These Highlights Do Not Include All The Information Needed To Use Pemetrexed Injection Safely And Effectively. See Full Prescribing Information For Pemetrexed Injection.

Limitations of Use: Pemetrexed Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer [see Clinical Studies 14.1].

Storage and Handling

Store Pemetrexed Injection at controlled refrigerated temperature, 2°C to 8°C (36°F to 46°F).

Pemetrexed Injection is a hazardous drug. Follow applicable special handling and disposal procedures. [see References (15)]

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

• 1.
  "OSHA Hazardous Drugs." OSHA. [https://www.osha.gov/hazardous-drugs]

Pemetrexed is a folate analog metabolic inhibitor. The drug substance, pemetrexed disodium (2.5 H₂O), has the chemical name N-[[4-[2-(2-Amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]phenyl]carbonyl]-L-glutamic acid disodium, hemipentahydrate with a molecular formula of C₂₀H₁₉N₅Na₂O₆ ∙2.5H₂O and a molecular weight of 516.41. The structural formula is as follows:

Pemetrexed Injection, 100 mg/4 mL, 500 mg/20 mL, and 1 g/40 mL are supplied as a sterile, preservative-free, clear, colorless to pale yellow ready-to-dilute solution in a single-dose vial for intravenous infusion. Each milliliter (mL) contains 25 mg pemetrexed (equivalent to 27.57 mg pemetrexed disodium), 1.2 mg monothioglycerol, water for injection and may contain sodium hydroxide for pH adjustment.

Pemetrexed Injection is indicated, in combination with cisplatin, for the initial treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.

The efficacy of pemetrexed was evaluated in Study JMCH (NCT00005636), a 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 1 of each 21-day cycle or to receive cisplatin 75 mg/m² intravenously over 2 hours on Day 1 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 1 to 3 weeks prior to the first dose of pemetrexed and continuing until 1 to 3 weeks after the last dose, vitamin B₁₂ 1000 mcg intramuscularly 1 to 3 weeks prior to first dose of pemetrexed and every 9 weeks thereafter, and dexamethasone 4 mg orally, twice daily, for 3 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 a baseline KPS score of 90–100% and 46% had a KPS score of 70–80%. With regard to tumor characteristics, 46% had Stage IV disease, 31% Stage III, 15% Stage II, and 7% Stage I 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.

Figure 8: Kaplan-Meier Curves for Overall Survival in Study JMCH

Based upon prospectively defined criteria (modified Southwest Oncology Group methodology) the objective tumor response rate for 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.

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 a 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 a creatinine clearance of less than 45 mL/minute [see Dosage and Administration (2.3)].

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 4 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 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)].

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

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)]

Ibuprofen increased risk of Pemetrexed Injection toxicity in patients with mild to moderate renal impairment. Modify the ibuprofen dosage as recommended for patients with a creatinine clearance between 45 mL/min and 79 mL/min. (2.5, 5.6, 7)

Pemetrexed Injection dosing recommendations are provided for patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater [see Dosage and Administration (2.1, 2.2)]. There is no recommended dose for patients whose creatinine clearance is less than 45 mL/min [see Use in Specific Populations (8.6)].

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.

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.

Pemetrexed Injection is a folate analog metabolic inhibitor indicated:

• •
  In combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous, non-small cell lung cancer (NSCLC). (1.1)
• •
  As a single agent for the maintenance treatment of patients with locally advanced or metastatic, non -squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. (1.1)
• •
  As a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy. (1.1)
• •
  Limitations of Use: Pemetrexed Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer. (1.1)
• •
  Initial treatment, in combination with cisplatin, of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. (1.2)

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

Based on findings from animal studies and its mechanism of action, Pemetrexed Injection can cause fetal harm when administered to a 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 a fetus. Advise females of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

• •
  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 a fetus and to use effective contraception. (5.7, 8.1, 8.3)

• •
  The recommended dose of Pemetrexed Injection, administered as a single agent or with cisplatin, in patients with creatinine clearance of 45 mL/minute or greater is 500 mg/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. (2.1, 2.2)
• •
  Initiate folic acid 400 mcg to 1000 mcg orally, once daily, beginning 7 days prior to the first dose of Pemetrexed Injection and continue until 21 days after the last dose of Pemetrexed Injection. (2.4)
• •
  Administer vitamin B₁₂, 1 mg intramuscularly, 1 week prior to the first dose of Pemetrexed Injection and every 3 cycles. (2.4)
• •
  Administer dexamethasone 4 mg orally, twice daily the day before, the day of, and the day after Pemetrexed Injection administration. (2.4)

Pemetrexed Injection is a clear colorless to pale yellow ready-to-dilute solution available in single-dose vials as follows:

• •
  100 mg/4 mL (25 mg/mL)
• •
  500 mg/20 mL (25 mg/mL)
• •
  1 g/40 mL (25 mg/mL)

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.

The following adverse reactions have been identified during post-approval use of pemetrexed. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a 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

Lactation: Advise not to breastfeed. (8.2)

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.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Pemetrexed Injection is a 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 a 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 [2°C to 8°C (36°F to 46°F)] for no more than 24 hours from the time of dilution. Discard after 24 hours.

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)].

The recommended dose of Pemetrexed Injection when administered with cisplatin in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable 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.

Rx only

NDC 0409-0020-02

Single Dose Vial - Discard Unused Portion

Sterile

Pemetrexed Injection

100 mg/4 mL

(25 mg/mL)

For Intravenous Infusion After Dilution

Store refrigerated at 2°C to 8°C (36°F to 46°F).

Warning: Hazardous Drug

Novaplus

Rx only

NDC 0409-0021-03

Single Dose Vial - Discard Unused Portion

Sterile

Pemetrexed Injection

500 mg/20 mL

(25 mg/mL)

For Intravenous Infusion After Dilution

Store refrigerated at 2°C to 8°C (36°F to 46°F).

Warning:

Hazardous Drug

1 x 4 mL vial

NDC 0409-0020-02

Sterile

Rx only

Pemetrexed

Injection

100 mg/4 mL

(25 mg/mL)

For Intravenous

Infusion After Dilution

Single Dose Vial

Discard Unused Portion

Novaplus

Warning: Hazardous Drug

Rx only

NDC 0409-0004-04

Single Dose Vial - Discard Unused Portion

Sterile

Pemetrexed Injection

1 g/40 mL

(25 mg/mL)

For Intravenous Infusion After Dilution

Store refrigerated at 2°C to 8°C (36°F to 46°F).

Warning: Hazardous Drug

1 x 20 mL vial

NDC 0409-0021-03

Sterile

Rx only

Pemetrexed

Injection

500 mg/20 mL

(25 mg/mL)

For Intravenous

Infusion After Dilution

Single Dose Vial

Discard Unused Portion

Novaplus

Warning: Hazardous Drug

1 x 40 mL vial

NDC 0409-0004-04

Sterile

Rx only

Pemetrexed

Injection

1 g/40 mL

(25 mg/mL)

For Intravenous

Infusion After Dilution

Single Dose Vial

Discard Unused Portion

Novaplus

Warning: Hazardous Drug

• •
  The recommended dose of Pemetrexed Injection when administered with cisplatin for initial treatment of locally advanced or metastatic non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m² as an intravenous infusion over 10 minutes administered prior to cisplatin on Day 1 of each 21-day cycle for up to six cycles in the absence of disease progression or unacceptable toxicity.
• •
  The recommended dose of Pemetrexed Injection for maintenance treatment of non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity after four cycles of platinum-based first-line chemotherapy.
• •
  The recommended dose of Pemetrexed Injection for treatment of recurrent non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity.

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.

Based on animal data, pemetrexed can cause malformations and developmental delays when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pemetrexed Injection is indicated:

• •
  In combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous, non-small cell lung cancer (NSCLC).
• •
  As a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.
• •
  As a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy.

No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in an in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, Chinese Hamster Ovary cell assay).

Pemetrexed administered intraperitoneally at doses of ≥0.1 mg/kg/day to male mice (approximately 0.0006 times the recommended human dose based on BSA) resulted in reduced fertility, hypospermia, and testicular atrophy.

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 2 days before, the day of, and 2 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)].

Pemetrexed can cause severe myelosuppression resulting in a 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 a 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%.

In patients with creatinine clearances between 45 mL/min and 79 mL/min, modify administration of ibuprofen as follows [see Warnings and Precautions (5.6), Drug Interactions (7) and Clinical Pharmacology (12.3)]:

• •
  Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of Pemetrexed Injection.
• •
  Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided.

Limitations of Use: Pemetrexed Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer [see Clinical Studies 14.1].

Storage and Handling

Store Pemetrexed Injection at controlled refrigerated temperature, 2°C to 8°C (36°F to 46°F).

Pemetrexed Injection is a hazardous drug. Follow applicable special handling and disposal procedures. [see References (15)]

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

• 1.
  "OSHA Hazardous Drugs." OSHA. [https://www.osha.gov/hazardous-drugs]

Pemetrexed is a folate analog metabolic inhibitor. The drug substance, pemetrexed disodium (2.5 H₂O), has the chemical name N-[[4-[2-(2-Amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]phenyl]carbonyl]-L-glutamic acid disodium, hemipentahydrate with a molecular formula of C₂₀H₁₉N₅Na₂O₆ ∙2.5H₂O and a molecular weight of 516.41. The structural formula is as follows:

Pemetrexed Injection, 100 mg/4 mL, 500 mg/20 mL, and 1 g/40 mL are supplied as a sterile, preservative-free, clear, colorless to pale yellow ready-to-dilute solution in a single-dose vial for intravenous infusion. Each milliliter (mL) contains 25 mg pemetrexed (equivalent to 27.57 mg pemetrexed disodium), 1.2 mg monothioglycerol, water for injection and may contain sodium hydroxide for pH adjustment.

Pemetrexed Injection is indicated, in combination with cisplatin, for the initial treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.

The efficacy of pemetrexed was evaluated in Study JMCH (NCT00005636), a 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 1 of each 21-day cycle or to receive cisplatin 75 mg/m² intravenously over 2 hours on Day 1 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 1 to 3 weeks prior to the first dose of pemetrexed and continuing until 1 to 3 weeks after the last dose, vitamin B₁₂ 1000 mcg intramuscularly 1 to 3 weeks prior to first dose of pemetrexed and every 9 weeks thereafter, and dexamethasone 4 mg orally, twice daily, for 3 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 a baseline KPS score of 90–100% and 46% had a KPS score of 70–80%. With regard to tumor characteristics, 46% had Stage IV disease, 31% Stage III, 15% Stage II, and 7% Stage I 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.

Figure 8: Kaplan-Meier Curves for Overall Survival in Study JMCH

Based upon prospectively defined criteria (modified Southwest Oncology Group methodology) the objective tumor response rate for 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.

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 a 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 a creatinine clearance of less than 45 mL/minute [see Dosage and Administration (2.3)].

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 4 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 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)].

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

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)]

Ibuprofen increased risk of Pemetrexed Injection toxicity in patients with mild to moderate renal impairment. Modify the ibuprofen dosage as recommended for patients with a creatinine clearance between 45 mL/min and 79 mL/min. (2.5, 5.6, 7)

Pemetrexed Injection dosing recommendations are provided for patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater [see Dosage and Administration (2.1, 2.2)]. There is no recommended dose for patients whose creatinine clearance is less than 45 mL/min [see Use in Specific Populations (8.6)].

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.

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.

Pemetrexed Injection is a folate analog metabolic inhibitor indicated:

• •
  In combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous, non-small cell lung cancer (NSCLC). (1.1)
• •
  As a single agent for the maintenance treatment of patients with locally advanced or metastatic, non -squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. (1.1)
• •
  As a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy. (1.1)
• •
  Limitations of Use: Pemetrexed Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer. (1.1)
• •
  Initial treatment, in combination with cisplatin, of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. (1.2)

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

Based on findings from animal studies and its mechanism of action, Pemetrexed Injection can cause fetal harm when administered to a 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 a fetus. Advise females of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

• •
  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 a fetus and to use effective contraception. (5.7, 8.1, 8.3)

• •
  The recommended dose of Pemetrexed Injection, administered as a single agent or with cisplatin, in patients with creatinine clearance of 45 mL/minute or greater is 500 mg/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. (2.1, 2.2)
• •
  Initiate folic acid 400 mcg to 1000 mcg orally, once daily, beginning 7 days prior to the first dose of Pemetrexed Injection and continue until 21 days after the last dose of Pemetrexed Injection. (2.4)
• •
  Administer vitamin B₁₂, 1 mg intramuscularly, 1 week prior to the first dose of Pemetrexed Injection and every 3 cycles. (2.4)
• •
  Administer dexamethasone 4 mg orally, twice daily the day before, the day of, and the day after Pemetrexed Injection administration. (2.4)

Pemetrexed Injection is a clear colorless to pale yellow ready-to-dilute solution available in single-dose vials as follows:

• •
  100 mg/4 mL (25 mg/mL)
• •
  500 mg/20 mL (25 mg/mL)
• •
  1 g/40 mL (25 mg/mL)

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.

The following adverse reactions have been identified during post-approval use of pemetrexed. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a 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

Lactation: Advise not to breastfeed. (8.2)

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.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Pemetrexed Injection is a 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 a 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 [2°C to 8°C (36°F to 46°F)] for no more than 24 hours from the time of dilution. Discard after 24 hours.

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)].

The recommended dose of Pemetrexed Injection when administered with cisplatin in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable 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.

Rx only

NDC 0409-0020-02

Single Dose Vial - Discard Unused Portion

Sterile

Pemetrexed Injection

100 mg/4 mL

(25 mg/mL)

For Intravenous Infusion After Dilution

Store refrigerated at 2°C to 8°C (36°F to 46°F).

Warning: Hazardous Drug

Novaplus

Rx only

NDC 0409-0021-03

Single Dose Vial - Discard Unused Portion

Sterile

Pemetrexed Injection

500 mg/20 mL

(25 mg/mL)

For Intravenous Infusion After Dilution

Store refrigerated at 2°C to 8°C (36°F to 46°F).

Warning:

Hazardous Drug

1 x 4 mL vial

NDC 0409-0020-02

Sterile

Rx only

Pemetrexed

Injection

100 mg/4 mL

(25 mg/mL)

For Intravenous

Infusion After Dilution

Single Dose Vial

Discard Unused Portion

Novaplus

Warning: Hazardous Drug

Rx only

NDC 0409-0004-04

Single Dose Vial - Discard Unused Portion

Sterile

Pemetrexed Injection

1 g/40 mL

(25 mg/mL)

For Intravenous Infusion After Dilution

Store refrigerated at 2°C to 8°C (36°F to 46°F).

Warning: Hazardous Drug

1 x 20 mL vial

NDC 0409-0021-03

Sterile

Rx only

Pemetrexed

Injection

500 mg/20 mL

(25 mg/mL)

For Intravenous

Infusion After Dilution

Single Dose Vial

Discard Unused Portion

Novaplus

Warning: Hazardous Drug

1 x 40 mL vial

NDC 0409-0004-04

Sterile

Rx only

Pemetrexed

Injection

1 g/40 mL

(25 mg/mL)

For Intravenous

Infusion After Dilution

Single Dose Vial

Discard Unused Portion

Novaplus

Warning: Hazardous Drug

• •
  The recommended dose of Pemetrexed Injection when administered with cisplatin for initial treatment of locally advanced or metastatic non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m² as an intravenous infusion over 10 minutes administered prior to cisplatin on Day 1 of each 21-day cycle for up to six cycles in the absence of disease progression or unacceptable toxicity.
• •
  The recommended dose of Pemetrexed Injection for maintenance treatment of non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity after four cycles of platinum-based first-line chemotherapy.
• •
  The recommended dose of Pemetrexed Injection for treatment of recurrent non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity.

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.

Based on animal data, pemetrexed can cause malformations and developmental delays when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pemetrexed Injection is indicated:

• •
  In combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous, non-small cell lung cancer (NSCLC).
• •
  As a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.
• •
  As a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy.

No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in an in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, Chinese Hamster Ovary cell assay).

Pemetrexed administered intraperitoneally at doses of ≥0.1 mg/kg/day to male mice (approximately 0.0006 times the recommended human dose based on BSA) resulted in reduced fertility, hypospermia, and testicular atrophy.

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 2 days before, the day of, and 2 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)].

Pemetrexed can cause severe myelosuppression resulting in a 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 a 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%.

In patients with creatinine clearances between 45 mL/min and 79 mL/min, modify administration of ibuprofen as follows [see Warnings and Precautions (5.6), Drug Interactions (7) and Clinical Pharmacology (12.3)]:

• •
  Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of Pemetrexed Injection.
• •
  Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided.