PHARMACOKINETICS SECTION.

12.3Pharmacokinetics. AbsorptionThe pharmacokinetics of pemetrexed 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.. DistributionPemetrexed 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.. MetabolismPemetrexed 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 GroupsThe 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 FluidThe 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 TransporterIbuprofen, 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 StudiesPemetrexed 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.. AspirinAspirin, administered in low to moderate doses (325 mg every hours), does not affect the pharmacokinetics of pemetrexed.. CisplatinCisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed.. VitaminsNeither 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.

ADVERSE REACTIONS SECTION.

6ADVERSE 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)] 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 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.. The most common adverse reactions (incidence >=20%) of pemetrexed when administered as 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). 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 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 CisplatinThe safety of pemetrexed 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 500 mg/m2 intravenously and cisplatin 75 mg/m2 intravenously on Day of each 21-day cycle (n=839) or gemcitabine 1250 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 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 median of cycles of pemetrexed.Table 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 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 JMDBAdverse ReactionNCI CTCAE version 2.0 Pemetrexed/Cisplatin (N=839)Gemcitabine/Cisplatin (N=830)All Grades (%)Grade 3-4 (%)All Grades (%)Grade 3-4 (%)All adverse reactions90379153 Laboratory Hematologic Anemia3364610 Neutropenia29153827 Thrombocytopenia1042713RenalElevated creatinine10171Clinical Constitutional symptoms Fatigue437455Gastrointestinal Nausea567534 Vomiting406366 Anorexia272241 Constipation211200 Stomatitis/pharyngitis141120 Diarrhea121132 Dyspepsia/heartburn5060Neurology Sensory neuropathy90121 Taste disturbance8090Dermatology/Skin Alopecia120211 Rash/Desquamation7081The 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 -- 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 Containing Platinum-Based ChemotherapyIn Study JMEN, the safety of pemetrexed 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 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 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 and relative dose intensity of pemetrexed 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.Table provides the frequency and severity of adverse reactions reported in >=5% of the 438 pemetrexed-treated patients in Study JMEN.Table 3: Adverse Reactions Occurring in >=5% of Patients Receiving Pemetrexed in Study JMENAdverse ReactionNCI CTCAE version 3.0 Pemetrexed/Cisplatin (N=438)Placebo (N=218)All Grades (%)Grade 3-4 (%)All Grades (%)Grade 3-4 (%)All adverse reactions6616374 Laboratory Hematologic Anemia15361 Neutropenia6300Hepatic Increased ALT10040 Increased AST8040Clinical Constitutional symptoms Fatigue255111Gastrointestinal Nausea19161 Anorexia19250 Vomiting9010 Mucositis/stomatitis7120 Diarrhea5130Infection5220Neurology Sensory neuropathy9140Dermatology/Skin Rash/Desquamation10030The 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 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, pruritus/itching Gastrointestinal -- constipation General Disorders -- edema, fever Hematologic -- thrombocytopenia Eye Disorder -- ocular surface disease (including conjunctivitis), increased lacrimationIncidence <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 ChemotherapyThe safety of pemetrexed was 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 pemetrexed in 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. Patients in both study arms received folic acid and vitamin B12 supplementation.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 folic acid, vitamin B12 or 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 4: Adverse Reactions Occurring in >=5% of Patients Receiving Pemetrexed in PARAMOUNTAdverse ReactionNCI CTCAE version 3.0 Pemetrexed (N=333)Placebo (N=167)All Grades (%)Grade 3-4 (%)All Grades (%)Grade 3-4 (%)All adverse reactions5317344.8 Laboratory Hematologic Anemia154.84.80.6 Neutropenia93.90.60Clinical Constitutional symptoms Fatigue184.5110.6Gastrointestinal Nausea120.32.40 Vomiting601.80 Mucositis/stomatitis50.32.40General disorders Edema503.60The 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 neutropeniaIncidence <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 ChemotherapyThe safety of pemetrexed 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 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 or corticosteroids were also excluded from the study.The data described below reflect exposure to pemetrexed 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-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 Table below.Table 5: Adverse Reactions Occurring in >=5% of Fully Supplemented Patients Receiving Pemetrexed in Study JMEIAdverse ReactionNCI CTCAE version 2.0 Pemetrexed (N=265)Docetaxel (N=276)All Grades (%)Grade 3-4 (%)All Grades (%)Grade 3-4 (%)Laboratory Hematologic Anemia194224 Neutropenia1154540 Thrombocytopenia8210 Hepatic Increased ALT8210 Increased AST7110Clinical Gastrointestinal Nausea313172 Anorexia222243 Vomiting162121 Stomatitis/pharyngitis151171 Diarrhea130243 Constipation6040Constitutional symptoms Fatigue345365 Fever8080Dermatology/Skin Rash/desquamation14060 Pruritus7020 Alopecia61382The 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 neuropathyIncidence <1%Cardiovascular -- supraventricular arrhythmias Renal -- renal failure. MesotheliomaThe safety of pemetrexed 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 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 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-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 6: Adverse Reactions Occurring in >=5% of Fully Supplemented Subgroup of Patients Receiving Pemetrexed/Cisplatin in Study JMCHIn Study JMCH, 226 patients received at least one dose of pemetrexed 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 in combination with cisplatin (168 patients) or cisplatin alone (163 patients) who received full supplementation with folic acid and vitamin B12 during study therapy. Adverse ReactionNCI CTCAE version 2.0 Pemetrexed/cisplatin (N=168)Cisplatin (N=163)All Grades (%)Grade 3-4 (%)All Grades (%)Grade 3-4 (%)Laboratory Hematologic Neutropenia5623133 Anemia264100 Thrombocytopenia23590Renal Elevated creatinine111101 Decreased creatinine clearance161182Clinical Eye Disorder Conjunctivitis5010Gastrointestinal Nausea8212776 Vomiting5711504 Stomatitis/pharyngitis23360 Anorexia201141 Diarrhea17480 Constipation12171 Dyspepsia5110Constitutional Symptoms Fatigue4810429Metabolism and Nutrition Dehydration7411Neurology Sensory neuropathy100101 Taste disturbance8060Dermatology/Skin Rash16150 Alopecia11060The following additional adverse reactions were observed in patients receiving pemetrexed 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 failureIncidence <1%Cardiovascular -- arrhythmia Neurology -- motor neuropathy. Exploratory Subgroup Analyses based on Vitamin SupplementationTable provides the results of exploratory analyses of the frequency and severity of NCI CTCAE Grade or adverse reactions reported in more pemetrexed-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 7: Exploratory Subgroup Analysis of Selected Grade 3/4 Adverse Reactions Occurring in Patients Receiving Pemetrexed in Combination with Cisplatin with or without Full Vitamin Supplementation in Study JMCHNCI CTCAE version 2.0 Grade 3-4 Adverse ReactionsFully Supplemented Patients N=168 (%)Never Supplemented Patients N=32 (%)Neutropenia2338Thrombocytopenia59Vomiting1131Febrile neutropenia19Infection with Grade 3/4 neutropenia06Diarrhea49The 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%).. hypertension (11% versus 3%),. chest pain (8% versus 6%),. thrombosis/embolism (6% versus 3%).. Additional Experience Across Clinical TrialsSepsis, with or without neutropenia, including fatal cases: 1%Severe esophagitis, resulting in hospitalization: <1%. 6.2Postmarketing Experience. The following adverse reactions have been identified during post-approval use of pemetrexed. 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.Blood and Lymphatic System -- immune-mediated hemolytic anemia Gastrointestinal -- colitis, pancreatitis General Disorders and Administration Site Conditions -- edema Injury, Poisoning, and Procedural Complications -- radiation recall Respiratory -- interstitial pneumonitis Skin -- Serious and fatal bullous skin conditions, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

CLINICAL PHARMACOLOGY SECTION.

12CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. Pemetrexed Injection is 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.. 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.. 12.3Pharmacokinetics. AbsorptionThe pharmacokinetics of pemetrexed 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.. DistributionPemetrexed 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.. MetabolismPemetrexed 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 GroupsThe 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 FluidThe 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 TransporterIbuprofen, 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 StudiesPemetrexed 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.. AspirinAspirin, administered in low to moderate doses (325 mg every hours), does not affect the pharmacokinetics of pemetrexed.. CisplatinCisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed.. VitaminsNeither 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.

14CLINICAL STUDIES. 14.1Non-Squamous NSCLC. Initial Treatment in Combination with CisplatinThe efficacy of pemetrexed 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 pemetrexed 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 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 21-day 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.A total of 1725 patients were enrolled with 862 patients randomized to pemetrexed 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 and Figure 1.Table 8: Efficacy Results in Study JMDBEfficacy ParameterPemetrexed plus Cisplatin (N=862)Gemcitabine plus Cisplatin (N=863)Overall Survival Median (months)10.310.3 (95% CI)(9.8-11.2)(9.6-10.9) Hazard ratio (HR)Unadjusted for multiple comparisons. Adjusted for gender, stage, basis of diagnosis, and performance status. 0.94 (95% CI)(0.84-1.05)Progression-Free Survival Median (months)4.85.1 (95% CI)(4.6-5.3)(4.6-5.5) Hazard ratio (HR) 1.04 (95% CI)(0.94-1.15)Overall Response Rate27.1%24.7%(95% CI)(24.2-30.1)(21.8-27.6)Figure 1: Kaplan-Meier Curves for Overall Survival in Study JMDBIn 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 and Figures and 3. This difference in treatment effect for pemetrexed based on histology demonstrating lack of efficacy in squamous cell histology was also observed in Studies JMEN and JMEI.Table 9: Overall Survival in NSCLC Histologic Subgroups in Study JMDBHistologic SubgroupsPemetrexed plus Cisplatin(N=862)Gemcitabine plus Cisplatin(N=863)Non-squamous NSCLC (N=1252) Median (months)11.010.1 (95% CI)(10.1-12.5)(9.3-10.9) HRUnadjusted for multiple comparisons. Adjusted for ECOG PS, gender, disease stage, and basis for pathological diagnosis (histopathological/cytopathological). 0.84 (95% CI)(0.74-0.96)Adenocarcinoma (N=847) Median (months)12.610.9 (95% CI)(10.7-13.6)(10.2-11.9) HR 0.84 (95% CI)(0.71-0.99)Large Cell (N=153) Median (months)10.46.7 (95% CI)(8.6-14.1)(5.5-9.0) HR 0.67 (95% CI)(0.48-0.96)Non-squamous, not otherwise specified (N=252) Median (months)8.69.2 (95% CI)(6.8-10.2)(8.1-10.6) HR 1.08 (95% CI)(0.81-1.45)Squamous Cell (N=473) Median (months)9.410.8 (95% CI)(8.4-10.2)(9.5-12.1) HR 1.23 (95% CI)(1.00-1.51)Figure 2: Kaplan-Meier Curves for Overall Survival in Non-squamous NSCLC in Study JMDBFigure 3: Kaplan-Meier Curves for Overall Survival in Squamous NSCLC in Study JMDB. Figure 1. Figure 2. Figure 3. Maintenance Treatment Following First-line Non-Pemetrexed Containing Platinum-Based ChemotherapyThe 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.A total of 663 patients were enrolled with 441 patients randomized to pemetrexed and 222 patients randomized to placebo. The median age was 61 years (range 26-83 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 10 and Figure 4.Table 10: Efficacy Results in Study JMENEfficacy ParameterPemetrexedPlaceboOverall survivalN=441N=222 Median (months)13.410.6 (95% CI)(11.9-15.9)(8.7-12.0) Hazard ratioHazard ratios are adjusted for multiplicity but not for stratification variables. 0.79 (95% CI)(0.65-0.95) p-valuep=0.012Progression-free survival per independent reviewN=387N=194 Median (months)4.02.0 (95% CI)(3.1-4.4)(1.5-2.8) Hazard ratio 0.60 (95% CI)(0.49-0.73)p-valuep<0.00001Figure 4: Kaplan-Meier Curves for Overall Survival in Study JMENThe results of pre-specified subgroup analyses by NSCLC histology are presented in Table 11 and Figures and 6.Table 11: Efficacy Results in Study JMEN by Histologic SubgroupEfficacy ParameterOverall SurvivalProgression-Free Survival Per Independent ReviewPemetrexed (N=441)Placebo (N=222)Pemetrexed (N=387)Placebo (N=194)Non-squamous NSCLC (n=481) Median (months)15.510.34.41.8 HRHazard ratios are not adjusted for multiplicity 0.700.47 (95% CI)(0.56-0.88)(0.37-0.60)Adenocarcinoma (n=328) Median (months)16.811.54.62.7 HR 0.730.51 (95% CI)(0.56-0.96)(0.38-0.68)Large cell carcinoma (n=20) Median (months)8.47.94.51.5 HR 0.980.40 (95% CI)(0.36-2.65)(0.12-1.29)OtherPrimary diagnosis of NSCLC not specified as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma. (n=133) Median (months)11.37.74.11.6 HR 0.610.44 (95% CI)(0.40-0.94)(0.28-0.68)Squamous cell NSCLC (n=182) Median (months)9.910.82.42.5 HR 1.071.03 (95% CI)(0.77-1.50)(0.71-1.49)Figure 5: Kaplan-Meier Curves for Overall Survival in Non-squamous NSCLC in Study JMENFigure 6: Kaplan-Meier Curves for Overall Survival in Squamous NSCLC in Study JMEN. Figure 4. Figure 5. Figure 6. Maintenance Treatment Following First-line Pemetrexed Plus Platinum ChemotherapyThe 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 pemetrexed 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 pemetrexed 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 12 and Figure 7.Table 12: Efficacy Results in PARAMOUNTEfficacy ParameterPemetrexed (N=359)Placebo (N=180)Overall survival Median (months)13.911.0 (95% CI)(12.8-16.0)(10.0-12.5) Hazard ratio (HR)Hazard ratios are adjusted for multiplicity but not for stratification variables. 0.78 (95% CI)(0.64-0.96) p-valuep=0.02Progression-free survivalBased on investigators assessment. Median (months)4.12.8 (95% CI)(3.2-4.6)(2.6-3.1) Hazard ratio (HR) 0.62 (95% CI)(0.49-0.79) p-valuep<0.0001Figure 7: Kaplan-Meier Curves for Overall Survival in PARAMOUNT. Figure 7. Treatment of Recurrent Disease After Prior ChemotherapyThe efficacy of pemetrexed was 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 pemetrexed also received folic acid and vitamin B12. The study was designed to show that overall survival with pemetrexed 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.A total of 571 patients were enrolled with 283 patients randomized to pemetrexed 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 13 and 14, 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 in Studies JMDB and JMEN [see Clinical Studies (14.1)].Table 13: Efficacy Results in Study JMEIEfficacy ParameterPemetrexed (N=283)Docetaxel (N=288)Overall survival Median (months)8.37.9 (95% CI)(7.0-9.4)(6.3-9.2) Hazard ratioHazard ratios are not adjusted for multiplicity or for stratification variables. 0.99 (95% CI)(0.82-1.20)Progression-free survival Median (months)2.92.9 (95% CI)(2.4-3.1)(2.7-3.4) Hazard ratio 0.97 (95% CI)(0.82-1.16)Overall response rate8.5%8.3% (95% CI)(5.2-11.7)(5.1-11.5)Table 14: Exploratory Efficacy Analyses by Histologic Subgroup in Study JMEIHistologic SubgroupsPemetrexed (N=283)Docetaxel (N=288)Non-squamous NSCLC (N=399) Median (months)9.38.0 (95% CI)(7.8-9.7)(6.3-9.3) HRHazard ratio unadjusted for multiple comparisons. 0.89 (95% CI)(0.71-1.13)Adenocarcinoma (N=301) Median (months)9.09.2 (95% CI)(7.6-9.6)(7.5-11.3) HR 1.09 (95% CI)(0.83-1.44)Large Cell (N=47) Median (months)12.84.5 (95% CI)(5.8-14.0)(2.3-9.1) HR 0.38 (95% CI)(0.18-0.78)OtherPrimary diagnosis of NSCLC not specified as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma. (N=51) Median (months)9.47.9 (95% CI)(6.0-10.1)(4.0-8.9) HR 0.62 (95% CI)(0.32-1.23)Squamous NSCLC (N=172) Median (months)6.27.4 (95% CI)(4.9-8.0)(5.6-9.5) HR 1.32 (95% CI)(0.93-1.86). 14.2Mesothelioma. The efficacy of pemetrexed 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 and continuing until to weeks after the last dose, vitamin B12 1000 mcg intramuscularly to weeks prior to first dose of pemetrexed 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.A 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, 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 15 and Figure 8.Table 15: Efficacy Results in Study JMCHEfficacy ParameterAll Randomized and Treated Patients (N=448)Fully Supplemented Patients (N=331)Pemetrexed/Cisplatin (N=226)Cisplatin(N=222)Pemetrexed/Cisplatin (N=168)Cisplatin (N=163)Median overall survival(months)12.19.313.310.0(95% CI)(10.0-14.4)(7.8-10.7)(11.4-14.9)(8.4-11.9)Hazard ratioHazard ratios are not adjusted for stratification variables. 0.770.75Log rank p-value0.020NANot pre-specified analysis. Figure 8: Kaplan-Meier Curves for Overall Survival in Study JMCHBased upon prospectively defined criteria (modified Southwest Oncology Group methodology) the objective tumor response rate for pemetrexed 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 pemetrexed plus cisplatin arm compared to the control arm.. Figure 8.

CLINICAL TRIALS EXPERIENCE SECTION.

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 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 CisplatinThe safety of pemetrexed 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 500 mg/m2 intravenously and cisplatin 75 mg/m2 intravenously on Day of each 21-day cycle (n=839) or gemcitabine 1250 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 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 median of cycles of pemetrexed.Table 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 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 JMDBAdverse ReactionNCI CTCAE version 2.0 Pemetrexed/Cisplatin (N=839)Gemcitabine/Cisplatin (N=830)All Grades (%)Grade 3-4 (%)All Grades (%)Grade 3-4 (%)All adverse reactions90379153 Laboratory Hematologic Anemia3364610 Neutropenia29153827 Thrombocytopenia1042713RenalElevated creatinine10171Clinical Constitutional symptoms Fatigue437455Gastrointestinal Nausea567534 Vomiting406366 Anorexia272241 Constipation211200 Stomatitis/pharyngitis141120 Diarrhea121132 Dyspepsia/heartburn5060Neurology Sensory neuropathy90121 Taste disturbance8090Dermatology/Skin Alopecia120211 Rash/Desquamation7081The 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 -- 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 Containing Platinum-Based ChemotherapyIn Study JMEN, the safety of pemetrexed 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 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 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 and relative dose intensity of pemetrexed 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.Table provides the frequency and severity of adverse reactions reported in >=5% of the 438 pemetrexed-treated patients in Study JMEN.Table 3: Adverse Reactions Occurring in >=5% of Patients Receiving Pemetrexed in Study JMENAdverse ReactionNCI CTCAE version 3.0 Pemetrexed/Cisplatin (N=438)Placebo (N=218)All Grades (%)Grade 3-4 (%)All Grades (%)Grade 3-4 (%)All adverse reactions6616374 Laboratory Hematologic Anemia15361 Neutropenia6300Hepatic Increased ALT10040 Increased AST8040Clinical Constitutional symptoms Fatigue255111Gastrointestinal Nausea19161 Anorexia19250 Vomiting9010 Mucositis/stomatitis7120 Diarrhea5130Infection5220Neurology Sensory neuropathy9140Dermatology/Skin Rash/Desquamation10030The 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 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, pruritus/itching Gastrointestinal -- constipation General Disorders -- edema, fever Hematologic -- thrombocytopenia Eye Disorder -- ocular surface disease (including conjunctivitis), increased lacrimationIncidence <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 ChemotherapyThe safety of pemetrexed was 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 pemetrexed in 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. Patients in both study arms received folic acid and vitamin B12 supplementation.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 folic acid, vitamin B12 or 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 4: Adverse Reactions Occurring in >=5% of Patients Receiving Pemetrexed in PARAMOUNTAdverse ReactionNCI CTCAE version 3.0 Pemetrexed (N=333)Placebo (N=167)All Grades (%)Grade 3-4 (%)All Grades (%)Grade 3-4 (%)All adverse reactions5317344.8 Laboratory Hematologic Anemia154.84.80.6 Neutropenia93.90.60Clinical Constitutional symptoms Fatigue184.5110.6Gastrointestinal Nausea120.32.40 Vomiting601.80 Mucositis/stomatitis50.32.40General disorders Edema503.60The 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 neutropeniaIncidence <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 ChemotherapyThe safety of pemetrexed 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 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 or corticosteroids were also excluded from the study.The data described below reflect exposure to pemetrexed 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-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 Table below.Table 5: Adverse Reactions Occurring in >=5% of Fully Supplemented Patients Receiving Pemetrexed in Study JMEIAdverse ReactionNCI CTCAE version 2.0 Pemetrexed (N=265)Docetaxel (N=276)All Grades (%)Grade 3-4 (%)All Grades (%)Grade 3-4 (%)Laboratory Hematologic Anemia194224 Neutropenia1154540 Thrombocytopenia8210 Hepatic Increased ALT8210 Increased AST7110Clinical Gastrointestinal Nausea313172 Anorexia222243 Vomiting162121 Stomatitis/pharyngitis151171 Diarrhea130243 Constipation6040Constitutional symptoms Fatigue345365 Fever8080Dermatology/Skin Rash/desquamation14060 Pruritus7020 Alopecia61382The 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 neuropathyIncidence <1%Cardiovascular -- supraventricular arrhythmias Renal -- renal failure. MesotheliomaThe safety of pemetrexed 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 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 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-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 6: Adverse Reactions Occurring in >=5% of Fully Supplemented Subgroup of Patients Receiving Pemetrexed/Cisplatin in Study JMCHIn Study JMCH, 226 patients received at least one dose of pemetrexed 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 in combination with cisplatin (168 patients) or cisplatin alone (163 patients) who received full supplementation with folic acid and vitamin B12 during study therapy. Adverse ReactionNCI CTCAE version 2.0 Pemetrexed/cisplatin (N=168)Cisplatin (N=163)All Grades (%)Grade 3-4 (%)All Grades (%)Grade 3-4 (%)Laboratory Hematologic Neutropenia5623133 Anemia264100 Thrombocytopenia23590Renal Elevated creatinine111101 Decreased creatinine clearance161182Clinical Eye Disorder Conjunctivitis5010Gastrointestinal Nausea8212776 Vomiting5711504 Stomatitis/pharyngitis23360 Anorexia201141 Diarrhea17480 Constipation12171 Dyspepsia5110Constitutional Symptoms Fatigue4810429Metabolism and Nutrition Dehydration7411Neurology Sensory neuropathy100101 Taste disturbance8060Dermatology/Skin Rash16150 Alopecia11060The following additional adverse reactions were observed in patients receiving pemetrexed 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 failureIncidence <1%Cardiovascular -- arrhythmia Neurology -- motor neuropathy. Exploratory Subgroup Analyses based on Vitamin SupplementationTable provides the results of exploratory analyses of the frequency and severity of NCI CTCAE Grade or adverse reactions reported in more pemetrexed-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 7: Exploratory Subgroup Analysis of Selected Grade 3/4 Adverse Reactions Occurring in Patients Receiving Pemetrexed in Combination with Cisplatin with or without Full Vitamin Supplementation in Study JMCHNCI CTCAE version 2.0 Grade 3-4 Adverse ReactionsFully Supplemented Patients N=168 (%)Never Supplemented Patients N=32 (%)Neutropenia2338Thrombocytopenia59Vomiting1131Febrile neutropenia19Infection with Grade 3/4 neutropenia06Diarrhea49The 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%).. hypertension (11% versus 3%),. chest pain (8% versus 6%),. thrombosis/embolism (6% versus 3%).. Additional Experience Across Clinical TrialsSepsis, with or without neutropenia, including fatal cases: 1%Severe esophagitis, resulting in hospitalization: <1%.

DOSAGE & ADMINISTRATION SECTION.

2DOSAGE AND ADMINISTRATION. The recommended dose of Pemetrexed 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)Initiate folic acid 400 mcg to 1000 mcg orally, once daily, beginning 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 B12, mg intramuscularly, week prior to the first dose of Pemetrexed Injection and every cycles. (2.4)Administer dexamethasone mg orally, twice daily the day before, the day of, and the day after Pemetrexed Injection administration. (2.4). The recommended dose of Pemetrexed 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). Initiate folic acid 400 mcg to 1000 mcg orally, once daily, beginning 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 B12, mg intramuscularly, week prior to the first dose of Pemetrexed Injection and every cycles. (2.4). Administer dexamethasone mg orally, twice daily the day before, the day of, and the day after Pemetrexed Injection administration. (2.4). 2.1Recommended 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 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 Injection for maintenance treatment of 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 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 Injection for treatment of recurrent 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 on Day of each 21-day cycle until disease progression or unacceptable toxicity.. The recommended dose of Pemetrexed 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 Injection for maintenance treatment of 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 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 Injection for treatment of recurrent 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 on Day of each 21-day cycle until disease progression or unacceptable toxicity.. 2.2Recommended Dosage for Mesothelioma. The recommended dose of Pemetrexed Injection 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.. 2.3Renal Impairment. Pemetrexed 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)].. 2.4Premedication and Concomitant Medications to Mitigate Toxicity. Vitamin SupplementationInitiate folic acid 400 mcg to 1000 mcg orally once daily, beginning 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 B12, mg intramuscularly, week prior to the first dose of Pemetrexed Injection and every cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with Pemetrexed Injection [see Warnings and Precautions (5.1)]. Do not substitute oral vitamin B12 for intramuscular vitamin B12 .. Initiate folic acid 400 mcg to 1000 mcg orally once daily, beginning 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 B12, mg intramuscularly, week prior to the first dose of Pemetrexed Injection and every cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with Pemetrexed Injection [see Warnings and Precautions (5.1)]. Do not substitute oral vitamin B12 for intramuscular vitamin B12 .. CorticosteroidsAdminister dexamethasone mg orally twice daily for three consecutive days, beginning the day before each Pemetrexed Injection administration.. Administer dexamethasone mg orally twice daily for three consecutive days, beginning the day before each Pemetrexed Injection administration.. 2.5Dosage 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 days before, the day of, and days following administration of Pemetrexed Injection.Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided.. Avoid administration of ibuprofen for days before, the day of, and days following administration of Pemetrexed Injection.. Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided.. 2.6Dosage 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 Injection if the creatinine clearance is less than 45 mL/min.Delay initiation of the next cycle of Pemetrexed Injection until:Recovery of non-hematologic toxicity to Grade 0-2,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 Injection in the next cycle as specified in Table 1.For dosing modifications for cisplatin, refer to the prescribing information for cisplatin.Table 1: Recommended Dosage Modifications for Adverse ReactionsNational Cancer Institute Common Toxicity Criteria for Adverse Events version (NCI CTCAE v2) Toxicity in Most Recent Treatment CyclePemetrexed Injection Dose Modification for Next CycleMyelosuppressive 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 bleeding75% of previous dosePlatelet count less than 50,000/mm3 with bleeding50% of previous doseRecurrent Grade or myelosuppression after dose reductionsDiscontinueNon-hematologic toxicityAny Grade or toxicities EXCEPT mucositis or neurologic toxicity or diarrhea requiring hospitalization75% of previous doseGrade or mucositis50% of previous doseRenal toxicity [see Warnings and Precautions (5.2)] Withhold until creatinine clearance is 45 mL/min or greaterGrade or neurologic toxicityPermanently discontinueRecurrent Grade or non-hematologic toxicity after dose reductionsPermanently discontinueSevere and life-threatening Skin Toxicity [see Warnings and Precautions (5.3)] Permanently discontinueInterstitial Pneumonitis [see Warnings and Precautions (5.4)] Permanently discontinue. Recovery of non-hematologic toxicity to Grade 0-2,. Absolute neutrophil count (ANC) is 1500 cells/mm3 or higher, and Platelet count is 100,000 cells/mm3 or higher.. 2.7Preparation for Administration. Pemetrexed Injection is hazardous drug. Follow applicable special handling and disposal procedures.1 Calculate the dose of Pemetrexed Injection and determine the number of vials needed.Withdraw the calculated dose of Pemetrexed Injection from the vial(s) and discard vial with any unused portion.Dilute Pemetrexed Injection with 0.9% Sodium Chloride Injection, USP (preservative-free) to achieve total volume of 100 mL for intravenous infusion. Visually inspect for particulate matter and discoloration prior to administration. Discard if particulate matter or discoloration is observed.Administer Pemetrexed Injection as an intravenous infusion over 10 minutes. If not used immediately, store diluted product under refrigerated conditions [2C to 8C (36F to 46F)] for no more than 24 hours from the time of dilution. Discard after 24 hours.. Calculate the dose of Pemetrexed Injection and determine the number of vials needed.. Withdraw the calculated dose of Pemetrexed Injection from the vial(s) and discard vial with any unused portion.. Dilute Pemetrexed Injection with 0.9% Sodium Chloride Injection, USP (preservative-free) to achieve total volume of 100 mL for intravenous infusion. Visually inspect for particulate matter and discoloration prior to administration. Discard if particulate matter or discoloration is observed.. Administer Pemetrexed Injection as an intravenous infusion over 10 minutes. If not used immediately, store diluted product under refrigerated conditions [2C to 8C (36F to 46F)] for no more than 24 hours from the time of dilution. Discard after 24 hours.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONPemetrexed (peh-meh-TREX-ed) Injectionfor intravenous useThis Patient Information has been approved by the U.S. Food and Drug Administration.Issued: 6/2022 What is Pemetrexed InjectionPemetrexed Injection is prescription medicine used to treat:a kind of lung cancer called non-squamous non-small cell lung cancer (NSCLC). Pemetrexed Injection is used: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.Pemetrexed Injection is not for use for the treatment of people with squamous cell, non-small cell lung cancer.a kind of cancer called malignant pleural mesothelioma. This cancer affects the lining of the lungs and chest wall. Pemetrexed 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.Pemetrexed Injection has not been shown to be safe and effective in children.Do not take Pemetrexed Injection if you have had severe allergic reaction to any medicine that contains pemetrexed.Before taking Pemetrexed 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 Injection can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider will check to see if you are pregnant before you start treatment with Pemetrexed Injection. You should use effective birth control (contraception) during treatment with Pemetrexed Injection and for months after the last dose. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with Pemetrexed Injection. Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment with Pemetrexed Injection and for months after the last dose.are breastfeeding or plan to breastfeed. It is not known if Pemetrexed Injection passes into breast milk. Do not breastfeed during treatment with Pemetrexed Injection and for week after the last 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 Injection.How is Pemetrexed Injection givenIt is very important to take folic acid and vitamin B12 during your treatment with Pemetrexed 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 Injection and continue taking folic acid until 21 days (3 weeks) after your last dose of Pemetrexed Injection.Your healthcare provider will give you vitamin B12 injections during treatment with Pemetrexed Injection. You will get your first vitamin B12 injection days (1 week) before your first dose of Pemetrexed 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 Injection.Pemetrexed Injection is given to you by intravenous (IV) infusion into your vein. The infusion is given over 10 minutes.Pemetrexed Injection is usually given once every 21 days (3 weeks).What are the possible side effects of Pemetrexed InjectionPemetrexed 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 tests to check your blood cell counts regularly during your treatment with Pemetrexed Injection. Tell your healthcare provider right away if you have any signs of infection, fever, bleeding, or severe tiredness during your treatment with Pemetrexed Injection. Kidney problems, including kidney failure. Pemetrexed 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 the amount of urine you make.Severe 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 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 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 Injection when given alone are:tirednessnausealoss of appetiteThe most common side effects of Pemetrexed Injection when given with cisplatin are:vomitingswelling or sores in your mouth or sore throatconstipationlow white blood cell counts (neutropenia)low platelet counts (thrombocytopenia)low red blood cell counts (anemia)Pemetrexed 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 tests to check for side effects during treatment with Pemetrexed Injection. Your healthcare provider may change your dose of Pemetrexed 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 of the possible side effects of Pemetrexed 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 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 Injection that is written for health professionals.What are the ingredients in Pemetrexed InjectionActive ingredient: pemetrexed Inactive ingredient: monothioglycerol, water for injection and may contain sodium hydroxide for pH adjustment. Manufactured by: Zydus Hospira Oncology Private Ltd.Ahmedabad 382-213, Gujarat, India. Distributed by: Hospira, Inc., Lake Forest, IL 60045 USA LAB-1432-1.0 For more information, please visit http://www.pfizer.com.. kind of lung cancer called non-squamous non-small cell lung cancer (NSCLC). Pemetrexed Injection is used: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.Pemetrexed Injection is not for use for the treatment of people with squamous cell, non-small cell lung cancer.. 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.. kind of cancer called malignant pleural mesothelioma. This cancer affects the lining of the lungs and chest wall. Pemetrexed 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.. have kidney problems.. have had radiation therapy.. are pregnant or plan to become pregnant. Pemetrexed Injection can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider will check to see if you are pregnant before you start treatment with Pemetrexed Injection. You should use effective birth control (contraception) during treatment with Pemetrexed Injection and for months after the last dose. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with Pemetrexed Injection. Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment with Pemetrexed Injection and for months after the last dose.. are breastfeeding or plan to breastfeed. It is not known if Pemetrexed Injection passes into breast milk. Do not breastfeed during treatment with Pemetrexed Injection and for week after the last dose.. It is very important to take folic acid and vitamin B12 during your treatment with Pemetrexed 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 Injection and continue taking folic acid until 21 days (3 weeks) after your last dose of Pemetrexed Injection.Your healthcare provider will give you vitamin B12 injections during treatment with Pemetrexed Injection. You will get your first vitamin B12 injection days (1 week) before your first dose of Pemetrexed Injection, and then every cycles. Take folic acid exactly as prescribed by your healthcare provider time day, beginning days (1 week) before your first dose of Pemetrexed Injection and continue taking folic acid until 21 days (3 weeks) after your last dose of Pemetrexed Injection.. Your healthcare provider will give you vitamin B12 injections during treatment with Pemetrexed Injection. You will get your first vitamin B12 injection days (1 week) before your first dose of Pemetrexed 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 Injection.. Pemetrexed Injection is given to you by intravenous (IV) infusion into your vein. The infusion is given over 10 minutes.. Pemetrexed Injection is usually given once every 21 days (3 weeks).. 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 tests to check your blood cell counts regularly during your treatment with Pemetrexed Injection. Tell your healthcare provider right away if you have any signs of infection, fever, bleeding, or severe tiredness during your treatment with Pemetrexed Injection. Kidney problems, including kidney failure. Pemetrexed 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 the amount of urine you make.. Severe 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 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 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.. tiredness. nausea. loss of appetite. vomiting. swelling or sores in your mouth or sore throat. constipation. low white blood cell counts (neutropenia). low platelet counts (thrombocytopenia). low red blood cell counts (anemia). Logo.

USE IN SPECIFIC POPULATIONS SECTION.

8USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1Pregnancy. Risk SummaryBased on findings from animal studies and its mechanism of action, Pemetrexed Injection can cause fetal harm when administered to 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/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.. Data. Animal 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).. 8.2Lactation. 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 Injection, advise women not to breastfeed during treatment with Pemetrexed Injection and for one week after last dose.. 8.3Females and Males of Reproductive Potential. Based on animal data, pemetrexed can cause malformations and developmental delays when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy TestingVerify pregnancy status of females of reproductive potential prior to initiating Pemetrexed Injection [see Use in Specific Populations (8.1)].. Contraception. FemalesBecause of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for months after the last dose of Pemetrexed Injection.. MalesBecause of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for months after the last dose [see Nonclinical Toxicology (13.1)].. Infertility. MalesPemetrexed 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)].. 8.4Pediatric 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 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.Pharmacokinetics of pemetrexed in 22 patients age to 18 years enrolled in NCT00070473 were within range of values in adults. 8.5Geriatric 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 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)].. 8.6Patients with Renal Impairment. Pemetrexed is primarily excreted by the kidneys. Decreased renal function results in reduced clearance and greater exposure (AUC) to pemetrexed 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.

5WARNINGS AND PRECAUTIONS. Myelosuppression: Can cause severe bone marrow suppression resulting in cytopenia and an increased risk of infection. Do not administer Pemetrexed 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 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). Myelosuppression: Can cause severe bone marrow suppression resulting in cytopenia and an increased risk of infection. Do not administer Pemetrexed 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 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). 5.1Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation. Pemetrexed 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 3-4 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 Injection; continue vitamin supplementation during treatment and for 21 days after the last dose of Pemetrexed Injection to reduce the severity of hematologic and gastrointestinal toxicity of Pemetrexed Injection [see Dosage and Administration (2.4)]. Obtain complete blood count at the beginning of each cycle. Do not administer Pemetrexed Injection until the ANC is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3. Permanently reduce Pemetrexed 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 3-4 neutropenia was 15% and 23%, the incidence of Grade 3-4 anemia was 6% and 4%, and incidence of Grade 3-4 thrombocytopenia was 4% and 5%, respectively. In Study JMCH, 18% of patients in the pemetrexed 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 3-4 neutropenia ranged from 3% to 5%, and incidence of Grade 3-4 anemia ranged from 3% to 5%.. 5.2Renal Failure. Pemetrexed 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 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 Injection. Withhold Pemetrexed Injection in patients with creatinine clearance of less than 45 mL/minute [see Dosage and Administration (2.3)].. 5.3Bullous 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. Permanently discontinue Pemetrexed Injection for severe and life-threatening bullous, blistering or exfoliating skin toxicity.. 5.4Interstitial Pneumonitis. Serious interstitial pneumonitis, including fatal cases, can occur with pemetrexed treatment. Withhold Pemetrexed Injection 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 Injection.. 5.5Radiation Recall. Radiation recall can occur with pemetrexed 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 Injection for signs of radiation recall.. 5.6Increased 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 Injection. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for Pemetrexed Injection adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity [see Dosage and Administration (2.5), Drug Interactions (7), and Clinical Pharmacology (12.3)].. 5.7Embryo-Fetal Toxicity. Based on findings from animal studies and its mechanism of action, Pemetrexed Injection 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 fetus. Advise females of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for months after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].