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 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.

Limitations of Use:Pemetrexed for injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer  [see Clinical Studies14.1].

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 2as 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 2as 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 2as 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 2as 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 2as 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 3or higher, and
• platelet count is 100,000 cells/mm 3or 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  hazardous 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)
  • Do not use calcium-containing solutions for reconstitution.
• Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in color from colorless to yellow or green-yellow. FURTHER DILUTION IS REQUIRED prior to administration.
• Store reconstituted, preservative-free product under refrigerated conditions [2-8°C (36-46°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 [2-8°C (36-46°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;  continue  vitamin  supplementation  during  treatment  and  for 21 days after the last dose of pemetrexed to reduce the severity of hematologic and gastrointestinal  toxicity  of  pemetrexed  for  injection  [s ee  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 for injection arm  required red  blood cell  transfusions  compared to 7%  of  patients  in the cisplatin arm [ see Adverse Reactions (6.1)]. In Studies JMEN, PARAMOUNT, and  JMEI,  where  all patients received vitamin supplementation, incidence of Grade 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.

5.5 Radiation Recall

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

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

Exposure  to  pemetrexed  is  increased  in  patients  with  mild  to  moderate  renal impairment  who  take  concomitant  ibuprofen,  increasing  the  risks  of  adverse  reactions  of pemetrexed.  In  patients  with  creatinine  clearances  between  45  mL/min  and  79 mL/min,  avoid  administration  of  ibuprofen  for  2  days  before,  the  day  of,  and  2  days  following administration  of  pemetrexed.  If  concomitant  ibuprofen  use  cannot  be  avoided, monitor  patients  more  frequently  for  pemetrexed  adverse  reactions,  including myelosuppression,   renal,   and   gastrointestinal   toxicity   [see   Dosage   and   Administration   (2.5),DrugInteractions ( 7), and Clinical Pharmacology ( 12.3)].

5.7 Embryo-Fetal Toxicity

Based   on   findings   from   animal   studies   and   its   mechanism   of   action,   pemetrexed   can cause  fetal  harm  when  administered  to  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 a fetus.  Advise  females  of  reproductive  potential  to  use  effective  contraception  during treatment  with  pemetrexed and  for  6  months  after  the last  dose.  Advise  males with  female  partners  of  reproductive  potential  to  use  effective  contraception  during  treatment with  pemetrexed and  for  3  months  after  the last  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 for injection,  when administered as  a single  agent, are  fatigue,  nausea,  and anorexia. The  most  common adverse reactions (incidence ≥20%) of pemetrexed for injection, when  administered in combination with cisplatin are vomiting,  neutropenia,  anemia,  stomatitis/pharyngitis,  thrombocytopenia,  and  constipation.  The most  common  adverse  reactions  (incidence  ≥20%)  of  pemetrexed for injection,  when  administered  in combination  with  pembrolizumab  and  platinum  chemotherapy,  are  fatigue/asthenia,  nausea, constipation,  diarrhea,  decreased  appetite,  rash,  vomiting,  cough,  dyspnea,  and  pyrexia.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of pemetrexed for injection. Because these reactions are reported voluntarily from 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

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

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to initiating pemetrexed for injection [see Use in Specific Populations (8.1)].

8.4 Pediatric Use

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


The safety and pharmacokinetics of pemetrexed for injection were evaluated in two clinical studies conducted in pediatric patients with recurrent solid tumors (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.


Single-dose pharmacokinetics of pemetrexed were evaluated in 22 patients age 4 to 18 years enrolled in NCT00070473 were within range of values in adults.

8.5 Geriatric Use

Of  the  3,946  patients  enrolled  in  clinical  studies  of  pemetrexed  for injection,  34%  were  65  and  over  and  4% were 75 and over. No  overall differences in effectiveness were observed between these patients and  younger patients. The incidences of Grade  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 for   injection   is   primarily   excreted   by the   kidneys. Decreased   renal   function results in reduced clearance and  greater exposure (AUC) to pemetrexed for injection compared with patients  with  normal  renal  function  [ Warnings  and  Precautions  (5.2,  5.6)  and  Clinical  Pharmacology (12.3)].  No  dose  is  recommended  for  patients  with  creatinine  clearance  less  than  45  mL/min  [ see Dosage and Administration (2.3)].

12.1 Mechanism of Action

Pemetrexed  for 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.

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 0.0006 times the recommended human dose based on BSA) resulted in reduced fertility, hypospermia, and testicular atrophy.

14.1 Non-Squamous NSCLC

Maintenance Treatment Following First-line Non-Pemetrexed for injection 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 2intravenously  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  andAdministration (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 for injection 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

Efficacy Parameter	Pemetrexed for injection	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

aHazard ratios are adjusted for multiplicity but not for stratification variables.

Figure 5: Kaplan-Meier Curves for Overall Survival in Study JMEN

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

Table 14: Efficacy Results in Study JMEN by Histologic Subgroup

Efficacy Parameter	Overall Survival		Progression-Free Survival Per Independent Review
	Pemetrexed for injection (N=441)	Placebo (N=222)	Pemetrexed for injection (N=387)	Placebo (N=194)
Non-squamous NSCLC (n=481)
Median (months)	15.5	10.3	4.4	1.8
HR a         (95% CI)	0.70 (0.56-0.88)		0.47 (0.37-0.60)
Adenocarcinoma (n=328)
Median (months	16.8	11.5	4.6	2.7
HR a         (95% CI)	0.73 (0.56-0.96)		0.51 (0.38-0.68)
Large cell carcinoma (n=20)
Median (months)	8.4	7.9	4.5	1.5
HR a         (95% CI)	0.98 (0.36-2.65)		0.40 (0.12-1.29)
Other b(n=133)
Median (months)	11.3	7.7	4.1	1.6
HR a         (95% CI)	0.61 (0.40-0.94)		0.44 (0.28-0.68)
Squamous cell NSCLC (n=182)
Median (months)	9.9	10.8	2.4	2.5
HR a         (95% CI)	1.07 (0.77-1.50)		1.03 (0.71-1.49)

a Hazard ratios are not adjusted for multiplicity.

bPrimary diagnosis of NSCLC not specified as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma.

Figure 6: Kaplan-Meier Curves for Overall Survival in Non-squamous NSCLC in Study JMEN

Maintenance Treatment Following First-line Pemetrexed for injection 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 2intravenously  every  21  days  or  placebo  until  disease  progression.  Randomization  was  stratified by  response  to  pemetrexed for injection  in  combination  with  cisplatin  induction  therapy  (CR  or  PR  versus SD),  disease stage (IIIb versus IV), and ECOG PS (0 versus 1). Patients in both arms received folic acid, vitamin 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 for injection  and  180  patients randomized  to  placebo.  The median  age  was  61  years  (range 32  to  83  years);  58% were  male; 95%  were White, 4.5% were  Asian,  and <1% were Black or  African  American; 67% had an ECOG PS of 1; 78% were current or former smokers; and  43% of  the population achieved 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

Efficacy Parameter	Pemetrexed for injection (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 survivalb
Median (months)         (95% CI)	4.1 (3.2-4.6)	2.8 (2.6-3.1)
Hazard ratio (HR) a         (95% CI)	0.62 (0.49-0.79)
p-value	p<0.0001

a Hazard ratios are adjusted for multiplicity but not for stratification variables.

bBased on investigator's assessment.

Figure 8: Kaplan-Meier Curves for Overall Survival in PARAMOUNT

14.2 Mesothelioma

The efficacy of pemetrexed for injection 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 for injection 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 for injection 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 for injection, 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  18and   Figure 9.

a Hazard ratios are not adjusted for stratification variables.

bNot a pre-specified analysis.

Figure 9: Kaplan-Meier Curves for Overall Survival in Study JMCH

Based upon prospectively defined criteria (modified Southwest Oncology Group methodology)  the  objective  tumor  response  rate  for  pemetrexed for injection  plus  cisplatin  was greater than the objective tumor response rate for cisplatin  alone.  There  was  also improvement in lung function (forced vital capacity) in the pemetrexed for injection plus cisplatin arm  compared to the control arm.

How Supplied

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

NDC 70069-834-01: Carton containing one (1) single-dose vial of 100 mg pemetrexed.

NDC 70069-835-01: Carton containing one (1) single-dose vial of 500 mg pemetrexed.

Storage and Handling

Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. 

Pemetrexed for injection USP is a hazardous drug. Follow applicable special handling and disposal procedures.  1

Premedication and Concomitant Medication: Instruct patients to take folic acid as directed and to keep appointments for vitamin B 12injections 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 last 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 last 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 last dose [see Use in Specific Populations ( 8.2)] .

Manufactured for:
Somerset Therapeutics, LLC.
Somerset, NJ 08873
Made  in   India