidence 1% to <5% Body as Whole -- abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection Dermatology/Skin -- erythema multiforme Neurology -- motor neuropathy, sensory neuropathy Incidence <1% Cardiovascular -- supraventricular arrhythmias Renal -- renal failure MesotheliomaThe safety of pemetrexed for injection was evaluated in Study JMCH, randomized (1:1), single-blind study conducted in patients with MPM who had received no prior chemotherapy for MPM. Patients received pemetrexed 500 mg/m2 intravenously in combination with cisplatin 75 mg/m2 intravenously on Day of each 21-day cycle or cisplatin 75 mg/m2 intravenously on Day of each 21-day cycle administered until disease progression or unacceptable toxicity. Safety was assessed in 226 patients who received at least one dose of pemetrexed in combination with cisplatin and 222 patients who received at least one dose of cisplatin alone. Among 226 patients who received pemetrexed in combination with cisplatin, 74% (n=168) received full supplementation with folic acid and vitamin B12 during study therapy, 14% (n=32) were never supplemented, and 12% (n=26) were partially supplemented. Study JMCH excluded patients with Karnofsky Performance Scale (KPS) of less than 70, inadequate bone marrow reserve and organ function, or calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs were also excluded from the study. The data described below reflect exposure to pemetrexed for injection in 168 patients that were fully supplemented with folic acid and vitamin B12. Median age was 60 years (range 19 to 85 years); 82% were men; 92% were White, 5% were Hispanic or Latino, 3.0% were Asian, and <1% were other ethnicities; 54% had KPS of 90-100. The median number of treatment cycles administered was in the pemetrexed /cisplatin fully supplemented group and in the pemetrexed/cisplatin never supplemented group. Patients receiving pemetrexed for injection in the fully supplemented group had relative dose intensity of 93% of the protocol-specified pemetrexed dose intensity. The most common adverse reaction resulting in dose delay was neutropenia. Table provides the frequency and severity of adverse reactions >=5% in the subgroup of pemetrexed for injection-treated patients who were fully vitamin supplemented in Study JMCH. Study JMCH was not designed to demonstrate statistically significant reduction in adverse reaction rates for pemetrexed, as compared to the control arm, for any specified adverse reaction listed in the table below. Table 8: Adverse Reactions Occurring in >=5% of Fully Supplemented Subgroup of Patients Receiving Pemetrexed for Injection /Cisplatin in Study JMCHa Adverse Reactionb Pemetrexed for Injection /cisplatin (N=168)Cisplatin (N=163)All Grades (%)Grade 3-4 (%)All Grades (%)Grade 3-4 (%)LaboratoryHematologicNeutropenia5623133Anemia 264100Thrombocytopenia 23590RenalElevated creatinine 111101Decreased creatinine clearance 161182ClinicalEye DisorderConjunctivitis 5010GastrointestinalNausea 8212776Vomiting 5711504Stomatitis/pharyngitis 23360Anorexia 201141Diarrhea 17480Constipation 12171Dyspepsia 5110Constitutional SymptomsFatigue 4810429Metabolism and NutritionDehydration 7411NeurologySensory neuropathy 100101Taste disturbance 8060Dermatology/SkinRash 16150Alopecia 11060a In Study JMCH, 226 patients received at least one dose of pemetrexed for injection in combination with cisplatin and 222 patients received at least one dose of cisplatin. Table provides the ADRs for subgroup of patients treated with pemetrexed for injection in combination with cisplatin (168 patients) or cisplatin alone (163 patients) who received full supplementation with folic acid and vitamin B12 during study therapy. NCI CTCAE version 2.0. The following additional adverse reactions were observed in patients receiving pemetrexed for injection plus cisplatin:Incidence 1% to <5% Body as Whole -- febrile neutropenia, infection, pyrexia Dermatology/Skin -- urticaria General Disorders -- chest pain Metabolism and Nutrition -- increased AST, increased ALT, increased GGT Renal -- renal failure Incidence <1% Cardiovascular -- arrhythmia Neurology -- motor neuropathy Exploratory Subgroup Analyses based on Vitamin Supplementation Table provides the results of exploratory analyses of the frequency and severity of NCI CTCAE Grade or adverse reactions reported in more pemetrexed for injection-treated patients who did not receive vitamin supplementation (never supplemented) as compared with those who received vitamin supplementation with daily folic acid and vitamin B12 from the time of enrollment in Study JMCH (fully-supplemented). Table 9: Exploratory Subgroup Analysis of Selected Grade 3/4 Adverse Reactions Occurring in Patients Receiving Pemetrexed for Injection in Combination with Cisplatin with or without Full Vitamin Supplementation in Study JMCHa Grade to Adverse ReactionsFully Supplemented PatientsN=168 (%)Never Supplemented PatientsN=32 (%)Neutropenia 2338Thrombocytopenia 59Vomiting 1131Febrile neutropenia 19Infection with Grade 3/4 neutropenia 06Diarrhea 49a NCI CTCAE version 2.0. The following adverse reactions occurred more frequently in patients who were fully vitamin supplemented than in patients who were never supplemented: hypertension (11% versus 3%), chest pain (8% versus 6%), thrombosis/embolism (6% versus 3%). Additional Experience Across Clinical Trials Sepsis, with or without neutropenia, including fatal cases: 1% Severe esophagitis, resulting in hospitalization: <1% 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of pemetrexed for injection. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. These reactions have occurred with pemetrexed for injection when used as single-agent and in combination therapies. Blood and Lymphatic System -- immune-mediated hemolytic anemiaGastrointestinal -- colitis, pancreatitisGeneral Disorders and Administration Site Conditions -- edema Injury, poisoning, and procedural complications -- Radiation recall has been reported in patients who have previously received radiotherapy. Respiratory -- interstitial pneumonitis Skin -- Bullous conditions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Some cases were fatal.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Pemetrexed for injection, is folate analog metabolic inhibitor that exerts its action by 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. Polyglutamation is time- and concentration-dependent process that occurs in tumor cells and, is thought to occur to lesser extent, in normal tissues. Polyglutamated metabolites are thought to have an increased intracellular half-life resulting in prolonged drug action in malignant cells. 12.2 Pharmacodynamics. Pemetrexed inhibited the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052) and showed synergistic effects when combined with cisplatin. Based on population pharmacodynamic analyses, the depth of the absolute neutrophil counts (ANC) nadir correlates with the systemic exposure to pemetrexed and supplementation with folic acid and vitamin B12. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles. 12.3 Pharmacokinetics. Absorption The pharmacokinetics of pemetrexed for injection when pemetrexed was administered as single agent in doses ranging from 0.2 to 838 mg/m2 infused over 10-minute period have been evaluated in 426 cancer patients with variety of solid tumors. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (Cmax) increased proportionally with increase of dose. The pharmacokinetics of pemetrexed did not change over multiple treatment cycles. Distribution Pemetrexed has steady-state volume of distribution of 16.1 liters. In vitro studies indicated that pemetrexed is 81% bound to plasma proteins. EliminationThe total systemic clearance of pemetrexed is 91.8 mL/min and the elimination half-life of pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min). As renal function decreases, the clearance of pemetrexed decreases and exposure (AUC) of pemetrexed increases. Metabolism Pemetrexed is not metabolized to an appreciable extent. ExcretionPemetrexed is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. In vitro studies indicated that pemetrexed is substrate of OAT3 (organic anion transporter 3), transporter that is involved in the active secretion of pemetrexed. Specific PopulationsAge (26 to 80 years) and sex had no clinically meaningful effect on the systemic exposure of pemetrexed based on population pharmacokinetic analyses. Racial Groups The pharmacokinetics of pemetrexed were similar in Whites and Blacks or African Americans. Insufficient data are available for other ethnic groups. Patients with Hepatic ImpairmentPemetrexed has not been formally studied in patients with hepatic impairment. No effect of elevated AST, ALT, or total bilirubin on the PK of pemetrexed was observed in clinical studies. Patients with Renal ImpairmentPharmacokinetic analyses of pemetrexed included 127 patients with impaired renal function. Plasma clearance of pemetrexed decreases as renal function decreases, with resultant increase in systemic exposure. Patients with creatinine clearances of 45, 50, and 80 mL/min had 65%, 54%, and 13% increases, respectively in systemic exposure (AUC) compared to patients with creatinine clearance of 100 mL/min [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)]. Third-Space Fluid The pemetrexed plasma concentrations in patients with various solid tumors with stable, mild to moderate third-space fluid were comparable to those observed in patients without third-space fluid collections. The effect of severe third-space fluid on pharmacokinetics is not known. Drug Interaction Studies Drugs Inhibiting OAT3 Transporter Ibuprofen, an OAT3 inhibitor, administered at 400 mg four times day decreased the clearance of pemetrexed and increased its exposure (AUC) by approximately 20% in patients with normal renal function (creatinine clearance >80 mL/min).In Vitro Studies Pemetrexed is substrate for OAT3. Ibuprofen, an OAT3 inhibitor inhibited the uptake of pemetrexed in OAT3-expressing cell cultures with an average [Iu]/IC50 ratio of 0.38. In vitro data predict that at clinically relevant concentrations, other NSAIDs (naproxen, diclofenac, celecoxib) would not inhibit the uptake of pemetrexed by OAT3 and would not increase the AUC of pemetrexed to clinically significant extent. [see Drug Interactions (7)]. Pemetrexed is substrate for OAT4. In vitro, ibuprofen and other NSAIDs (naproxen, diclofenac, celecoxib) are not inhibitors of OAT4 at clinically relevant concentrations. Aspirin Aspirin, administered in low to moderate doses (325 mg every hours), does not affect the pharmacokinetics of pemetrexed. Cisplatin Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed. Vitamins Neither folic acid nor vitamin B12 affect the pharmacokinetics of pemetrexed. Drugs Metabolized by Cytochrome P450 EnzymesIn vitro studies suggest that pemetrexed does not inhibit the clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Non-Squamous NSCLC. Initial Treatment in Combination with Pembrolizumab and PlatinumThe efficacy of pemetrexed for injection in combination with pembrolizumab and platinum chemotherapy was investigated in Study KEYNOTE-189 (NCT02578680), randomized, multicenter, double-blind, active-controlled trial conducted in patients with metastatic non-squamous NSCLC, regardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease and in whom there were no EGFR or ALK genomic tumor aberrations. Patients with autoimmune disease that required systemic therapy within years of treatment; medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by smoking status (never versus former/current), choice of platinum (cisplatin versus carboplatin), and tumor PD-L1 status (TPS <1% [negative] versus TPS >=1%). Patients were randomized (2:1) to one of the following treatment arms:Pemetrexed for injection 500 mg/m2, pembrolizumab 200 mg, and investigators choice of cisplatin 75 mg/m2 or carboplatin AUC mg/mL/min intravenously on Day of each 21-day cycle for cycles followed by pemetrexed for injection 500 mg/m2 and pembrolizumab 200 mg intravenously every weeks. pemetrexed for injection was administered after pembrolizumab and prior to platinum chemotherapy on Day 1.Placebo, pemetrexed for injection 500 mg/m2, and investigators choice of cisplatin 75 mg/m2 or carboplatin AUC mg/mL/min intravenously on Day of each 21-day cycle for cycles followed by placebo and pemetrexed or injection 500 mg/m2 intravenously every weeks.Treatment with pemetrexed for injection continued until RECIST v1.1 (modified to follow maximum of 10 target lesions and maximum of target lesions per organ)-defined progression of disease as determined by the investigator or unacceptable toxicity. Patients randomized to placebo,pemetrexed for injection ,and platinum chemotherapy were offered pembrolizumab as single agent at the time of disease progression.Assessment of tumor status was performed at Week 6, Week 12, and then every weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by BICR RECIST v1.1, modified to follow maximum of 10 target lesions and maximum of five target lesions per organ. Additional efficacy outcome measures were ORR and duration of response, as assessed by the BICR according to RECIST v1.1, modified to follow maximum of 10 target lesions and maximum of target lesions per organ.A total of 616 patients were randomized: 410 patients to the pemetrexed for injection, pembrolizumab, and platinum chemotherapy arm and 206 to the placebo, pemetrexed for injection and platinum chemotherapy arm. The study population characteristics were: median age of 64 years (range: 34 to 84); 49% age 65 or older; 59% male; 94% White and 3% Asian; 56% ECOG performance status of 1; and 18% with history of brain metastases. Thirty-one percent had tumor PD-L1 expression TPS <1%. Seventy-two percent received carboplatin and 12% were never smokers. total of 85 patients in the placebo, pemetrexed for injection and chemotherapy arm received an anti-PD-1/PD-L1 monoclonal antibody at the time of disease progression.The trial demonstrated statistically significant improvement in OS and PFS for patients randomized to pemetrexed in combination with pembrolizumab and platinum chemotherapy compared with placebo, pemetrexed or injection, and platinum chemotherapy (see Table 10 and Figure 1).Table 10: Efficacy Results of KEYNOTE-189EndpointPemetrexed for Injection Pembrolizumab Platinum Chemotherapy n=410Placebo Pemetrexed for Injection Platinum Chemotherapy n=206OSNumber (%) of patients with event127 (31%)108 (52%)Median in months (95% CI)NR (NR, NR)11.3(8.7, 15.1)Hazard ratioa (95% CI)0.49 (0.38, 0.64)p-valueb<0.0001PFSNumber of patients with event (%)244 (60%)166 (81%)Median in months (95% CI)8.8 (7.6, 9.2)4.9 (4.7, 5.5)Hazard ratioa (95% CI)0.52 (0.43, 0.64)p-valueb<0.0001ORROverall response ratec (95% CI)48% (43, 53)19% (14, 25)Complete response0.5%0.5%Partial response47%18%p-valued<0.0001Duration of ResponseMedian in months (range)11.2 (1.1+, 18.0+)7.8 (2.1+, 16.4+)a Based on the stratified Cox proportional hazard model.b Based on stratified log-rank test.c Response: Best objective response as confirmed complete response or partial response.d Based on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy and smoking status.NR not reachedA+P+C pemetrexed pembrolizumab platinum chemotherapy.A+C pemetrexed platinum chemotherapy placebo.Figure1: Kaplan-Meier Curve for Overall Survival in KEYNOTE-189Initial Treatment in Combination with Cisplatin The efficacy of pemetrexed for injection was evaluated in Study JMDB (NCT00087711), multi-center, randomized (1:1), open-label study conducted in 1725 chemotherapy-naive patients with Stage IIIb/IV NSCLC. Patients were randomized to receive pemetrexedfor injection with cisplatin or gemcitabine with cisplatin. Randomization was stratified by Eastern Cooperative Oncology Group Performance Status (ECOG PS versus 1), gender, disease stage, basis for pathological diagnosis (histopathological /cytopathological), history of brain metastases, and investigative center. Pemetrexed was administered intravenously over 10 minutes at dose of 500 mg/m2 on Day of each 21-day cycle. Cisplatin was administered intravenously at dose of 75 mg/m2 approximately 30 minutes after pemetrexed for injection administration on Day of each cycle, gemcitabine was administered at dose of 1250 mg/m2 on Day and Day 8, and cisplatin was administered intravenously at dose of 75 mg/m2 approximately 30 minutes after administration of gemcitabine, on Day of each 21day cycle. Treatment was administered up to total of cycles; patients in both arms received folic acid, vitamin B12, and dexamethasone [see Dosage and Administration (2.4)]. The primary efficacy outcome measure was overall survival. total of 1725 patients were enrolled with 862 patients randomized to pemetrexed for injection in combination with cisplatin and 863 patients to gemcitabine in combination with cisplatin. The median age was 61 years (range 26-83 years), 70% were male, 78% were White, 17% were Asian, 2.9% were Hispanic or Latino, and 2.1% were Black or African American, and <1% were other ethnicities. Among patients for whom ECOG PS (n=1722) and smoking history (n=1516) were collected, 65% had an ECOG PS of 1, 36% had an ECOG PS of 0, and 84% were smokers. For tumor characteristics, 73% had non-squamous NSCLC and 27% had squamous NSCLC; 76% had Stage IV disease. Among 1252 patients with non-squamous NSCLC histology, 68% had diagnosis of adenocarcinoma, 12% had large cell histology and 20% had other histologic subtypes. Efficacy results in Study JMDB are presented in Table 11 and Figure 2. Table 11: Efficacy Results in Study JMDBEfficacy ParameterPemetrexed for injection plus Cisplatin(N=862)Gemcitabine plus Cisplatin(N=863)Overall SurvivalMedian (months) (95% CI) 10.3 (9.8 11.2)10.3 (9.6 to 10.9)Hazard ratio (HR)a,b (95% CI) 0.94 (0.84 1.05)Progression-Free SurvivalMedian (months) (95% CI) 4.8 (4.6 5.3)5.1 (4.6- 5.5)Hazard ratio (HR)a,b (95% CI) 1.04 (0.94 to 1.15)Overall Response Rate (95% CI) 27.1% (24.2 30.1)24.7% (21.8 27.6) aUnadjusted for multiple comparisons.b Adjusted for gender, stage, basis of diagnosis, and performance status.Figure 2: Kaplan-Meier Curves for Overall Survival in Study JMDB In pre-specified analyses assessing the impact of NSCLC histology on overall survival, clinically relevant differences in survival according to histology were observed. These subgroup analyses are shown in Table 12 and Figures and 4. This difference in treatment effect for pemetrexed for injection based on histology demonstrating lack of efficacy in squamous cell histology was also observed in Studies JMEN and JMEI. Table 12: Overall Survival in NSCLC Histologic Subgroups in Study JMDB Histologic SubgroupsPemetrexed plus Cisplatin (N=862)Gemcitabine plus Cisplatin(N=863)Non-squamous NSCLC (N=1252) Median (months) (95% CI) 11.0 (10.1- 12.5)10.1 (9.3 -10.9)HRa,b (95% CI) 0.84 (0.74 -0.96)Adenocarcinoma (N=847) Median (months) (95% CI) 12.6 (10.7 13.6)10.9 (10.2 11.9)HRa,b (95% CI) 0.84 (0.71 0.99)Large Cell (N=153) Median (months) (95% CI) 10.4 (8.6 14.1)6.7 (5.5 -9.0)HRa,b (95% CI) 0.67 (0.48 -0.96)Non-squamous, not otherwise specified (N=252)Median (months) (95% CI) 8.6 (6.8 -10.2)9.2 (8.1- 10.6)HRa,b (95% CI) 1.08 (0.81 -1.45)Squamous Cellc (N=473) Median (months) (95% CI) 9.4 (8.4 10.2)10.8 (9.5 -12.1)HRa,b (95% CI) 1.23 (1.00 -1.51)a Unadjusted for multiple comparisons. bAdjusted for ECOG PS, gender, disease stage, and basis for pathological diagnosis (histopathological/cytopathological).Figure 3: Kaplan-Meier Curves for Overall Survival in Non-squamous NSCLC in Study JMDBFigure 4: Kaplan-Meier Curves for Overall Survival in Squamous NSCLC in Study JMDB Maintenance Treatment Following First-line Non-Pemetrexedfor injection Containing Platinum-Based Chemotherapy The efficacy of pemetrexed as maintenance therapy following first-line platinum-based chemotherapy was evaluated in Study JMEN (NCT00102804), multicenter, randomized (2:1), double-blind, placebo-controlled study conducted in 663 patients with Stage IIIb/IV NSCLC who did not progress after four cycles of platinum-based chemotherapy. Patients were randomized to receive pemetrexed 500 mg/m2 intravenously every 21 days or placebo until disease progression or intolerable toxicity. Patients in both study arms received folic acid, vitamin B12, and dexamethasone [see Dosage and Administration (2.4)]. Randomization was carried out using minimization approach [Pocock and Simon (1975)] using the following factors: gender, ECOG PS (0 versus 1), response to prior chemotherapy (complete or partial response versus stable disease), history of brain metastases (yes versus no), non-platinum component of induction therapy (docetaxel versus gemcitabine versus paclitaxel), and disease stage (IIIb versus IV). The major efficacy outcome measures were progression-free survival based on assessment by independent review and overall survival; both were measured from the date of randomization in Study JMEN. total of 663 patients were enrolled with 441 patients randomized to pemetrexed for injectionand 222 patients randomized to placebo. The median age was 61 years (range 26 to 83 years); 73% were male; 65% were White, 32% were Asian, 2.9% were Hispanic or Latino, and <2% were other ethnicities; 60% had an ECOG PS of 1; and 73% were current or former smokers. Median time from initiation of platinum-based chemotherapy to randomization was 3.3 months (range 1.6 to 5.1 months) and 49% of the population achieved partial or complete response to first-line, platinum-based chemotherapy. With regard to tumor characteristics, 81% had Stage IV disease, 73% had non-squamous NSCLC and 27% had squamous NSCLC. Among the 481 patients with non-squamous NSCLC, 68% had adenocarcinoma, 4% had large cell, and 28% had other histologies. Efficacy results are presented in Table 13 and Figure 5. Table 13: Efficacy Results in Study JMEN Efficacy ParameterPemetrexed for InjectionPlaceboOverall survival N=441N=222Median (months) (95% CI) 13.4 (11.9- 15.9)10.6 (8.7-12.0)Hazard ratioa (95% CI) 0.79 (0.65- 0.95)p-value p=0.012Progression-free survival per independent review N=387N=194Median (months) (95% CI) 4.0 (3.1-4.4)2.0 (1.5-2.8)Hazard ratioa (95% CI) 0.60 (0.49-0.73)p-value p<0.00001a Hazard ratios are adjusted for multiplicity but not for stratification variables.Figure 5: Kaplan-Meier Curves for Overall Survival in Study JMEN The results of pre-specified subgroup analyses by NSCLC histology are presented in Table 14 and Figures and 7. Table 14: Efficacy Results in Study JMEN by Histologic SubgroupEfficacy ParameterOverall SurvivalProgression-Free Survival Per Independent ReviewPemetrexed for InjectionPlacebo (N=222)Pemetrexed for InjectionPlacebo (N=194)Non-squamous NSCLC (n=481) Median (months) 15.510.34.41.8HRa (95% CI) 0.70 (0.56 0.88)0.47 (0.37 0.60)Adenocarcinoma (n=328) Median (months 16.811.54.62.7HRa (95% CI) 0.73 (0.56 0.96)0.51 (0.38 0.68)Large cell carcinoma (n=20) Median (months) 8.47.94.51.5HRa (95% CI) 0.98 (0.36- 2.65)0.40 (0.12 -1.29)Otherb (n=133) Median (months) 11.37.74.11.6HRa (95% CI) 0.61 (0.40 -0.94)0.44 (0.28 -0.68)Squamous cell NSCLC (n=182) Median (months) 9.910.82.42.5HRa (95% CI) 1.07 (0.77- 1.50)1.03 (0.71- 1.49)a Hazard ratios are not adjusted for multiplicity. Primary diagnosis of NSCLC not specified as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma.Figure 6: Kaplan-Meier Curves for Overall Survival in Non-squamous NSCLC in Study JMENFigure 7: Kaplan-Meier Curves for Overall Survival in Squamous NSCLC in Study JMENMaintenance Treatment Following First-line Pemetrexedfor injection Plus Platinum Chemotherapy The efficacy of pemetrexed as maintenance therapy following first-line platinum-based chemotherapy was also evaluated in PARAMOUNT (NCT00789373), multi-center, randomized (2:1), double-blind, placebo-controlled study conducted in patients with Stage IIIb/IV non-squamous NSCLC who had completed four cycles of pemetrexed in combination with cisplatin and achieved complete response (CR) or partial response (PR) or stable disease (SD). Patients were required to have an ECOG PS of or 1. Patients were randomized to receive pemetrexed 500 mg/m2 intravenously every 21 days or placebo until disease progression. Randomization was stratified by response to pemetrexedfor injection in combination with cisplatin induction therapy (CR or PR versus SD), disease stage (IIIb versus IV), and ECOG PS (0 versus 1). Patients in both arms received folic acid, vitamin B12, and dexamethasone. The main efficacy outcome measure was investigator-assessed progression-free survival (PFS) and an additional efficacy outcome measure was overall survival (OS); PFS and OS were measured from the time of randomization.A total of 539 patients were enrolled with 359 patients randomized to pemetrexedfor injection and 180 patients randomized to placebo. The median age was 61 years (range 32 to 83 years); 58% were male; 95% were White, 4.5% were Asian, and <1% were Black or African American; 67% had an ECOG PS of 1; 78% were current or former smokers; and 43% of the population achieved partial or complete response to first-line, platinum-based chemotherapy. With regard to tumor characteristics, 91% had Stage IV disease, 87% had adenocarcinoma, 7% had large cell, and 6% had other histologies. Efficacy results for PARAMOUNT are presented in Table 15 and Figure 8. Table 15: Efficacy Results in PARAMOUNTEfficacy Parameter Pemetrexed for InjectionPlacebo (N=180) Overall survival Median (months) (95% CI) 13.9 (12.8 16.0) 11.0 (10.0 12.5) Hazard ratio (HR)a (95% CI) 0.78 (0.64 0.96)p-value p=0.02Progression-free survivalb Median (months) (95% CI) 4.1 (3.2 4.6) 2.8 (2.6 3.1) Hazard ratio (HR)a (95% CI) 0.62 (0.49 -0.79)p-value p<0.0001a Hazard ratios are adjusted for multiplicity but not for stratification variables. Based on investigators assessment.Figure 8: Kaplan-Meier Curves for Overall Survival in PARAMOUNTTreatment of Recurrent Disease After Prior Chemotherapy The efficacy of pemetrexed for injectionwas evaluated in Study JMEI (NCT00004881), multicenter, randomized (1:1), open-label study conducted in patients with Stage III or IV NSCLC that had recurred or progressed following one prior chemotherapy regimen for advanced disease. Patients were randomized to receive pemetrexed 500 mg/m2 intravenously or docetaxel 75 mg/m2 as 1-hour intravenous infusion once every 21 days. Patients randomized to pemetrexedfor injection also received folic acid and vitamin B12. The study was designed to show that overall survival with pemetrexedfor injection was non-inferior to docetaxel, as the major efficacy outcome measure, and that overall survival was superior for patients randomized to pemetrexed compared to docetaxel, as secondary outcome measure. total of 571 patients were enrolled with 283 patients randomized to pemetrexedfor injection and 288 patients randomized to docetaxel. The median age was 58 years (range 22 to 87 years); 72% were male; 71% were White, 24% were Asian, 2.8% were Black or African American, 1.8% were Hispanic or Latino, and <2% were other ethnicities; 88% had an ECOG PS of or 1. With regard to tumor characteristics, 75% had Stage IV disease; 53% had adenocarcinoma, 30% had squamous histology; 8% large cell; and 9% had other histologic subtypes of NSCLC. The efficacy results in the overall population and in subgroup analyses based on histologic subtype are provided in Tables 16 and 17, respectively. Study JMEI did not show an improvement in overall survival in the intent-to-treat population. In subgroup analyses, there was no evidence of treatment effect on survival in patients with squamous NSCLC; the absence of treatment effect in patients with NSCLC of squamous histology was also observed Studies JMDB and JMEN [see Clinical Studies (14.1)].Table 16: Efficacy Results in Study JMEI Efficacy ParameterPemetrexed for Injection(N=283)Docetaxel(N=288)Overall survival Median (months) (95% CI) 8.3 (7.0- 9.4)7.9 (6.3 9.2)Hazard ratioa (95% CI) 0.99 (0.82 to 1.20)Progression-free survival Median (months) (95% CI) 2.9 (2.4-3.1)2.9 (2.7 -3.4)Hazard ratioa (95% CI) 0.97 (0.82-1.16)Overall response rate (95% CI) 8.5% (5.2 -11.7)8.3% (5.1- 11.5)a Hazard ratios are not adjusted for multiplicity or for stratification variables.Table 17: Exploratory Efficacy Analyses by Histologic Subgroup in Study JMEI Histologic SubgroupsPemetrexed for InjectionDocetaxel (N=288)Non-squamous NSCLC (N=399) Median (months) (95% CI) 9.3 (7.8 -9.7)8.0 (6.3 9.3)HRa (95% CI) 0.89 (0.71- 1.13)Adenocarcinoma (N=301) Median (months) (95% CI) 9.0 (7.6- 9.6)9.2 (7.5 -11.3) HRa (95% CI) 1.09 (0.83 -1.44)Large Cell (N=47) Median (months) (95% CI) 12.8 (5.8 14.0)4.5 (2.3- 9.1)HRa (95% CI) 0.38 (0.18- 0.78)Otherb (N=51) Median (months) (95% CI) 9.4 (6.0 10.1)7.9 (4.0 8.9)HRa (95% CI) 0.62 (0.32 1.23)Squamous NSCLC (N=172) Median (months) (95% CI) 6.2 (4.9 8.0)7.4 (5.6 9.5)HRa (95% CI) 1.32 (0.93 1.86)a Hazard ratio unadjusted for multiple comparisons. Primary diagnosis of NSCLC not specified as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma.. 14.2 Mesothelioma. The efficacy of pemetrexedfor injection was evaluated in Study JMCH (NCT00005636), multicenter, randomized (1:1), single-blind study conducted in patients with MPM who had received no prior chemotherapy. Patients were randomized (n=456) to receive pemetrexed 500 mg/m2 intravenously over 10 minutes followed 30 minutes later by cisplatin 75 mg/m2 intravenously over two hours on Day of each 21-day cycle or to receive cisplatin 75 mg/m2 intravenously over hours on Day of each 21-day cycle; treatment continued until disease progression or intolerable toxicity. The study was modified after randomization and treatment of 117 patients to require that all patients receive folic acid 350 mcg to 1000 mcg daily beginning to weeks prior to the first dose of pemetrexed for injectionand continuing until to weeks after the last dose, vitamin B12 1000 mcg intramuscularly to weeks prior to first dose of pemetrexedfor injection and every weeks thereafter, and dexamethasone mg orally, twice daily, for days starting the day prior to each pemetrexed dose. Randomization was stratified by multiple baseline variables including KPS, histologic subtype (epithelial, mixed, sarcomatoid, other), and gender. The major efficacy outcome measure was overall survival and additional efficacy outcome measures were time to disease progression, overall response rate, and response duration. total of 448 patients received at least one dose of protocol-specified therapy; 226 patients were randomized to and received at least one dose of pemetrexed plus cisplatin, and 222 patients were randomized to and received cisplatin. Among the 226 patients who received cisplatin with pemetrexed for injection, 74% received full supplementation with folic acid and vitamin B12 during study therapy, 14% were never supplemented, and 12% were partially supplemented. Across the study population, the median age was 61 years (range: 20 to 86 years); 81% were male; 92% were White, 5% were Hispanic or Latino, 3.1% were Asian, and <1% were other ethnicities; and 54% had baseline KPS score of 90-100% and 46% had KPS score of 70-80%. With regard to tumor characteristics, 46% had Stage IV disease, 31% Stage III, 15% Stage II, and 7% Stage disease at baseline; the histologic subtype of mesothelioma was epithelial in 68% of patients, mixed in 16%, sarcomatoid in 10% and other histologic subtypes in 6%. The baseline demographics and tumor characteristics of the subgroup of fully supplemented patients was similar to the overall study population. The efficacy results from Study JMCH are summarized in Table 18 and Figure 9.Table 18: Efficacy Results in Study JMCH Efficacy ParameterAll Randomized and Treated Patients(N=448)Fully Supplemented Patients (N=331)Pemetrexed for Injection /Cisplatin(N=226)Cisplatin(N=222)pemetrexed for Injection /Cisplatin(N=168)Cisplatin(N=163)Median overall survival (months) 12.19.313.310.0(95% CI) (10.0 to 14.4)(7.8 to 10.7)(11.4 to 14.9)(8.4 to11.9)Hazard ratioa 0.770.75Log rank p-value 0.020NAb aHazard ratios are not adjusted for stratification variablesb Not pre-specified analysis. Figure 9: Kaplan-Meier Curves for Overall Survival in Study JMCH Based upon prospectively defined criteria (modified Southwest Oncology Group methodology) the objective tumor response rate for pemetrexedfor injection plus cisplatin was greater than the objective tumor response rate for cisplatin alone. There was also improvement in lung function (forced vital capacity) in the pemetrexedfor injection plus cisplatin arm compared to the control arm.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. o The recommended dose of pemetrexed for injection administered with pembrolizumab and platinum chemotherapy in patients with creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes, administered after pembrolizumab and prior to platinum chemotherapy, on Day of each 21-day cycle. (2.1)oThe recommended dose of pemetrexed for injection, administered as single agent or with cisplatin, in patients with creatinine clearance of 45 mL/minute or greater is 500 mg/m2 as an intravenous infusion over 10 minutes on Day of each 21-day cycle. (2.1, 2.2)oInitiate folic acid 400 mcg to 1000 mcg orally, once daily, beginning days prior to the first dose of pemetrexed for injection and continue until 21 days after the last dose of pemetrexed for injection (2.4) oAdminister vitamin B12, mg intramuscularly, week prior to the first dose of pemetrexed for injection and every cycles. (2.4) oAdminister dexamethasone mg orally, twice daily the day before, the day of, and the day after pemetrexed for injection administration. (2.4) 2.1 Recommended Dosage for Non-Squamous NSCLC o The recommended dose of pemetrexed for injection when administered with pembrolizumab and platinum chemotherapy for the initial treatment of metastatic non-squamous NSCLC in patients with creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes administered after pembrolizumab and prior to carboplatin or cisplatin on Day of each 21-day cycle for cycles. Following completion of platinum-based therapy, treatment with pemetrexed for injection with or without pembrolizumab is administered until disease progression or unacceptable toxicity. Please refer to the full prescribing information for pembrolizumab and for carboplatin or cisplatin.o The recommended dose of pemetrexed for injection when administered with cisplatin for initial treatment of locally advanced or metastatic non-squamous NSCLC in patients with creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes administered prior to cisplatin on Day of each 21-day cycle for up to six cycles in the absence of disease progression or unacceptable toxicity. The recommended dose of pemetrexed for injection for maintenance treatment ofnon-squamous NSCLC in patients with creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes on Day 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 for injection for treatment of recurrent NSCLC in patients with creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes on Day of each 21 day cycle until disease progression or unacceptable toxicity. The recommended dose of pemetrexed for injection when administered with carboplatin and pembrolizumab for the initial treatment of NSCLC in patients with creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 administered as an intravenous infusion over 10 minutes prior to carboplatin on Day of each 21 day cycle for cycles. Following completion of platinum-based therapy, pemetrexed for injection may be administered as maintenance therapy, alone or with pembrolizumab, until disease progression or unacceptable toxicity. Pembrolizumab should be administered prior to pemetrexed for injection when given on the same day. Please refer to the full prescribing information for pembrolizumab and for carboplatin.. 2.2 Recommended Dosage for Mesothelioma o The recommended dose of pemetrexed for injection administered when administered with cisplatin, in patients with creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes on Day of each 21 day cycle until disease progression or unacceptable toxicity. 2.3 Renal Impairment o Pemetrexed for injection dosing recommendations are provided for patients with 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 oInitiate folic acid 400 mcg to 1000 mcg orally once daily, beginning days before the first dose of pemetrexed for injection and continuing until 21 days after the last dose of pemetrexed for injection [see Warnings and Precautions (5.1)]. oAdminister vitamin B12, mg intramuscularly, week prior to the first dose of pemetrexed for injection and every cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with pemetrexed for injection [see Warnings and Precautions (5.1)]. Do not substitute oral vitamin 12 for intramuscular vitamin 12 Corticosteroids Administer dexamethasone mg orally twice daily for three consecutive days, beginning the day before each pemetrexed for injection administration. 2.5 Dosage Modification of Ibuprofen in Patients with Mild to Moderate Renal Impairment Receiving Pemetrexed for 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 days before, the day of, and days following administration of pemetrexed for injection. Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided. 2.6 Dosage Modifications for Adverse Reactions Obtain complete blood count on Days 1, 8, and 15 of each cycle. Assess creatinine clearance prior to each cycle. Do not administer pemetrexed for injection if the creatinine clearance is less than 45 mL/min. Delay initiation of the next cycle of pemetrexed for injection until: recovery of non-hematologic toxicity to Grade to 2, absolute neutrophil count (ANC) is 1500 cells/mm3 or higher, and platelet count is 100,000 cells/mm3 or higher. Upon recovery, modify the dosage of pemetrexed for injection in the next cycle as specified in Table 1. For dosing modifications for cisplatin, refer to the prescribing information for cisplatin. For dosing modifications for cisplatin, carboplatin, or pembrolizumab, refer to their prescribing information.Table 1: Recommended Dosage Modifications for Adverse Reactionsa Toxicity in Most Recent Treatment Cycle Pemetrexed for Injection Dose Modification for Next Cycle Myelosuppressive toxicity [see Warnings and Precautions (5.1)] ANC less than 500/mm3 and platelets greater than or equal to 50,000/mm3 OR Platelet count less than 50,000/mm3 without bleeding. 75% of previous dose Platelet count less than 50,000/mm3 with bleeding 50% of previous dose Recurrent Grade or myelosuppression after dose reductions Discontinue Non-hematologic toxicity Any Grade or toxicities EXCEPT mucositis or neurologic toxicity OR Diarrhea requiring hospitalization 75% of previous dose Grade or mucositis 50% of previous dose Renal toxicity [see Warnings and Precautions (5.2)] Withhold until creatinine clearance is 45 mL/min or greater Grade or neurologic toxicity Permanently discontinue Recurrent Grade or non-hematologic toxicity after dose reductions Permanently discontinue Severe and life-threatening Skin Toxicity [see Warnings and Precautions (5.3)] Permanently discontinue Interstitial Pneumonitis [see Warnings and Precautions (5.4)] Permanently discontinue National Cancer Institute Common Toxicity Criteria for Adverse Events version (NCI CTCAE v2).. 2.7 Preparation for Administration o Pemetrexed for injection is cytotoxic drug. Follow applicable special handling and disposal procedures.1 Calculate the dose of pemetrexed for injection and determine the number of vials needed. Reconstitute pemetrexed for injection to achieve concentration of 25 mg/mL as follows: Reconstitute each 100-mg vial with 4.2 mL of 0.9% Sodium Chloride Injection, USP (preservative-free) Reconstitute each 500-mg vial with 20 mL of 0.9% Sodium Chloride Injection, USP (preservative-free)- Reconstitute each g vial with 40 mL of 0.9% Sodium Chloride Injection, USP (preservative-free)- Do not use calcium-containing solutions for reconstitution. Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in color from colorless to yellow or green-yellow. FURTHER DILUTION IS REQUIRED prior to administration. Store reconstituted, preservative-free product under refrigerated conditions to 8C (36 to 46F) or 20 to 25C (68 to 77F) for no longer than 24 hours from the time of reconstitution. Discard vial after 24 hours. Inspect reconstituted product visually for particulate matter and discoloration prior to further dilution. If particulate matter is observed, discard vial. Withdraw the calculated dose of pemetrexed for injection from the vial(s) and discard vial with any unused portion. Further dilute pemetrexed for injection with 0.9% Sodium Chloride Injection (preservative-free) to achieve total volume of 100 mL for intravenous infusion. Store diluted, reconstituted product under refrigerated conditions to 8C (36 to 46F) or 20 to 25C (68 to 77F) for no more than 24 hours from the time of reconstitution. Discard after 24 hours.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION PEMETREXED FOR INJECTION (pem-e-TREX-ed) What is Pemetrexed for Injection Pemetrexed for injection is prescription medicine used to treat: a kind of lung cancer called non-squamous non-small cell lung cancer (NSCLC). Pemetrexed for injection is used: -as the first treatment in combination with pembrolizumab and platinum chemotherapy when your lung cancer with no abnormal EGFR or ALK gene has spread (advanced NSCLC). -as the first treatment in combination with cisplatin when your lung cancer has spread (advanced NSCLC). -alone as maintenance treatment after you have received cycles of chemotherapy that contains platinum for first treatment of your advanced NSCLC and your cancer has not progressed. alone when your lung cancer has returned or spread after prior chemotherapy. a kind of cancer called malignant pleural mesothelioma. This cancer affects the lining of the lungs and chest wall. Pemetrexed for injection is used in combination with cisplatin as the first treatment for malignant pleural mesothelioma that cannot be removed by surgery or you are not able to have surgery. It is not known if pemetrexed for Injection is safe and effective in children. Do not take pemetrexed for injection: if you have had severe allergic reaction to any medicine that contains pemetrexed. Before taking pemetrexed for injection, tell your healthcare provider about all of your medical conditions, including if you: have kidney problems. have had radiation therapy. are pregnant or plan to become pregnant. pemetrexed for injection can harm your unborn baby. Females who are able to become pregnant should use effective birth control (contraception) during treatment with pemetrexed for injection and for months after the final dose. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with pemetrexed for Injection. Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment with pemetrexed for injection and for months after the final dose. are breastfeeding or plan to breastfeed. It is not known if pemetrexed for injection passes into breast milk. Do not breastfeed during treatment with pemetrexed for Injection and for week after the final dose. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Tell your healthcare provider if you have kidney problems and take medicine that contains ibuprofen. You should avoid taking ibuprofen for days before, the day of, and days after receiving treatment with pemetrexed for injection. How is Pemetrexed for injection given It is very important to take folic acid and vitamin B12 during your treatment with pemetrexed for injection to lower your risk of harmful side effects. Take folic acid exactly as prescribed by your healthcare provider time day, beginning days (1 week) before your first dose of pemetrexed for Injection and continue taking folic acid until 21 days (3 weeks) after your last dose of pemetrexed for injection. Your healthcare provider will give you vitamin B12 injections during treatment with pemetrexed for injection. You will get your first vitamin B12 injection days (1 week) before your first dose of pemetrexed for injection, and then every cycles. Your healthcare provider will prescribe medicine called corticosteroid for you to take times day for days, beginning the day before each treatment with pemetrexed for injection. Pemetrexed for injection is given to you by intravenous (IV) infusion into your vein. The infusion is given over 10 minutes. Pemetrexed for injection is usually given once every 21 days (3 weeks). What are the possible side effects of Pemetrexed for Injection Pemetrexed for injection can cause serious side effects, including: Low blood cell counts. Low blood cell counts can be severe, including low white blood cell counts (neutropenia), low platelet counts (thrombocytopenia), and low red blood cell counts (anemia). Your healthcare provider will do blood test to check your blood cell counts regularly during your treatment with pemetrexed for injection. Tell your healthcare provider right away if you have any signs of infection, fever, bleeding, or severe tiredness during your treatment with pemetrexed for injection. Kidney problems, including kidney failure. Pemetrexed for injection can cause severe kidney problems that can lead to death. Severe vomiting or diarrhea can lead to loss of fluids (dehydration) which may cause kidney problems to become worse. Tell your healthcare provider right away if you have decrease in amount of urine. oSevere skin reactions. Severe skin reactions that may lead to death can happen with pemetrexed injection. Tell your healthcare provider right away if you develop blisters, skin sores, skin peeling, or painful sores, or ulcers in your mouth, nose, throat or genital area. Lung problems (pneumonitis). Pemetrexed for injection can cause serious lung problems that can lead to death. Tell your healthcare provider right away if you get any new or worsening symptoms of shortness of breath, cough, or fever. Radiation recall. Radiation recall is skin reaction that can happen in people who have received radiation treatment in the past and are treated with pemetrexed for injection. Tell your healthcare provider if you get swelling, blistering, or rash that looks like sunburn in an area that was previously treated with radiation. The most common side effects of pemetrexed for Injection when given alone are: tiredness nausea loss of appetite The most common side effects of pemetrexed for Injection when given with cisplatin are: vomiting low white blood cell counts (neutropenia) swelling or sores in your mouth or sore throat low platelet counts (thrombocytopenia) constipation low red blood cell counts (anemia) The most common side effects of pemetrexed for injection when given with pembrolizumab and platinum chemotherapy are: tiredness/weakness constipation loss of appetite vomiting shortness of breath nausea diarrhea rash cough feverPemetrexed for injection may cause fertility problems in males. This may affect your ability to father child. It is not known if these effects are reversible. Talk to your healthcare provider if this is concern for you. Your healthcare provider will do blood test to check for side effects during treatment with pemetrexed for injection. Your healthcare provider may change your dose of pemetrexed for Injection, delay treatment, or stop treatment if you have certain side effects. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the side effects of pemetrexed for injection. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of Pemetrexed for Injection. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about pemetrexed for injection that is written for health professionals. What are the ingredients in Pemetrexed for Injection Active ingredient: pemetrexed Inactive ingredients:mannitol, hydrochloric acid and/or sodium hydroxide may have been added to adjust pH. For more information, call 1-888-375-3784.To reorder additional patient information sheets, please contact Dr. Reddys Customer Service at 1-866-733-3952. This Patient Information has been approved by the U.S. Food and Drug Administration. Rx Only Distributor: Dr. Reddys Laboratories Inc., Princeton, NJ 08540 Made in IndiaIssued:0719.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on findings from animal studies and its mechanism of action, pemetrexed for injection can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on pemetrexed for 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/m2 [see Data]. Advise pregnant women of the potential risk to 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 to 4% and 15 to 20%, respectively. DataAnimal DataPemetrexed 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/m2. At doses, based on BSA, greater than or equal to 0.0012 times the 500 mg/m2 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 SummaryThere 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 for injection, advise women not to breastfeed during treatment with pemetrexed for injection and for one week after last dose. 8.3 Females and Males of Reproductive Potential ContraceptionFemales Pemetrexed for injection can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with pemetrexed for injection for at least months after the final dose of pemetrexed for injection. MalesBecause of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with pemetrexed for injection and for months after the final dose [see Nonclinical Toxicology (13.1)]. InfertilityMalesPemetrexed for 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 for injection in pediatric patients have not been established. The safety and pharmacokinetics of pemetrexed for injection were evaluated in two clinical studies conducted in pediatric patients with recurrent solid tumors. Pemetrexed for injection was administered at doses ranging from 400 to 2,480 mg/m2 intravenously over 10 minutes on Day of 21-day cycle to 32 pediatric patients with recurrent solid tumors in dose-finding study. The maximum tolerated dose (MTD) was determined to be 1,910 mg/m2 (60 mg/kg for patients <12 months old). Pemetrexed for injection was administered at the MTD every 21 days in an activity-estimating study enrolling 72 patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral primitive neural ectodermal tumor (PNET), rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, or non-brainstem high grade glioma. Patients in both studies received concomitant vitamin B12 and folic acid supplementation and dexamethasone. No tumor responses were observed. Adverse reactions observed in pediatric patients were similar to those observed in adults. Single-dose pharmacokinetics of pemetrexed for injection administered at doses ranging from 400 to 2,480 mg/m2 were evaluated in 22 patients (13 males and females) age to 18 years (average age 12 years). Pemetrexed exposure (AUC and Cmax) appeared to increase proportionally with dose. Average clearance (2.30 L/h/m2) and half-life (2.3 hours) were similar in pediatric patients compared to adults.. 8.5 Geriatric Use. Of the 3,946 patients enrolled in clinical studies of pemetrexed for injection, 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 to anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher in patients 65 years of age and older as compared to younger patients: in at least one of five randomized clinical trials. [see Adverse Reactions (6.1) and Clinical Studies (14.1, 14.2)].. 8.6 Patients with Renal Impairment Pemetrexed for injection is primarily excreted by the kidneys. Decreased renal function results in reduced clearance and greater exposure (AUC) to pemetrexed for injection compared with patients with normal renal function [Warnings and Precautions (5.2, 5.6) and Clinical Pharmacology (12.3)]. No dose is recommended for patients with creatinine clearance less than 45 mL/min [see Dosage and Administration (2.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. o Myelosuppression: Can cause severe bone marrow suppression resulting in cytopenia and an increased risk of infection. Do not administer pemetrexed for injection when the absolute neutrophil count is less than 1500 cells/mm3 and platelets are less than 100,000 cells/mm3.Initiate supplementation with oral folic acid and intramuscular vitamin B12 to reduce the severity of hematologic and gastrointestinal toxicity of pemetrexed for injection (2.4, 5.1) Renal Failure:Can cause severe, and sometimes fatal, renal failure. Do not administer when creatinine clearance is less than 45 mL/min. (2.3, 5.2) Bullous and Exfoliative Skin Toxicity: Permanently discontinue for severe and life-threatening bullous, blistering or exfoliating skin toxicity. (5.3) Interstitial Pneumonitis: Withhold for acute onset of new or progressive unexplained pulmonary symptoms. Permanently discontinue if pneumonitis is confirmed. (5.4) Radiation Recall: Can occur in patients who received radiation weeks to years previously; permanently discontinue for signs of radiation recall. (5.5) Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to fetus and to use effective contraception. (5.7, 8.1, 8.3) 5.1 Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation Pemetrexed forinjection can cause severe myelosuppression resulting in requirement for transfusions and which may lead to neutropenic infection. The risk of myelosuppression is increased in patients who do not receive vitamin supplementation. In Study JMCH, incidences of Grade to neutropenia (38% versus 23%), thrombocytopenia (9% versus 5%), febrile neutropenia (9% versus 0.6%), and neutropenic infection (6% versus 0) were higher in patients who received pemetrexed plus cisplatin without vitamin supplementation as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout pemetrexed plus cisplatin treatment. Initiate supplementation with oral folic acid and intramuscular vitamin B12 prior to the first dose of pemetrexed; continue vitamin supplementation during treatment and for 21 days after the last dose of pemetrexed to reduce the severity of hematologic and gastrointestinal toxicity of pemetrexed for injection [see Dosage and Administration (2.4)]. Obtain complete blood count at the beginning of each cycle. Do not administer pemetrexed for injection until the ANC is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3. Permanently reduce pemetrexed for injection in patients with an ANC of less than 500 cells/mm3 or platelet count of less than 50,000 cells/mm3 in previous cycles [see Dosage and Administration (2.6)]. In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade to neutropenia was 15% and 23%, the incidence of Grade to anemia was 6% and 4%, and incidence of Grade to thrombocytopenia was 4% and 5%, respectively. In Study JMCH, 18% of patients in the pemetrexed for injection arm required red blood cell transfusions compared to 7% of patients in the cisplatin arm [see Adverse Reactions (6.1)]. In Studies JMEN, PARAMOUNT, and JMEI, where all patients received vitamin supplementation, incidence of Grade to neutropenia ranged from 3% to 5%, and incidence of Grade to anemia ranged from 3% to 5%. 5.2 Renal Failure Pemetrexed for injection can cause severe, and sometimes fatal, renal toxicity. The incidences of renal failure in clinical studies in which patients received pemetrexed with cisplatin were: 2.1% in Study JMDB and 2.2% in Study JMCH. The incidence of renal failure in clinical studies in which patients received pemetrexed for injection as single agent ranged from 0.4% to 0.6% (Studies JMEN, PARAMOUNT, and JMEI [see Adverse Reactions (6.1)]. Determine creatinine clearance before each dose and periodically monitor renal function during treatment with pemetrexed for injection. Withhold pemetrexed for injection in patients with creatinine clearance of less than 45 mL/minute [see Dosage and Administration (2.3)]. 5.3 Bullous and Exfoliative Skin Toxicity Serious and sometimes fatal, bullous, blistering and exfoliative skin toxicity, including cases suggestive of Stevens-Johnson Syndrome/Toxic epidermal necrolysis can occur with pemetrexed for injection. Permanently discontinue pemetrexed for severe and life-threatening bullous, blistering or exfoliating skin toxicity. 5.4 Interstitial Pneumonitis Serious interstitial pneumonitis, including fatal cases, can occur with pemetrexed for injection treatment. Withhold pemetrexed for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation. If pneumonitis is confirmed, permanently discontinue pemetrexed. 5.5 Radiation Recall Radiation recall can occur with pemetrexed for injection in patients who have received radiation weeks to years previously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue pemetrexed for injection for signs of radiation recall. 5.6 Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment Exposure to pemetrexed is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen, increasing the risks of adverse reactions of pemetrexed. In patients with creatinine clearances between 45 mL/min and 79 mL/min, avoid administration of ibuprofen for days before, the day of, and days following administration of pemetrexed. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for pemetrexed adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity [see Dosage and Administration (2.5), Drug Interactions (7), and Clinical Pharmacology (12.3)]. 5.7 Embryo-Fetal Toxicity. Based on findings from animal studies and its mechanism of action, pemetrexed can cause fetal harm when administered to pregnant woman. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and increased malformations at doses lower than the recommended human dose of 500 mg/m2. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with pemetrexed and for months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with pemetrexed and for months after the final dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].