PODOXRED

Pemetrexed is a folate analog metabolic inhibitor.

The drug substance, Pemetrexed Disodium Hemipentahydrate, has the chemical name disodium N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl] benzoyl]-L-glutamic acid hemipentahydrate, with a molecular formula of C 20 H 19 N 5 Na 2 O 6 •2.5 H 2 O and a molecular weight of 516.41.

The structural formula is as follows

PEMRYDI RTU is a sterile clear, colorless to pale yellow to green-yellow ready-to-use solution in single-dose vials.

Each milliliter of solution contains 10 mg of pemetrexed (equivalent to 12.1 mg pemetrexed disodium hemipentahydrate), 10 mg of mannitol, 9 mg of sodium chloride, 1 mg of L-cysteine hydrochloride, sodium hydroxide and/or hydrochloric acid to adjust pH and water for injection.

RTU ® is a folate analog metabolic inhibitor indicated: in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non-squamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous NSCLC. as a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy.

PEMRYDI RTU is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer. initial treatment, in combination with cisplatin, of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. 1.1 Non-Squamous Non-Small Cell Lung Cancer (NSCLC) PEMRYDI RTU ® is indicated: in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non-squamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous NSCLC. as a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy.

PEMRYDI RTU is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer. 1.2 Mesothelioma PEMRYDI RTU is indicated, in combination with cisplatin, for the initial treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.

PHARMACOLOGY 12.1 Mechanism of Action Pemetrexed is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic processes essential for cell replication.

In vitro studies show that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides.

Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems.

Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase.

The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. 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 B 12.

There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles. 12.3 Pharmacokinetics Absorption The pharmacokinetics of pemetrexed when pemetrexed injection was administered as a single agent in doses ranging from 0.2 to 838 mg/m 2 infused over a 10-minute period have been evaluated in 426 cancer patients with a variety of solid tumors.

Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (C max ) increased proportionally with increase of dose.

The pharmacokinetics of pemetrexed did not change over multiple treatment cycles.

Pemetrexed has a steady-state volume of distribution of 16.1 liters.

In vitro studies indicated that pemetrexed is 81% bound to plasma proteins.

The 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.

Pemetrexed is not metabolized to an appreciable extent.

Pemetrexed 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 a substrate of OAT3 (organic anion transporter 3), a transporter that is involved in the active secretion of pemetrexed.

Age (26 to 80 years) and sex had no clinically meaningful effect on the systemic exposure of pemetrexed based on population pharmacokinetic analyses.

Racial Groups The pharmacokinetics of pemetrexed were similar in Whites and Blacks or African Americans.

Insufficient data are available for other ethnic groups.

Pemetrexed 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.

Pharmacokinetic analyses of pemetrexed included 127 patients with impaired renal function.

Plasma clearance of pemetrexed decreases as renal function decreases, with a 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.

The pemetrexed plasma concentrations in patients with various solid tumors with stable, mild to moderate third-space fluid were comparable to those observed in patients without third space fluid collections.

The effect of severe third space fluid on pharmacokinetics is not known.

OAT3 Transporter Ibuprofen, an OAT3 inhibitor, administered at 400 mg four times a day decreased the clearance of pemetrexed and increased its exposure (AUC) by approximately 20% in patients with normal renal function (creatinine clearance > 80 mL/min).

In Vitro Studies Pemetrexed is a substrate for OAT3.

Ibuprofen, an OAT3 inhibitor inhibited the uptake of pemetrexed in OAT3-expressing cell cultures with an average [Iu]/IC 50 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 a clinically significant extent.

Pemetrexed is a substrate for

In vitro, ibuprofen and other NSAIDs (naproxen, diclofenac, celecoxib) are not inhibitors of OAT4 at clinically relevant concentrations.

Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not affect the pharmacokinetics of pemetrexed.

Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed.

Vitamins Neither folic acid nor vitamin

B 12 affect the pharmacokinetics of pemetrexed.

P450 Enzymes In vitro studies suggest that pemetrexed does not inhibit the clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2.

The following adverse reactions are discussed in greater detail in other sections of the labeling: Myelosuppression Renal failure Bullous and exfoliative skin toxicity Interstitial pneumonitis Radiation recall The most common adverse reactions (incidence ≥ 20%) of pemetrexed, when administered as a single agent are fatigue, nausea, and anorexia.

The most common adverse reactions (incidence ≥ 20%) of pemetrexed when administered with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.

The most common adverse reactions (incidence ≥ 20%) of pemetrexed when administered in combination with pembrolizumab and platinum chemotherapy are fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, and pyrexia.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, the most common adverse reactions (incidence ≥ 20%) of pemetrexed, when administered as a single agent, are fatigue, nausea, and anorexia.

The most common adverse reactions (incidence ≥ 20 %) of pemetrexed, when administered in combination with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.

The most common adverse reactions (incidence ≥ 20%) of pemetrexed, when administered in combination with pembrolizumab and platinum chemotherapy, are fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, and pyrexia.

Non-Squamous NSCLC First-line Treatment of Metastatic Non-squamous NSCLC with Pembrolizumab and Platinum Chemotherapy The safety of pemetrexed, in combination with pembrolizumab and investigator’s choice of platinum (either carboplatin or cisplatin), was investigated in Study KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated, metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations.

A total of 607 patients received pemetrexed, pembrolizumab, and platinum every 3 weeks for 4 cycles followed by pemetrexed and pembrolizumab (n=405), or placebo, pemetrexed, and platinum every 3 weeks for 4 cycles followed by placebo and pemetrexed (n=202).

Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

The median duration of exposure to pemetrexed was 7.2 months (range: 1 day to 1.7 years).

Seventy-two percent of patients received carboplatin.

The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 years or older, 59% male, 94% White and 3% Asian, and 18% with history of brain metastases at baseline.

Pemetrexed was discontinued for adverse reactions in 23% of patients in the pemetrexed, pembrolizumab, and platinum arm.

The most common adverse reactions resulting in discontinuation of pemetrexed in this arm were acute kidney injury (3%) and pneumonitis (2%).

Adverse reactions leading to interruption of pemetrexed occurred in 49% of patients in the pemetrexed, pembrolizumab, and platinum arm.

The most common adverse reactions or laboratory abnormalities leading to interruption of pemetrexed in this arm (≥ 2%) were neutropenia (12%), anemia (7%), asthenia (4%), pneumonia (4%), thrombocytopenia (4%), increased blood creatinine (3%), diarrhea (3%), and fatigue (3%).

Table 2 summarizes the adverse reactions that occurred in ≥ 20% of patients treated with pemetrexed, pembrolizumab, and platinum.

Table 2: Adverse Reactions Occurring in ≥ 20% of Patients in KEYNOTE-189 Pemetrexed Pembrolizumab Platinum Chemotherapy n=405 Placebo Pemetrexed Platinum Chemotherapy n=202 Adverse Reaction All Grades a (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Gastrointestinal.

Disorders Nausea 56 3.5 52 3.5 Constipation 35 1.0 32 0.5 Diarrhea 31 5 21 3.0 Vomiting 24 3.7 23 3.0 General.

Disorders and Administration Site Conditions Fatigue b 56 12 58 6 Pyrexia 20 0.2 15 0 Metabolism and Nutrition.

Disorders Decreased appetite 28 1.5 30 0.5 Skin and Subcutaneous Tissue.

Disorders Rash c 25 2.0 17 2.5 Respiratory, Thoracic and Mediastinal.

Disorders Cough 21 0 28 0 Dyspnea 21 3.7 26 5 a Graded per NCI CTCAE version 4.03. b Includes asthenia and fatigue. c Includes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular.

Table 3 summarizes the laboratory abnormalities that worsened from baseline in at least 20% of patients treated with pemetrexed, pembrolizumab, and platinum.

Table 3: Laboratory Abnormalities Worsened from Baseline in ≥ 20% of Patients in KEYNOTE-189 Pemetrexed Pembrolizumab Platinum Chemotherapy Placebo Pemetrexed Platinum Chemotherapy Laboratory Test a All Grades b % Grades 3-4 % All Grades % Grades 3-4 % Chemistry Hyperglycemia 63 9 60 7 Increased ALT 47 3.8 42 2.6 Increased AST 47 2.8 40 1.0 Hypoalbuminemia 39 2.8 39 1.1 Increased creatinine 37 4.2 25 1.0 Hyponatremia 32 7 23 6 Hypophosphatemia 30 10 28 14 Increased alkaline phosphatase 26 1.8 29 2.1 Hypocalcemia 24 2.8 17 0.5 Hyperkalemia 24 2.8 19 3.1 Hypokalemia 21 5 20 5 Hematology Anemia 85 17 81 18 Lymphopenia 64 22 64 25 Neutropenia 48 20 41 19 Thrombocytopenia 30 12 29 8 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: pemetrexed/pembrolizumab/platinum chemotherapy (range: 381 to 401 patients) and placebo/pemetrexed/platinum chemotherapy (range: 184 to 197 patients). b Graded per NCI CTCAE version 4.03.

Initial Treatment in Combination with Cisplatin

The safety of pemetrexed was evaluated in Study JMDB, a randomized (1:1), open-label, multicenter trial conducted in chemotherapy-naive patients with locally advanced or metastatic NSCLC.

Patients received either pemetrexed 500 mg/m 2 intravenously and cisplatin 75 mg/m 2 intravenously on Day of each 21-day cycle (n=839) or gemcitabine 1,250 mg/m 2 intravenously on Days and 8 and cisplatin 75 mg/m 2 intravenously on Day of each 21-day cycle (n=830).

All patients were fully supplemented with folic acid and vitamin B 12.

Study JMDB excluded patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS of 2 or greater), uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B 12 or corticosteroids were also excluded from the study.

The data described below reflect exposure to pemetrexed plus cisplatin in 839 patients in Study JMDB.

Median age was 61 years (range 26-83 years); 70% of patients were men; 78% were White, 16% were Asian, 2.9% were Hispanic or Latino, 2.1% were Black or African American, and <1% were other ethnicities; 36% had an ECOG PS 0.

Patients received a median of 5 cycles of pemetrexed.

Table 4 provides the frequency and severity of adverse reactions that occurred in ≥ 5% of 839 patients receiving pemetrexed in combination with cisplatin in Study JMDB.

JMDB was not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed, as compared to the control arm, for any specified adverse reaction listed in Table 4.

Table 4: Adverse Reactions Occurring in ≥ 5% of Fully Vitamin-Supplemented Patients Receiving Pemetrexed in Combination with Cisplatin Chemotherapy in Study JMDB Adverse Reaction a Pemetrexed/Cisplatin (N=839) Gemcitabine/Cisplatin (N=830) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) All adverse reactions 90 37 91 53 Laboratory Hematologic Anemia 33 6 46 10 Neutropenia 29 15 38 27 Thrombocytopenia 10 4 27 13 Renal Elevated creatinine 10 1 7 1 Clinical Gastrointestinal Nausea 56 7 53 4 Vomiting 40 6 36 6 Anorexia 27 2 24 1 Constipation 21 1 20 0 Stomatitis/pharyngitis 14 1 12 0 Diarrhea 12 1 13 2 Dyspepsia/heartburn 5 0 6 0 Constitutional symptoms Fatigue 43 7 45 5 Dermatology/Skin Alopecia 12 0 21 1 Rash/Desquamation 7 0 8 1 Neurology Sensory neuropathy 9 0 12 1 Taste disturbance 8 0 9 0 a NCI CTCAE version 2.0.

The following additional adverse reactions were observed in patients assigned to receive pemetrexed.

Incidence 1% to < 5% Body as a Whole — febrile neutropenia, infection, pyrexia General.

Disorders — dehydration Metabolism and Nutrition — increased AST, increased ALT Renal —renal failure Eye Disorder — conjunctivitis Incidence < 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 Chemotherapy In Study JMEN, the safety of pemetrexed was evaluated in a randomized (2:1), placebo-controlled, multicenter trial conducted in patients with non-progressive locally advanced or metastatic NSCLC following four cycles of a first-line, platinum-based chemotherapy regimen.

Patients received either pemetrexed 500 mg/m 2 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 B 12.

Study JMEN excluded patients with an ECOG PS of 2 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B 12 or corticosteroids were also excluded from the study.

The data described below reflect exposure to pemetrexed 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 a median of 5 cycles of pemetrexed and a 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 5 provides the frequency and severity of adverse reactions reported in ≥ 5% of the 438 pemetrexed-treated patients in Study JMEN.

Table 5: Adverse Reactions Occurring in ≥ 5% of Patients Receiving Pemetrexed in Study JMEN Adverse Reaction a Pemetrexed (N=438) Placebo (N=218) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) All adverse reactions 66 16 37 4 Laboratory Hematologic Anemia 15 3 6 1 Neutropenia 6 3 0 0 Hepatic Increased ALT 10 0 4 0 Increased AST 8 0 4 0 Clinical Constitutional symptoms Fatigue 25 5 11 1 Gastrointestinal Nausea 19 1 6 1 Anorexia 19 2 5 0 Vomiting 9 0 1 0 Mucositis/stomatitis 7 1 2 0 Diarrhea 5 1 3 0 Dermatology/Skin Rash/desquamation 10 0 3 0 Neurology Sensory neuropathy 9 1 4 0 Infection 5 2 2 0 a NCI CTCAE version 3.0.

The requirement for transfusions (9.5% versus 3.2%), primarily red blood cell transfusions, and for erythropoiesis stimulating agents (5.9% versus 1.8%) were higher in the pemetrexed arm compared to the placebo arm.

The following additional adverse reactions were observed in patients who received pemetrexed.

Incidence 1% to <5% Dermatology/Skin —.

No drugs are approved for the treatment of pemetrexed overdose.

Based on animal studies, administration of leucovorin may mitigate the toxicities of pemetrexed overdosage.

It is not known whether pemetrexed is dialyzable.

RTU is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed.

History of severe hypersensitivity reaction to pemetrexed.

DOSAGE AND ADMINISTRATION The recommended dose of PEMRYDI RTU administered with pembrolizumab and platinum chemotherapy in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m as an intravenous infusion over 10 minutes, administered after pembrolizumab and prior to platinum chemotherapy, on Day of each 21-day cycle.

The recommended dose of PEMRYDI

RTU, administered as a single agent or with cisplatin, in patients with creatinine clearance of 45 mL/minute or greater is 500 mg/m as an intravenous infusion over 10 minutes on Day of each 21-day cycle.

Initiate folic acid 400 mcg to 1,000 mcg orally, once daily, beginning 7 days prior to the first dose of PEMRYDI RTU and continue until 21 days after the last dose of PEMRYDI RTU.

Administer vitamin

B 12, 1 mg intramuscularly, 1 week prior to the first dose of PEMRYDI RTU and every 3 cycles.

Administer dexamethasone 4 mg orally, twice daily the day before, the day of, and the day after PEMRYDI RTU administration. 2.1 Recommended Dosage for Non-Squamous NSCLC The recommended dose of PEMRYDI RTU when administered with pembrolizumab and platinum chemotherapy for the initial treatment of metastatic non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m as an intravenous infusion over 10 minutes administered after pembrolizumab and prior to carboplatin or cisplatin on Day of each 21-day cycle for 4 cycles.

Following completion of platinum-based therapy, treatment with PEMRYDI RTU with or without pembrolizumab is administered until disease progression or unacceptable toxicity.

Please refer to the full prescribing information for pembrolizumab and for carboplatin or cisplatin.

RTU when administered with cisplatin for initial treatment of locally advanced or metastatic non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m 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.

RTU for maintenance treatment of non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m 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.

RTU for treatment of recurrent non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m as an intravenous infusion over 10 minutes on Day of each 21-day cycle until disease progression or unacceptable toxicity. 2.2 Recommended Dosage for Mesothelioma The recommended dose of PEMRYDI RTU when administered with cisplatin in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m as an intravenous infusion over 10 minutes on Day of each 21-day cycle until disease progression or unacceptable toxicity. 2.3 Renal Impairment PEMRYDI RTU dosing recommendations are provided for patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater.

There is no recommended dose for patients whose creatinine clearance is less than 45 mL/min. 2.4 Premedication and Concomitant Medications to Mitigate Toxicity Vitamin Supplementation Initiate folic acid 400 mcg to 1,000 mcg orally once daily, beginning 7 days before the first dose of PEMRYDI RTU and continuing until 21 days after the last dose of PEMRYDI RTU.

B 12, 1 mg intramuscularly, 1 week prior to the first dose of PEMRYDI RTU and every 3 cycles thereafter.

Subsequent vitamin

B 12 injections may be given the same day as treatment with PEMRYDI RTU.

Do not substitute oral vitamin B for intramuscular vitamin B 12.

Administer dexamethasone 4 mg orally twice daily for three consecutive days, beginning the day before each PEMRYDI RTU administration. 2.5 Dosage Modification of Ibuprofen in Patients with Mild to Moderate Renal Impairment Receiving PEMRYDI RTU In patients with creatinine clearances between 45 mL/min and 79 mL/min, modify administration of ibuprofen as follows: Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of PEMRYDI RTU.

Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided. 2.6 Dosage Modifications for Adverse Reactions Obtain complete blood count on Days 1, 8, and of each cycle.

Assess creatinine clearance prior to each cycle.

Do not administer PEMRYDI

RTU if the creatinine clearance is less than 45 mL/min. Delay initiation of the next cycle of PEMRYDI RTU until: recovery of non-hematologic toxicity to Grade 0-2, absolute neutrophil count (ANC) is 1,500 cells/mm 3 or higher, and platelet count is 100,000 cells/mm 3 or higher.

Upon recovery, modify the dosage of PEMRYDI RTU in the next cycle as specified in Table 1.

For dosing modifications for cisplatin, carboplatin, or pembrolizumab, refer to their prescribing information.

Table 1: Recommended Dosage Modifications for Adverse Reactions a Toxicity in Most Recent Treatment Cycle PEMRYDI RTU Dose Modification for Next Cycle Myelosuppressive toxicity ANC less than 500/mm and platelets greater than or equal to 50,000/mm 3 OR Platelet count less than 50,000/mm 3 without bleeding. 75% of previous dose Platelet count less than 50,000/mm with bleeding 50% of previous dose Recurrent Grade 3 or 4 myelosuppression after 2 dose reductions Discontinue Non-hematologic toxicity Any Grade 3 or 4 toxicities EXCEPT mucositis or neurologic toxicity OR Diarrhea requiring hospitalization 75% of previous dose Grade 3 or 4 mucositis 50% of previous dose Renal toxicity Withhold until creatinine clearance is 45 mL/min or greater Grade 3 or 4 neurologic toxicity Permanently discontinue Recurrent Grade 3 or 4 non-hematologic toxicity after 2 dose reductions Permanently discontinue Severe and life-threatening Skin Toxicity Permanently discontinue Interstitial Pneumonitis Permanently discontinue a National Cancer Institute Common Toxicity Criteria for Adverse Events version 2 (NCI CTCAE v2). 2.7 Preparation for Administration PEMRYDI RTU is a hazardous drug.

Follow applicable special handling and disposal procedures.

Calculate the dose of PEMRYDI RTU and determine the volume of needed PEMRYDI RTU.

Each vial contains an excess of PEMRYDI RTU to facilitate delivery of labeled amount.

Withdraw the calculated dose of PEMRYDI

RTU from the vial(s) and discard the vial(s) with any unused portion.

Transfer the calculated dose into an empty intravenous bag.

Do NOT further dilute PEMRYDI

Visually inspect for particulate matter and discoloration prior to administration.

Discard if particulate matter or discoloration is observed.

Immediately administer PEMRYDI

RTU undiluted, as an intravenous infusion over 10 minutes using an infusion pump.

If not used immediately, store undiluted PEMRYDI RTU solution in infusion bag for no more than 24 hours at controlled room temperature of 20°C to 25°C (68°F to 77°F) .

Discard the infusion bag solution if not used within 24 hours.

SUPPLIED/STORAGE AND HANDLING How Supplied PEMRYDI RTU (pemetrexed injection) is supplied as a sterile clear, colorless to pale yellow to green-yellow ready-to-use solution packaged in a USP type-I glass vial with rubber stopper and aluminium flip-off cap.

It is available as follows: 100 mg/10 mL (10 mg/mL): 1 Single-dose Vial in a Carton: NDC 70121-2453-1 500 mg/50 mL (10 mg/mL): 1 Single-dose Vial in a Carton: NDC 70121-2461-1 1,000 mg/100 mL (10 mg/mL): 1 Single-dose Vial in a Carton: NDC 70121-2462-1 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

RTU is a hazardous drug.

Follow applicable special handling and disposal procedures.

Based on findings from animal studies and its mechanism of action, pemetrexed can cause fetal harm when administered to a pregnant woman.

There are no available data on pemetrexed use in pregnant women.

In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and malformations at doses lower than the recommended human dose of 500 mg/m 2.

Advise pregnant women of the potential risk to a fetus.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Pemetrexed was teratogenic in mice.

Daily dosing of pemetrexed by intravenous injection to pregnant mice during the period of organogenesis increased the incidence of fetal malformations (cleft palate; protruding tongue; enlarged or misshaped kidney; and fused lumbar vertebra) at doses (based on BSA) 0.03 times the human dose of 500 mg/m 2.

At doses, based on BSA, greater than or equal to 0.0012 times the 500 mg/m 2 human dose, pemetrexed administration resulted in dose-dependent increases in developmental delays (incomplete ossification of talus and skull bone; and decreased fetal weight).

The safety and effectiveness of pemetrexed in pediatric patients have not been established.

The safety and pharmacokinetics of pemetrexed were evaluated in two clinical studies conducted in pediatric patients with recurrent solid tumors (NCT00070473 N=32 and NCT00520936 N=72).

Patients in both studies received concomitant vitamin B and folic acid supplementation and dexamethasone.

No tumor responses were observed.

Adverse reactions observed in pediatric patients were similar to those observed in adults.

Single-dose pharmacokinetics of pemetrexed were evaluated in 22 patients age to 18 years enrolled in NCT00070473 were within range of values in adults.

Of the 3,946 patients enrolled in clinical studies of pemetrexed, 34% were and over and 4% were 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.