1.1 Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

Pemetrexed for injection is indicated:

• in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non-squamous 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, 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.

1.2 Mesothelioma

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

2.1 Recommended Dosage for Non-Squamous NSCLC

• The recommended dose of pemetrexed for injection when administered with pembrolizumab and platinum chemotherapy for the initial treatment of metastatic non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes administered after pembrolizumab and prior to carboplatin or cisplatin on Day 1 of each 21-day cycle for 4 cycles. Following completion of platinum-based therapy, treatment with pemetrexed for injection with or without pembrolizumab is administered until disease progression or unacceptable toxicity. Please refer to the full prescribing information for pembrolizumab and for carboplatin or cisplatin.
• The recommended dose of pemetrexed for injection when administered with cisplatin for initial treatment of locally advanced or metastatic non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes administered prior to cisplatin on Day 1 of each 21-day cycle for up to six cycles in the absence of disease progression or unacceptable toxicity.
• The recommended dose of pemetrexed for injection for maintenance treatment of non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity after four cycles of platinum-based first-line chemotherapy.
• The recommended dose of pemetrexed for injection for treatment of recurrent non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity.

2.2 Recommended Dosage for Mesothelioma

• The recommended dose of pemetrexed for injection when administered with cisplatin in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity.

2.3 Renal Impairment

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

2.4 Premedication and Concomitant Medications to Mitigate Toxicity

2.5 Dosage Modification of Ibuprofen in Patients with Mild to Moderate Renal Impairment Receiving Pemetrexed for injection

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

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

2.6 Dosage Modifications for Adverse Reactions

Obtain complete blood count on Days 1, 8, and 15 of each cycle. Assess creatinine clearance prior to each cycle. Do not administer pemetrexed for injection if the creatinine clearance is less than 45 mL/min.

Delay initiation of the next cycle of pemetrexed for injection until:

• recovery of non-hematologic toxicity to Grade 0-2,
• absolute neutrophil count (ANC) is 1500 cells/mm 3 or higher, and
• platelet count is 100,000 cells/mm 3 or higher.

Upon recovery, modify the dosage of pemetrexed for injection in the next cycle as specified in Table 1.

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

2.7 Preparation for Administration

• Pemetrexed for injection is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1
• Calculate the dose of pemetrexed for injection and determine the number of vials needed.
• Reconstitute pemetrexed for injection to achieve a concentration of 25 mg/mL as follows:
  • Reconstitute each 100-mg vial with 4.2 mL of 0.9% Sodium Chloride Injection, USP (preservative-free)
  • Reconstitute each 500-mg vial with 20 mL of 0.9% Sodium Chloride Injection, USP (preservative-free)
  • Reconstitute each 1-gram vial with 40 mL of 0.9% Sodium Chloride Injection, USP (preservative-free)
  • Do not use calcium-containing solutions for reconstitution.
• Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in color from colorless to yellow or greenish-yellow. FURTHER DILUTION IS REQUIRED prior to administration.
• Store reconstituted, preservative-free product under refrigerated conditions [2 to 8°C (36 to 46°F)] for no longer than 24 hours from the time of reconstitution. Discard vial after 24 hours.
• Inspect reconstituted product visually for particulate matter and discoloration prior to further dilution. If particulate matter is observed, discard vial.
• Withdraw the calculated dose of pemetrexed for injection from the vial(s) and discard vial with any unused portion.
• Further dilute pemetrexed for injection with 0.9% Sodium Chloride Injection (preservative-free) to achieve a total volume of 100 mL for intravenous infusion.
• Store diluted, reconstituted product under refrigerated conditions [2 to 8°C (36 to 46°F)] for no more than 24 hours from the time of reconstitution. Discard after 24 hours.

5.1 Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation

Pemetrexed for injection 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 B 12 prior to and throughout pemetrexed plus cisplatin treatment.

Initiate supplementation with oral folic acid and intramuscular vitamin B 12 prior to the first dose of pemetrexed for injection; continue vitamin supplementation during treatment and for 21 days after the last dose of pemetrexed for injection to reduce the severity of hematologic and gastrointestinal toxicity of pemetrexed for injection [see Dosage and Administration ( 2.4)] . Obtain a complete blood count at the beginning of each cycle. Do not administer pemetrexed for injection until the ANC is at least 1500 cells/mm 3 and platelet count is at least 100,000 cells/mm 3. Permanently reduce pemetrexed for injection in patients with an ANC of less than 500 cells/mm 3 or platelet count of less than 50,000 cells/mm 3 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%.

5.2 Renal Failure

Pemetrexed for injection can cause severe, and sometimes fatal, renal toxicity. The incidences of renal failure in clinical studies in which patients received pemetrexed with cisplatin were: 2.1% in Study JMDB and 2.2% in Study JMCH. The incidence of renal failure in clinical studies in which patients received pemetrexed 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 for injection. Withhold pemetrexed for injection in patients with a creatinine clearance of less than 45 mL/minute [see Dosage and Administration ( 2.3)] .

5.3 Bullous and Exfoliative Skin Toxicity

Serious and sometimes fatal, bullous, blistering and exfoliative skin toxicity, including cases suggestive of Stevens-Johnson Syndrome/Toxic epidermal necrolysis can occur with pemetrexed for injection. Permanently discontinue pemetrexed for injection for severe and life-threatening bullous, blistering or exfoliating skin toxicity.

5.4 Interstitial Pneumonitis

Serious interstitial pneumonitis, including fatal cases, can occur with pemetrexed for injection treatment. Withhold pemetrexed for 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 for injection.

5.5 Radiation Recall

Radiation recall can occur with pemetrexed for injection in patients who have received radiation weeks to years previously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue pemetrexed for injection for signs of radiation recall.

5.6 Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment

Exposure to pemetrexed for injection is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen, increasing the risks of adverse reactions of pemetrexed for injection. 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 for injection. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for pemetrexed for injection adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity [see Dosage and Administration ( 2.5), Drug Interactions ( 7), and Clinical Pharmacology ( 12.3)] .

5.7 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, pemetrexed for 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/m 2. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with pemetrexed for injection and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with pemetrexed for injection and for 3 months after the final dose [see Use in Specific Populations ( 8.1, 8.3) and Clinical Pharmacology ( 12.1)] .

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 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.

6.2 Postmarketing Experience

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

Effects of Ibuprofen on Pemetrexed

Ibuprofen increases exposure (AUC) of pemetrexed [see Clinical Pharmacology ( 12.3)] . In patients with creatinine clearance between 45 mL/min and 79 mL/min:

• Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of pemetrexed for injection [see Dosage and Administration ( 2.5)] .
• Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and effectiveness of pemetrexed for injection in pediatric patients have not been established. The safety and pharmacokinetics of pemetrexed for injection were evaluated in two clinical studies conducted in pediatric patients with recurrent solid tumors.Pemetrexed was administered at doses ranging from 400 to 2480 mg/m 2 intravenously over 10 minutes on Day 1 of a 21-day cycle to 32 pediatric patients with recurrent solid tumors in a dose-finding study. The maximum tolerated dose (MTD) was determined to be 1910 mg/m 2 (60 mg/kg for patients <12 months old). Pemetrexed was administered at the MTD every 21 days in an activity-estimating study enrolling 72 patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral primitive neural ectodermal tumor (PNET), rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, or non-brainstem high grade glioma. Patients in both studies received concomitant vitamin B 12 and folic acid supplementation and dexamethasone.

No tumor responses were observed. Adverse reactions observed in pediatric patients were similar to those observed in adults.

Single-dose pharmacokinetics of pemetrexed administered at doses ranging from 400 to 2480 mg/m 2 were evaluated in 22 patients (13 males and 9 females) age 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and C max) appeared to increase proportionally with dose. Average clearance (2.30 L/h/m 2) and half-life (2.3 hours) were similar in pediatric patients compared to adults.

8.5 Geriatric Use

Of the 3,946 patients enrolled in clinical studies of pemetrexed, 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)].

8.6 Patients 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)].

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

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 0.006 times the recommended human dose based on BSA) resulted in reduced fertility, hypospermia, and testicular atrophy.

14.1 Non-Squamous NSCLC

Initial Treatment in Combination with Pembrolizumab and Platinum

The efficacy of pemetrexed in combination with pembrolizumab and platinum chemotherapy was investigated in Study KEYNOTE-189 (NCT02578680), a randomized, multicenter, double-blind, active-controlled trial conducted in patients with metastatic non-squamous NSCLC, regardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease and in whom there were no EGFR or ALK genomic tumor aberrations. Patients with autoimmune disease that required systemic therapy within 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. Randomization was stratified by smoking status (never versus former/current), choice of platinum (cisplatin versus carboplatin), and tumor PD-L1 status (TPS <1% [negative] versus TPS ≥1%). Patients were randomized (2:1) to one of the following treatment arms:

• Pemetrexed 500 mg/m 2, pembrolizumab 200 mg, and investigator's choice of cisplatin 75 mg/m 2 or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by pemetrexed 500 mg/m 2 and pembrolizumab 200 mg intravenously every 3 weeks. pemetrexed was administered after pembrolizumab and prior to platinum chemotherapy on Day 1.
• Placebo, pemetrexed 500 mg/m 2, and investigator's choice of cisplatin 75 mg/m 2 or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by placebo and pemetrexed 500 mg/m 2 intravenously every 3 weeks.

Treatment with pemetrexed continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease as determined by the investigator or unacceptable toxicity.

Patients randomized to placebo, pemetrexed, and platinum chemotherapy were offered pembrolizumab as a single agent at the time of disease progression.

Assessment of tumor status was performed at Week 6, Week 12, and then every 9 weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by BICR RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ. Additional efficacy outcome measures were ORR and duration of response, as assessed by the BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

A total of 616 patients were randomized: 410 patients to the pemetrexed, pembrolizumab, and platinum chemotherapy arm and 206 to the placebo, pemetrexed, and platinum chemotherapy arm. The study population characteristics were: median age of 64 years (range: 34 to 84); 49% age 65 or older; 59% male; 94% White and 3% Asian; 56% ECOG performance status of 1; and 18% with history of brain metastases. Thirty-one percent had tumor PD-L1 expression TPS <1%. Seventy-two percent received carboplatin and 12% were never smokers. A total of 85 patients in the placebo, pemetrexed, and chemotherapy arm received an anti-PD-1/PD-L1 monoclonal antibody at the time of disease progression.

The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to pemetrexed in combination with pembrolizumab and platinum chemotherapy compared with placebo, pemetrexed, and platinum chemotherapy (see Table 10 and Figure 1).

Table 10: Efficacy Results of KEYNOTE-189

a Based on the stratified Cox proportional hazard model.
b Based on stratified log-rank test.
c Response: Best objective response as confirmed complete response or partial response.
d Based on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy and smoking status.
NR = not reached
Endpoint	Pemetrexed Pembrolizumab Platinum Chemotherapy n=410	Placebo Pemetrexed Platinum Chemotherapy n=206
OS
Number (%) of patients with event	127 (31%)	108 (52%)
Median in months (95% CI)	NR (NR, NR)	11.3 (8.7, 15.1)
Hazard ratio a (95% CI)	0.49 (0.38, 0.64)
p-value b	<0.0001
PFS
Number of patients with event (%)	244 (60%)	166 (81%)
Median in months (95% CI)	8.8 (7.6, 9.2)	4.9 (4.7, 5.5)
Hazard ratio a (95% CI)	0.52 (0.43, 0.64)
p-value b	<0.0001
ORR
Overall response rate c (95% CI)	48% (43, 53)	19% (14, 25)
Complete response	0.5%	0.5%
Partial response	47%	18%
p-value d	<0.0001
Duration of Response
Median in months (range)	11.2 (1.1+, 18.0+)	7.8 (2.1+, 16.4+)

1. 
   
   P+P+C = Pemetrexed + pembrolizumab + platinum chemotherapy.
   
   P+C = Pemetrexed + platinum chemotherapy + placebo.

Initial Treatment in Combination with Cisplatin

The efficacy of pemetrexed was evaluated in Study JMDB (NCT00087711), a 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 0 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 a dose of 500 mg/m 2 on Day 1 of each 21-day cycle. Cisplatin was administered intravenously at a dose of 75 mg/m 2 approximately 30 minutes after pemetrexed administration on Day 1 of each cycle, gemcitabine was administered at a dose of 1250 mg/m 2 on Day 1 and Day 8, and cisplatin was administered intravenously at a dose of 75 mg/m 2 approximately 30 minutes after administration of gemcitabine, on Day 1 of each 21-day cycle. Treatment was administered up to a total of 6 cycles; patients in both arms received folic acid, vitamin B 12, 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 a diagnosis of adenocarcinoma, 12% had large cell histology and 20% had other histologic subtypes.

Efficacy results in Study JMDB are presented in Table 11 and Figure 2.

Table 11: Efficacy Results in Study JMDB

a Unadjusted for multiple comparisons.
b Adjusted for gender, stage, basis of diagnosis, and performance status.
Efficacy Parameter	Pemetrexed plus Cisplatin (N=862)	Gemcitabine plus Cisplatin (N=863)
Overall Survival
Median (months)         (95% CI)	10.3 (9.8-11.2)	10.3 (9.6-10.9)
Hazard ratio (HR) a,b         (95% CI)	0.94 (0.84-1.05)
Progression-Free Survival
Median (months)         (95% CI)	4.8 (4.6-5.3)	5.1 (4.6-5.5)
Hazard ratio (HR) a,b         (95% CI)	1.04 (0.94-1.15)
Overall Response Rate         (95% CI)	27.1% (24.2-30.1)	24.7% (21.8-27.6)

In pre-specified analyses assessing the impact of NSCLC histology on overall survival, clinically relevant differences in survival according to histology were observed. These subgroup analyses are shown in Table 12 and Figures 3 and 4. This difference in treatment effect for pemetrexed based on histology demonstrating a lack of efficacy in squamous cell histology was also observed in Studies JMEN and JMEI.

Table 12: Overall Survival in NSCLC Histologic Subgroups in Study JMDB

a Unadjusted for multiple comparisons.
b Adjusted for ECOG PS, gender, disease stage, and basis for pathological diagnosis (histopathological/cytopathological).
Histologic Subgroups	Pemetrexed plus Cisplatin (N=862)	Gemcitabine plus Cisplatin (N=863)
Non-squamous NSCLC (N=1252)
Median (months)         (95% CI)	11.0 (10.1-12.5)	10.1 (9.3-10.9)
HR a,b         (95% CI)	0.84 (0.74-0.96)
Adenocarcinoma (N=847)
Median (months)         (95% CI)	12.6 (10.7-13.6)	10.9 (10.2-11.9)
HR a,b         (95% CI)	0.84 (0.71-0.99)
Large Cell (N=153)
Median (months)         (95% CI)	10.4 (8.6-14.1)	6.7 (5.5-9.0)
HR a,b         (95% CI)	0.67 (0.48-0.96)
Non-squamous, not otherwise specified (N=252)
Median (months)         (95% CI)	8.6 (6.8-10.2)	9.2 (8.1-10.6)
HR a,b         (95% CI)	1.08 (0.81-1.45)
Squamous Cell (N=473)
Median (months)         (95% CI)	9.4 (8.4-10.2)	10.8 (9.5-12.1)
HR a,b         (95% CI)	1.23 (1.00-1.51)

Maintenance Treatment Following First-line Non-pemetrexed Containing Platinum-Based Chemotherapy

The efficacy of pemetrexed as maintenance therapy following first-line platinum-based chemotherapy was evaluated in Study JMEN (NCT00102804), a 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/m 2 intravenously every 21 days or placebo until disease progression or intolerable toxicity. Patients in both study arms received folic acid, vitamin B 12, and dexamethasone [see Dosage and Administration ( 2.4)]. Randomization was carried out using a 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 a partial or complete response to first-line, platinum-based chemotherapy. With regard to tumor characteristics, 81% had Stage IV disease, 73% had non-squamous NSCLC and 27% had squamous NSCLC. Among the 481 patients with non-squamous NSCLC, 68% had adenocarcinoma, 4% had large cell, and 28% had other histologies.

Efficacy results are presented in Table 13 and Figure 5.

Table 13: Efficacy Results in Study JMEN

a Hazard ratios are adjusted for multiplicity but not for stratification variables.
Efficacy Parameter	Pemetrexed	Placebo
Overall survival	N=441	N=222
Median (months)         (95% CI)	13.4 (11.9-15.9)	10.6 (8.7-12.0)
Hazard ratio a         (95% CI)	0.79 (0.65-0.95)
p-value	p=0.012
Progression-free survival per independent review	N=387	N=194
Median (months)         (95% CI)	4.0 (3.1-4.4)	2.0 (1.5-2.8)
Hazard ratio a         (95% CI)	0.60 (0.49-0.73)
p-value	p<0.00001

The results of pre-specified subgroup analyses by NSCLC histology are presented in Table 14 and Figures 6 and 7.

Table 14: Efficacy Results in Study JMEN by Histologic Subgroup

a Hazard ratios are not adjusted for multiplicity
b Primary diagnosis of NSCLC not specified as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma.
Efficacy Parameter	Overall Survival		Progression-Free Survival Per Independent Review
	Pemetrexed (N=441)	Placebo (N=222)	Pemetrexed (N=387)	Placebo (N=194)
Non-squamous NSCLC (n=481)
Median (months)	15.5	10.3	4.4	1.8
HR a	0.70		0.47
(95% CI)	(0.56-0.88)		(0.37-0.60)
Adenocarcinoma (n=328)
Median (months)	16.8	11.5	4.6	2.7
HR a	0.73		0.51
(95% CI)	(0.56-0.96)		(0.38-0.68)
Large cell carcinoma (n=20)
Median (months)	8.4	7.9	4.5	1.5
HR a	0.98		0.40
(95% CI)	(0.36-2.65)		(0.12-1.29)
Other b (n=133)
Median (months)	11.3	7.7	4.1	1.6
HR a	0.61		0.44
(95% CI)	(0.40-0.94)		(0.28-0.68)
Squamous cell NSCLC (n=182)
Median (months)	9.9	10.8	2.4	2.5
HR a	1.07		1.03
(95% CI)	(0.77-1.50)		(0.71-1.49)

Maintenance Treatment Following First-line Pemetrexed Plus Platinum Chemotherapy

The efficacy of pemetrexed as maintenance therapy following first-line platinum-based chemotherapy was also evaluated in PARAMOUNT (NCT00789373), a 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 a complete response (CR) or partial response (PR) or stable disease (SD). Patients were required to have an ECOG PS of 0 or 1. Patients were randomized to receive pemetrexed 500 mg/m 2 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 B 12, 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 a partial or complete response to first-line, platinum-based chemotherapy. With regard to tumor characteristics, 91% had Stage IV disease, 87% had adenocarcinoma, 7% had large cell, and 6% had other histologies.

Efficacy results for PARAMOUNT are presented in Table 15 and Figure 8.

Table 15: Efficacy Results in PARAMOUNT

a Hazard ratios are adjusted for multiplicity but not for stratification variables.
b Based on investigator's assessment.
Efficacy Parameter	Pemetrexed (N=359)	Placebo (N=180)
Overall survival
Median (months)         (95% CI)	13.9 (12.8-16.0)	11.0 (10.0-12.5)
Hazard ratio (HR) a         (95% CI)	0.78 (0.64-0.96)
p-value	p=0.02
Progression-free survival b
Median (months)         (95% CI)	4.1 (3.2-4.6)	2.8 (2.6-3.1)
Hazard ratio (HR) a         (95% CI)	0.62 (0.49-0.79)
p-value	p<0.0001

14.2 Mesothelioma

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/m 2 intravenously over 10 minutes followed 30 minutes later by cisplatin 75 mg/m 2 intravenously over two hours on Day 1 of each 21-day cycle or to receive cisplatin 75 mg/m 2 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 B 12 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 B 12 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 18 and Figure 9.

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.

How Supplied

Pemetrexed for injection, is a white to either light yellow or greenish yellow lyophilized powder supplied in single-dose vials for reconstitution for intravenous infusion.

NDC 68001-547-41: Carton containing one (1) single-dose vial of 100 mg pemetrexed.

NDC 68001-548-41: Carton containing one (1) single-dose vial of 500 mg pemetrexed.

NDC 68001-549-41: Carton containing one (1) single-dose vial of 1 gram pemetrexed.

Storage and Handling

Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Pemetrexed for injection is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1

Discard unused portion.

Premedication and Concomitant Medication: Instruct patients to take folic acid as directed and to keep appointments for vitamin B 12 injections to reduce the risk of treatment-related toxicity. Instruct patients of the requirement to take corticosteroids to reduce the risks of treatment-related toxicity [see Dosage and Administration ( 2.4) and Warnings and Precautions ( 5.1) ].

Myelosuppression: Inform patients of the risk of low blood cell counts and instruct them to immediately contact their physician for signs of infection, fever, bleeding, or symptoms of anemia [see Warnings and Precautions ( 5.1)] .

Renal Failure: Inform patients of the risks of renal failure, which may be exacerbated in patients with dehydration arising from severe vomiting or diarrhea. Instruct patients to immediately contact their healthcare provider for a decrease in urine output [see Warnings and Precautions ( 5.2)] .

Bullous and Exfoliative Skin Disorders: Inform patients of the risks of severe and exfoliative skin disorders. Instruct patients to immediately contact their healthcare provider for development of bullous lesions or exfoliation in the skin or mucous membranes [see Warnings and Precautions ( 5.3)] .

Interstitial Pneumonitis: Inform patients of the risks of pneumonitis. Instruct patients to immediately contact their healthcare provider for development of dyspnea or persistent cough [see Warnings and Precautions ( 5.4)] .

Radiation Recall: Inform patients who have received prior radiation of the risks of radiation recall. Instruct patients to immediately contact their healthcare provider for development of inflammation or blisters in an area that was previously irradiated [see Warnings and Precautions ( 5.5)] .

Increased Risk of Toxicity with Ibuprofen in Patients with Renal Impairment: Advise patients with mild to moderate renal impairment of the risks associated with concomitant ibuprofen use and instruct them to avoid use of all ibuprofen containing products for 2 days before, the day of, and 2 days following administration of pemetrexed for injection [see Dosage and Administration ( 2.5), Warnings and Precautions ( 5.6), and Drug Interactions ( 7)] .

Embryo-Fetal Toxicity: Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus [see Warnings and Precautions ( 5.7) and Use in Specific Populations ( 8.1)] . Advise females of reproductive potential to use effective contraception during treatment with pemetrexed for injection and for 6 months after the final dose. Advise females to inform their prescriber of a known or suspected pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment with pemetrexed for injection and for 3 months after the final dose [see Warnings and Precautions ( 5.7) and Use in Specific Populations ( 8.3)] .

Lactation: Advise women not to breastfeed during treatment with pemetrexed for injection and for 1 week after the final dose [see Use in Specific Populations ( 8.2)] .

Manufactured by:

Intas Pharmaceuticals Limited,

Plot No. 5 to 14, Pharmez,

Near Village Matoda,

Sarkhej-Bavla Highway,

Taluka Sanand, Ahmedabad,

Gujarat 382 213, India.

For BluePoint Laboratories

51 5679 0 729034

Rev.04/2022