PEMETREXED- pemetrexed disodium injection, powder, lyophilized, for solution

Pemetrexed by

Drug Labeling and Warnings

Pemetrexed by is a Prescription medication manufactured, distributed, or labeled by Somerset Therapeutics LLC, Reliance Life Sciences Private Limited. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    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 DOSAGE AND ADMINISTRATION

    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

    Vitamin Supplementation

    • Initiate folic acid 400 mcg to 1000 mcg orally once daily, beginning 7 days before the first dose of pemetrexed for injection and continuing until 21 days after the last dose of pemetrexed for injection [see Warnings and Precautions ( 5.1)] .
    • Administer vitamin B 12,1 mg intramuscularly, 1 week prior to the first dose of pemetrexed for injection and every 3 cycles thereafter. Subsequent vitamin B 12injections may be given the same day as treatment with pemetrexed for injection [see Warnings and Precautions ( 5.1)] . Do not substitute oral vitamin B12for intramuscular vitamin B12.

    Corticosteroids

    • Administer dexamethasone 4 mg orally twice daily for three consecutive days, beginning the day before each pemetrexed for injection administration.

    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 .

    Table 1: Recommended Dosage Modifications for Adverse Reactions *
  • * National Cancer Institute Common Toxicity Criteria for Adverse Events version 2 (NCI CTCAE v2)
    		•
    Toxicity in Most Recent Treatment Cycle
    		Pemetrexed for injection Dose Modification for Next Cycle
    Myelosuppressive toxicity[see Warnings and Precautions ( 5.1)]
    ANC less than 500/mm 3andplatelets greater than or equal to 50,000/mm 3
    OR
       Platelet count less than 50,000/mm 3without bleeding.
    		75% of previous dose
    Platelet count less than 50,000/mm 3with bleeding
    		50% of previous dose
    Recurrent Grade 3 or 4 myelosuppression after 2 dose reductions
    		Discontinue
    Non-hematologic toxicity
    Any Grade 3 or 4 toxicities EXCEPT mucositis or neurologic toxicity
    OR
       Diarrhea requiring hospitalization
    		75% of previous dose
    Grade 3 or 4 mucositis
    		50% of previous dose
    Renal toxicity [see Warnings and Precautions ( 5.2)]
    		Withhold until creatinine clearance is 45 mL/min or greater
    Grade 3 or 4 neurologic toxicity
    		Permanently discontinue
    Recurrent Grade 3 or 4 non-hematologic toxicity after 2 dose reductions
    		Permanently discontinue
    Severe and life-threatening Skin Toxicity [see Warnings and Precautions ( 5.3)]
    		Permanently discontinue
    Interstitial Pneumonitis [see Warnings and Precautions ( 5.4)]
    		Permanently discontinue

    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.
  • 3 DOSAGE FORMS AND STRENGTHS

    For injection: 100 mg or 500 mg pemetrexed for injection as a white to light-yellow or green-yellow lyophilized powder in single-dose vials for reconstitution.

  • 4 CONTRAINDICATIONS

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

  • 5 WARNINGS AND PRECAUTIONS

    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 ADVERSE REACTIONS

    The following adverse reactions are discussed in greater detail in other sections of the labeling:

    • Myelosuppression [see Warnings and Precautions ( 5.1)]
    • Renal failure [see Warnings and Precautions ( 5.2)]
    • Bullous and exfoliative skin toxicity [see Warning and Precautions ( 5.3)]
    • Interstitial pneumonitis [see Warnings and Precautions ( 5.4)]
    • Radiation recall [see Warnings and Precautions ( 5.5)]

    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.

    Non-Squamous NSCLC





    First-line Treatment of Metastatic Non-squamous NSCLC with Pembrolizumab and Platinum Chemotherapy


    The safety of pemetrexed for injection, in combination with pembrolizumab and investigator's choice of  platinum (either  carboplatin  or  cisplatin),  was  investigated  in  Study  KEYNOTE-189,  a  multicenter, double-blind, randomized (2:1), active-controlled  trial in patients with previously untreated, metastatic  non-squamous  NSCLC  with  no  EGFR  or ALK  genomic  tumor  aberrations.  A total  of 607  patients  received  pemetrexed for injection,  pembrolizumab,  and  platinum  every  3  weeks  for  4  cycles followed by pemetrexed for injection and pembrolizumab (n=405), or placebo, pemetrexed, and platinum every   3   weeks   for   4   cycles   followed   by   placebo   and   pemetrexed for injection   (n=202).   Patients   with   autoimmune disease that required systemic therapy within 2  years of treatment; a medical condition that required  immunosuppression;  or  who  had  received  more  than  30  Gy  of  thoracic radiation within the prior 26 weeks were  ineligible  [ see  Clinical Studies  (14.1)].
    The  median  duration  of  exposure  to  pemetrexed for injection  was  7.2  months  (range:  1  day  to  1.7  years). Seventy-two percent of  patients received carboplatin.  The study population characteristics were median age of 64 years (range: 34 to 84), 49%  age  65  years  or  older,  59%  male,  94% White and 3%  Asian, and 18% with history of brain metastases at baseline.

    Pemetrexed for injection was discontinued for adverse reactions in 23% of patients in the pemetrexed for injection, pembrolizumab, and platinum  arm.  The most common adverse reactions resulting in discontinuation of pemetrexed in  this  arm  were  acute  kidney  injury  (3%) and  pneumonitis  (2%).  Adverse  reactions leading  to  interruption  of  pemetrexed  occurred  in  49%  of  patients  in  the  pemetrexed for injection, pembrolizumab, and platinum arm. The most common adverse reactions or laboratory abnormalities leading  to  interruption  of  pemetrexed for injection  in  this  arm  (≥2%)  were  neutropenia  (12%),  anemia  (7%),  asthenia (4%),  pneumonia  (4%),  thrombocytopenia  (4%),  increased  blood  creatinine  (3%),  diarrhea  (3%), and  fatigue (3%).



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

    Table 2: Adverse Reactions Occurring in ≥20% of Patients in KEYNOTE-189
  • * Graded per NCI CTCAE version 4.03.
  • † Includes asthenia and fatigue.
  • ‡ Includes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular.
    		•

    Pemetrexed for injection
    Pembrolizumab
    PlatinumChemotherapy  
    n=405

    Placebo  
    Pemetrexed for injection
    Platinum Chemotherapy
    n=202
    Adverse Reaction
    		All Grades *
    (%)
    		Grade 3-4
    (%)
    		All Grades
    (%)
    		Grade 3-4
    (%)
    Gastrointestinal Disorders
    Nausea
    		56
    		3.5
    		52
    		3.5
    Constipation
    		35
    		1.0
    		32
    		0.5
    Diarrhea
    		31
    		5
    		21
    		3.0
    Vomiting
    		24
    		3.7
    		23
    		3.0
    General Disorders and Administration Site Conditions
    Fatigue †
    		56
    		12
    		58
    		6
    Pyrexia
    		20
    		0.2
    		15
    		0
    Metabolism and Nutrition Disorders
    Decreased appetite
    		28
    		1.5
    		30
    		0.5
    Skin and Subcutaneous Tissue Disorders
    Rash ‡
    		25
    		2.0
    		17
    		2.5
    Respiratory, Thoracic and Mediastinal Disorders
    Cough
    		21
    		0
    		28
    		0
    Dyspnea
    		21
    		3.7
    		26
    		5

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

    Table 3: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients in KEYNOTE-189
  • * Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: pemetrexed for injection/pembrolizumab/platinum chemotherapy (range: 381 to 401 patients) and placebo/ pemetrexed for injection/platinum chemotherapy (range: 184 to 197patients)
  • † Graded per NCI CTCAE version 4.03.
    		•

    Pemetrexed for injection
    Pembrolizumab
    Platinum Chemotherapy

    Placebo  

    Pemetrexed for injection   
    Platinum Chemotherapy
    Laboratory Test *
    		All Grades †
    %
    		Grades 3-4
    %
    		All Grades
    %
    		Grades 3-4
    %
    Chemistry
    Hyperglycemia
    		63
    		9
    		60
    		7
    Increased ALT
    		47
    		3.8
    		42
    		2.6
    Increased AST
    		47
    		2.8
    		40
    		1.0
    Hypoalbuminemia
    		39
    		2.8
    		39
    		1.1
    Increased creatinine
    		37
    		4.2
    		25
    		1.0
    Hyponatremia
    		32
    		7
    		23
    		6
    Hypophosphatemia
    		30
    		10
    		28
    		14
    Increased alkaline phosphatase
    		26
    		1.8
    		29
    		2.1
    Hypocalcemia
    		24
    		2.8
    		17
    		0.5
    Hyperkalemia
    		24
    		2.8
    		19
    		3.1
    Hypokalemia
    		21
    		5
    		20
    		5
    Hematology
    Anemia
    		85
    		17
    		81
    		18
    Lymphopenia
    		64
    		22
    		64
    		25
    Neutropenia
    		48
    		20
    		41
    		19
    Thrombocytopenia
    		30
    		12
    		29
    		8

    Initial Treatment in Combination with Cisplatin


    The safety of pemetrexed for injection was evaluated in Study JMDB, a randomized (1:1), open-label, multicenter trial conducted in  chemotherapy-naive patients with locally advanced or metastatic NSCLC. Patients received either pemetrexed for injection 500  mg/m 2intravenously and cisplatin 75 mg/m 2intravenously  on Day 1 of each 21-day cycle  (n=839) or gemcitabine  1250  mg/m 2intravenously on Days 1  and  8  and  cisplatin  75  mg/m 2 intravenously  on  Day  1  of  each  21-day  cycle  (n=830).  All patients  were  fully  supplemented  with  folic  acid  and  vitamin   B 12.

    Study JMDB excluded patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS  of  2  or  greater),  uncontrolled  third-space  fluid  retention,  inadequate  bone  marrow  reserve  and  organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or  other  non-steroidal  anti-inflammatory  drugs  or  unable  to  take  folic  acid,  vitamin  B 12 or  corticosteroids were also excluded from the study.
    The data described below reflect exposure to pemetrexed for injection plus cisplatin in 839 patients in Study JMDB. Median age was 61 years (range 26-83 years); 70% of patients were men; 78% were White,16% were Asian, 2.9% were Hispanic or Latino, 2.1% were Black or African American, and <1% were  other  ethnicities;  36% had  an  ECOG  PS  0.  Patients received  a  median  of  5  cycles  of  pemetrexed.

    Table 4provides the frequency and severity of adverse reactions that occurred in ≥5% of 839 patients receiving pemetrexed for injection in combination with cisplatin in Study JMDB. Study JMDB was not designed  to  demonstrate  a  statistically  significant  reduction  in  adverse  reaction  rates  for  pemetrexed for injection, as compared to the control arm, for any specified adverse reaction listed in Table 4.

    Table 4: Adverse Reactions Occurring in ≥5% of Fully Vitamin-Supplemented Patients Receiving Pemetrexed in Combination with Cisplatin Chemotherapy in Study JMDB
  • * NCI CTCAE version 2.0
    		•

    Adverse Reaction *
    Pemetrexed for injection /  
    Cisplatin   (N=839)
    Gemcitabine/Cisplatin
    (N=830)
    All Grades
    (%)
    		Grade 3-4
    (%)
    		All Grades
    (%)
    		Grade 3-4
    (%)
    All adverse reactions
    		90
    		37
    		91
    		53
     Laboratory
      Hematologic
    Anemia
    		33
    		6
    		46
    		10
    Neutropenia
    		29
    		15
    		38
    		27
    Thrombocytopenia
    		10
    		4
    		27
    		13
      Renal
    Elevated creatinine
    		10
    		1
    		7
    		1
     Clinical
      Constitutional symptoms
    Fatigue
    		43
    		7
    		45
    		5
      Gastrointestinal
    Nausea
    		56
    		7
    		53
    		4
    Vomiting
    		40
    		6
    		36
    		6
    Anorexia
    		27
    		2
    		24
    		1
    Constipation
    		21
    		1
    		20
    		0
    Stomatitis/pharyngitis
    		14
    		1
    		12
    		0
    Diarrhea
    		12
    		1
    		13
    		2
    Dyspepsia/heartburn
    		5
    		0
    		6
    		0
      Neurology
    Sensory neuropathy
    		9
    		0
    		12
    		1
    Taste disturbance
    		8
    		0
    		9
    		0
      Dermatology/Skin
    Alopecia
    		12
    		0
    		21
    		1
    Rash/Desquamation
    		7
    		0
    		8
    		1

    The following additional adverse reactions of pemetrexed  were observed.

    Incidence 1% to <5%
    Body as a Whole —febrile neutropenia, infection, pyrexia
    General Disorders —dehydration
    Metabolism and Nutrition —increased AST, increased ALT
    Renal —renal failure
    Eye Disorder —conjunctivitis

    Incidence <1%
    Cardiovascular —arrhythmia
    General Disorders —chest pain
    Metabolism and Nutrition —increased GGT
    Neurology —motor neuropathy










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


    In Study JMEN, the safety of pemetrexed was evaluated in a randomized (2:1), placebo- controlled, multicenter trial conducted in patients with non-progressive locally advanced or metastatic NSCLC following four cycles of a first-line, platinum-based chemotherapy regimen. Patients received either pemetrexed 500 mg/m 2or matching placebo intravenously every 21 days until disease progression or unacceptable toxicity. Patients in both study arms were fully supplemented with folic acid and vitamin B 12.





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

    The   data   described   below   reflect   exposure   to   pemetrexed for injection   in   438   patients   in   Study   JMEN.   Median   age was   61   years   (range   26-83   years),   73%   of   patients   were   men;   65%   were   White,   31%   were   Asian,   2.9% were  Hispanic  or  Latino,  and  <2% were  other ethnicities; 39% had an ECOG PS 0. Patients received a  median  of  5  cycles  of  pemetrexed for injection  and  a  relative  dose  intensity  of  pemetrexed for injection  of  96%.
    Approximately  half  the  patients  (48%)  completed  at  least  six,  21-day  cycles  and  23%  completed ten or more 21-day cycles of pemetrexed for injection.



    Table 5 provides the frequency and severity of adverse reactions reported in ≥5% of the 438 pemetrexed for injection-treated patients  in Study JMEN.

    Table 5: Adverse Reactions Occurring in ≥5% of Patients Receiving Pemetrexed for injection in Study JMEN

  • * NCI CTCAE version 3.0
    		•
    Adverse Reaction *

    Pemetrexed  for injection(N=438)

    Placebo
    (N=218)
    All Grades
    (%)
    		Grade 3-4
    (%)
    		All Grades
    (%)
    		Grade 3-4
    (%)
    All adverse reactions
    		66
    		16
    		37
    		4
    Laboratory
    Hematologic
    Anemia
    		15
    		3
    		6
    		1
    Neutropenia
    		6
    		3
    		0
    		0
    Hepatic
    Increased ALT
    		10
    		0
    		4
    		0
    Increased AST
    		8
    		0
    		4
    		0
    Clinical
    Constitutional symptoms
    Fatigue
    		25
    		5
    		11
    		1
    Gastrointestinal
    Nausea
    		19
    		1
    		6
    		1
    Anorexia
    		19
    		2
    		5
    		0
    Vomiting
    		9
    		0
    		1
    		0
    Mucositis/stomatitis
    		7
    		1
    		2
    		0
    Diarrhea
    		5
    		1
    		3
    		0
    Infection 
    		5
    		2
    		2
    		0
    Neurology
    Sensory neuropathy
    		9
    		1
    		4
    		0
    Dermatology/Skin
    Rash/desquamation
    		10
    		0
    		3
    		0


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

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


    Incidence 1% to <5%
    Dermatology/Skin — alopecia, pruritus/itching
    Gastrointestinal — constipation
    General Disorders — edema, fever

    Hematologic — thrombocytopenia
    Eye Disorder — ocular surface disease (including conjunctivitis), increased lacrimation


    Incidence <1%
    Cardiovascular — supraventricular arrhythmia
    Dermatology/Skin — erythema multiforme
    General Disorders — febrile neutropenia, allergic reaction/hypersensitivity
    Neurology — motor neuropathy
    Renal — renal failure


    Maintenance Treatment Following First-line Pemetrexed Plus Platinum Chemotherapy


    The safety of pemetrexed was evaluated in PARAMOUNT, a randomized (2:1), placebo-  controlled  study  conducted  in  patients  with  non-squamous  NSCLC  with  non-progressive  (stable  or responding disease) locally advanced or metastatic  NSCLC following four cycles of pemetrexed in combination  with  cisplatin  as  first-line  therapy  for  NSCLC.  Patients  were  randomized  to  receive pemetrexed  500  mg/m 2 or  matching  placebo  intravenously  on Day  1  of each 21-day  cycle  until disease  progression  or  unacceptable  toxicity.  Patients  in  both  study  arms  received  folic  acid and vitamin   B 12supplementation.

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

    The  data  described below  reflect exposure to pemetrexed in 333  patients  in PARAMOUNT. Median age was 61 years  (range 32 to 83 years);  58% of patients were  men; 94%  were  White, 4.8% were Asian, and <1% were Black or African  American; 36% had an ECOG PS 0. The median number  of  maintenance  cycles  was  4  for  pemetrexed  and  placebo  arms.  Dose  reductions  for adverse reactions occurred in 3.3%  of  patients in  the  pemetrexed arm and  0.6%  in the  placebo arm.  Dose delays for adverse reactions occurred in 22% of patients in the pemetrexed arm and  16% in the placebo arm.

    Table 6 provides the frequency and severity of adverse reactions reported in ≥5% of the 333 pemetrexed-treated patients  in PARAMOUNT.



    Table 6: Adverse Reactions Occurring in ≥5% of Patients Receiving Pemetrexed  in PARAMOUNT

    Adverse Reaction a
    		Pemetrexed 
    (N=333)
    		Placebo
    (N=167)
    All Grades
    (%)
    		Grade 3-4
    (%)
    		All Grades
    (%)
    		Grades 3-4
    (%)
    All adverse reactions
    		53
    		17
    		34
    		4.8
    Laboratory
    Hematologic
    Anemia
    		15
    		4.8
    		4.8
    		0.6
    Neutropenia
    		9
    		3.9
    		0.6
    		0
    Clinical
    Constitutional symptoms
    Fatigue
    		18
    		4.5
    		11
    		0.6
    Gastrointestinal
    Nausea
    		12
    		0.3
    		2.4
    		0
    Vomiting
    		6
    		0
    		1.8
    		0
    Mucositis/stomatitis
    		5
    		0.3
    		2.4
    		0
    General disorders
    Edema
    		5
    		0
    		3.6
    		0

    a NCI CTCAE version 3.0


    The requirement for red blood cell (13% versus 4.8%) and platelet (1.5% versus 0.6%) transfusions, erythropoiesis stimulating agents (12% versus 7%), and granulocyte colony stimulating factors (6% versus 0%) were higher in the pemetrexed  arm compared to the placebo arm.


    The following additional Grade 3 or 4 adverse reactions were observed more frequently in the pemetrexed arm.


    Incidence 1% to <5%

    Blood/Bone Marrow thrombocytopenia

    General Disorders febrile neutropenia


    Incidence <1%

    Cardiovascular- ventricular tachycardia, syncope

    General Disorders- pain

    Gastrointestinal- gastrointestinal obstruction

    Neurologic -depression

    Renal -renal failure

    Vascular -pulmonary embolism




    Treatment of  Recurrent Disease  After  Prior   Chemotherapy

    The  safety  of  pemetrexed for injection  was  evaluated  in  Study  JMEI,  a  randomized  (1:1),  open-label,  active- controlled trial conducted  in patients who had progressed following platinum-based chemotherapy.  Patients  received  pemetrexed  500  mg/m 2 intravenously  or  docetaxel  75  mg/m 2intravenously  on Day  1 of each  21-day  cycle.  All  patients  on the  pemetrexed for injection arm  received folic acid and vitamin B 12supplementation.

    Study  JMEI  excluded  patients  with  an  ECOG  PS  of  3  or  greater,  uncontrolled third-space  fluid  retention, inadequate bone  marrow reserve and organ function, or a calculated creatinine clearance less  than  45  mL/min.  Patients  unable  to  discontinue  aspirin  or  other  non-steroidal  anti- inflammatory  drugs  or  unable  to  take  folic  acid,  vitamin  B 12 or  corticosteroids  were also excluded from the study.

    The  data  described  below  reflect  exposure  to  pemetrexed  for injection  in  265  patients  in  Study  JMEI.  Median  age was  58  years  (range  22 to 87 years); 73% of patients were men; 70% were  White, 24% were Asian, 2.6%  were  Black  or African  American,  1.8%  were Hispanic or Latino, and <2% were other ethnicities; 19% had an ECOG PS 0.

    Table 7 provides the frequency and severity of adverse reactions reported in ≥5% of the 265 pemetrexed  for injection -treated patients  in Study JMEI. Study JMEI is not designed to demonstrate a statistically significant  reduction  in  adverse  reaction  rates  for  pemetrexed, as  compared to  the control  arm,  for any  specified  adverse  reaction  listed  in  the  Table  7  below.

    Table  7:  Adverse  Reactions  Occurring  in  ≥5%  of  Fully  Supplemented  Patients  Receiving Pemetrexed  for injection  in Study JMEI
    Adverse Reactiona


    Pemetrexed for injection     (N=265)
    		Docetaxel
    (N=276)
    All Grades
    (%)
    		Grades 3-4
    (%)
    		All Grade
    (%)
    		Grades 3-4
    (%)
    Laboratory
    Hematologic
    Anemia
    		19
    		4
    		22
    		4
    Neutropenia
    		11
    		5
    		45
    		40
    Thrombocytopenia
    		8
    		2
    		1
    		0
    Hepatic
    Increased ALT
    		8
    		2
    		1
    		0
    Increased AST
    		7
    		1
    		1
    		0
    Clinical
    Gastrointestinal
    Nausea
    		31
    		3
    		17
    		2
    Anorexia
    		22
    		2
    		24
    		3
    Vomiting
    		16
    		2
    		12
    		1
    Stomatitis/pharyngitis
    		15
    		1
    		17
    		1
    Diarrhea
    		13
    		0
    		24
    		3
    Constipation
    		6
    		0
    		4
    		0
    Constitutional symptoms
    Fatigue
    		34
    		5
    		36
    		5
    Fever
    		8
    		0
    		8
    		0
    Dermatology/Skin
    Rash/desquamation
    		14
    		0
    		6
    		0
    Pruritus
    		7
    		0
    		2
    		0
    Alopecia
    		6
    		1
    		38
    		2

    aNCI CTCAE version 2.0.

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


    Incidence 1% to <5%

    Body as a Whole— abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection

    Dermatology/Skin— erythema multiforme

    Neurology— motor neuropathy, sensory neuropathy


    Incidence <1%

    Cardiovascular— supraventricular arrhythmias

    Renal— renal failure

    Mesothelioma



    The  safety  of  pemetrexed for injection  was  evaluated  in  Study  JMCH,  a  randomized  (1:1),  single-blind  study conducted  in  patients  with  MPM  who  had  received  no  prior  chemotherapy  for  MPM.  Patients received pemetrexed 500 mg/m 2intravenously in  combination with cisplatin 75 mg/m 2intravenously on  Day  1 of each 21-day cycle or cisplatin 75  mg/m 2intravenously  on  Day  1  of  each  21-day  cycle administered until  disease  progression or  unacceptable  toxicity. Safety  was assessed  in 226 patients   who   received   at   least   one   dose   of   pemetrexed   in   combination   with   cisplatin   and   222   patients who  received  at  least  one dose of cisplatin alone. Among 226 patients who received pemetrexed in combination with cisplatin, 74% (n=168)  received full supplementation with folic acid and vitamin B 12during study therapy, 14% (n=32) were never supplemented,  and 12% (n=26) were partially supplemented.
    Study  JMCH  excluded  patients  with  Karnofsky  Performance  Scale  (KPS)  of  less  than  70, inadequate  bone  marrow  reserve  and  organ  function,  or  a  calculated  creatinine  clearance  less  than 45 mL/min. Patients unable to stop using aspirin  or  other non-steroidal anti-inflammatory drugs were also excluded from the study.
    The  data  described  below  reflect  exposure  to  pemetrexed  for injection  in  168  patients  that  were  fully  supplemented with folic acid and  vitamin B 12. Median age was 60 years (range 19 to 85 years); 82% were men; 92%  were  White,  5%  were  Hispanic  or  Latino,  3.0%  were  Asian,  and  <1%  were  other ethnicities; 54% had KPS of 90-100. The median number of treatment  cycles administered was 6  in the pemetrexed/cisplatin fully supplemented group and 2 in the pemetrexed/cisplatin never supplemented   group.   Patients   receiving   pemetrexed  for injection   in   the   fully   supplemented   group   had   a   relative dose intensity of 93%  of the protocol-specified pemetrexed dose intensity. The most common adverse reaction resulting in dose delay was  neutropenia.
    Table 8 provides the frequency and severity of adverse reactions ≥5% in the subgroup of pemetrexed  for injection  - treated patients who  were  fully  vitamin  supplemented  in  Study  JMCH. Study  JMCH  was  not  designed  to demonstrate  a  statistically  significant  reduction  in  adverse  reaction  rates  for  pemetrexed,  as compared  to  the  control  arm,  for  any  specified  adverse  reaction  listed  in  the  table  below.

    Table  8:  Adverse  Reactions  Occurring  in  ≥5%  of  Fully  Supplemented  Subgroup  of  Patients Receiving  Pemetrexed  for injection  /Cisplatin in Study JMCH a
    Adverse Reactionb
    		Pemetrexed for injection/Cisplatin
    (N=168)
    		Cisplatin
    (N=163)
    All Grades
    (%)
    		Grade 3-4
    (%)
    		All Grades
    (%)
    		Grade 3-4
    (%)
    Laboratory
    Hematologic
    Neutropenia
    		56
    		23
    		13
    		3
    Anemia
    		26
    		4
    		10
    		0
    Thrombocytopenia
    		23
    		5
    		9
    		0
    Renal
    Elevated creatinine
    		11
    		1
    		10
    		1
    Decreased creatinine clearance
    		16
    		1
    		18
    		2
    Clinical
    Eye Disorder
    Conjunctivitis
    		5
    		0
    		1
    		0
    Gastrointestinal
    Nausea
    		82
    		12
    		77
    		6
    Vomiting
    		57
    		11
    		50
    		4
    Stomatitis/pharyngitis
    		23
    		3
    		6
    		0
    Anorexia
    		20
    		1
    		14
    		1
    Diarrhea
    		17
    		4
    		8
    		0
    Constipation
    		12
    		1
    		7
    		1
    Dyspepsia
    		5
    		1
    		1
    		0
    Constitutional Symptoms
    Fatigue
    		48
    		10
    		42
    		9
    Metabolism and Nutrition
    Dehydration
    		7
    		4
    		1
    		1
    Neurology
    Sensory neuropathy
    		10
    		0
    		10
    		1
    Taste disturbance
    		8
    		0
    		6
    		0
    Dermatology/Skin
    Rash
    		16
    		1
    		5
    		0
    Alopecia
    		11
    		0
    		6
    		0

    a

    In  Study JMCH, 226 patients received at least  one dose of  pemetrexed  for injection in combination with cisplatin and 222 patients  received  at least one dose of cisplatin. Table 8 provides the  ADRs for subgroup of patients treated with pemetrexed for injection in  combination  with cisplatin (168  patients) or cisplatin  alone  (163  patients) who received  full supplementation with  folic  acid and vitamin B 12during study therapy.
    b NCI  CTCAE version   2.0

    The following additional adverse reactions were observed in patients receiving pemetrexed for injection plus cisplatin:


    Incidence 1% to <5%

    Body as a Whole— febrile neutropenia, infection, pyrexia

    Dermatology/Skin— urticaria

    General Disorders— chest pain

    Metabolism and Nutrition— increased AST, increased ALT, increased GGT

    Renal— renal failure


    Incidence <1%

    Cardiovascular— arrhythmia

    Neurology— motor neuropathy


    Exploratory Subgroup Analyses based on Vitamin Supplementation


    Table 9 provides the results  of exploratory  analyses of the  frequency  and  severity  of NCI  CTCAE Grade 3 or 4 adverse  reactions  reported  in  more  pemetrexed for injection  -treated  patients  who  did  not receive vitamin supplementation (never  supplemented) as compared with those who received vitamin  supplementation  with  daily  folic  acid  and  vitamin  B 12from  the  time  of  enrollment  in  Study JMCH (fully supplemented).
    Table  9:  Exploratory  Subgroup  Analysis  of  Selected  Grade  3/4  Adverse Reactions  Occurring in  Patients Receiving Pemetrexed  for injection  in  Combination  with  Cisplatin  with or without Full Vitamin Supplementation in Study JMCH a

    Grade 3-4 Adverse Reactions
    		Fully Supplemented Patients
    N=168
    (%)
    		Never Supplemented Patients
    N=32
    (%)
    Neutropenia
    		23
    		38
    Thrombocytopenia
    		5
    		9
    Vomiting
    		11
    		31
    Febrile neutropenia
    		1
    		9
    Infection with Grade 3/4 neutropenia
    		0
    		6
    Diarrhea
    		4
    		9

    aNCI CTCAE version 2.0

    The following adverse reactions occurred more frequently in patients who were fully vitamin supplemented than in patients who were never supplemented:

    • hypertension (11% versus 3%),
    • chest pain (8% versus 6%),
    • thrombosis/embolism (6% versus 3%).

    Additional Experience Across Clinical Trials

    Sepsis, with or without neutropenia, including fatal cases: 1%

    Severe esophagitis, resulting in hospitalization:<1%

    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

  • 7 DRUG INTERACTIONS

    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 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary


    Based on findings from animal studies and its mechanism of action, pemetrexed for injection can cause fetal  harm  when  administered  to  a  pregnant  woman  [ see  Clinical  Pharmacology  (12.1)].  There  are  no available  data on  pemetrexed for  injection  use  in  pregnant  women.  In  animal  reproduction studies, intravenous administration of pemetrexed to pregnant  mice during the period of  organogenesis was teratogenic, resulting in developmental delays and malformations at doses  lower than the recommended human dose of 500 mg/m 2[ see Data].  Advise pregnant women of the potential risk  to  a  fetus  [ see  Use  in  Special  Populations  (8.3)].

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

    Data

    Animal Data

    Pemetrexed was teratogenic in mice. Daily dosing of pemetrexed by intravenous injection to pregnant mice during the period of organogenesis increased the incidence of fetal malformations (cleft palate; protruding tongue; enlarged or misshaped kidney; and fused lumbar vertebra) at doses (based on BSA) 0.03 times the human dose of 500 mg/m 2. At doses, based on BSA, greater than or equal to 0.0012 times the 500 mg/m 2human dose, pemetrexed administration resulted in dose-dependent increases in developmental delays (incomplete ossification of talus and skull bone; and decreased fetal weight).

    8.2 Lactation

    Risk Summary

    There is no information regarding the presence of pemetrexed or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from pemetrexed for injection, advise women not to breastfeed during treatment with pemetrexed for injection and for one week after last dose.

    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)].

    Contraception

    Females

    Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with pemetrexed for injection and for 6 months after the last dose.

    Males

    Because of the potential for genotoxicity, 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 Nonclinical Toxicology ( 13.1)] .

    Infertility

    Males

    Pemetrexed for injection may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology ( 13.1)] .

    8.4 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)].

  • 10 OVERDOSAGE

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

  • 11 DESCRIPTION


    Pemetrexed for injection USP is a folate analog metabolic inhibitor. The drug substance, pemetrexed disodium hemi- pentahydrate, has the chemical name L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4- oxo-1H-pyrrolo[2,3-d] pyrimidin-5yl) ethyl] benzoyl]-, Disodium, hemi-pentahydrate with a molecular formula of C 20H 19N 5Na 2O 62.5 H 2O and a molecular weight of 516.37. The structural formula is as follows: Structural Formula
    Pemetrexed for injection USP is a sterile white-to-light yellow or green-yellow lyophilized powder in single-dose vials to be reconstituted for intravenous infusion. Each 100-mg vial of pemetrexed for injection USP contains 100 mg pemetrexed (equivalent to 110.3 mg pemetrexed disodium hemi- pentahydrate) and 106 mg mannitol. Each 500 mg vial of pemetrexed for injection USP contains 500 mg pemetrexed (equivalent to 551.4 mg pemetrexed disodium hemi- pentahydrate) and 500 mg mannitol. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.

  • 12 CLINICAL PHARMACOLOGY

    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

    Absorption


    The pharmacokinetics of pemetrexed when pemetrexed for injection was administered as a single agent in doses ranging from 0.2 to 838 mg/m 2infused over a 10-minute period have been evaluated in 426 cancer patients  with  a  variety  of  solid tumors.  Pemetrexed  total  systemic  exposure  (AUC) and  maximum  plasma concentration (C max) increased proportionally with increase of dose. The pharmacokinetics of pemetrexed did not change over multiple treatment cycles.

    Distribution

    Pemetrexed has a steady-state volume of distribution of 16.1 liters. In vitro studies indicated that pemetrexed is 81% bound to plasma proteins.

    Elimination

    The total systemic clearance of pemetrexed is 91.8 mL/min and the elimination half-life of pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min). As renal function decreases, the clearance of pemetrexed decreases and exposure (AUC) of pemetrexed increases.

    Metabolism

    Pemetrexed is not metabolized to an appreciable extent.

    Excretion

    Pemetrexed is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. In vitro studies indicated that pemetrexed is a substrate of OAT3 (organic anion transporter 3), a transporter that is involved in the active secretion of pemetrexed.

    Specific Populations

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

    Racial Groups

    The pharmacokinetics of pemetrexed were similar in Whites and Blacks or African Americans. Insufficient data are available for other ethnic groups.

    Patients with Hepatic Impairment

    Pemetrexed has not been formally studied in patients with hepatic impairment. No effect of elevated AST, ALT, or total bilirubin on the PK of pemetrexed was observed in clinical studies.

    Patients with Renal Impairment

    Pharmacokinetic analyses of pemetrexed included 127 patients with impaired renal function. Plasma clearance of pemetrexed decreases as renal function decreases, with a resultant increase in systemic exposure. Patients with creatinine clearances of 45, 50, and 80 mL/min had 65%, 54%, and 13% increases, respectively in systemic exposure (AUC) compared to patients with creatinine clearance of 100 mL/min [see Dosage and Administration ( 2.3) and Warnings and Precautions ( 5.2)] .

    Third-Space Fluid

    The pemetrexed plasma concentrations in patients with various solid tumors with stable, mild to moderate third-space fluid were comparable to those observed in patients without third space fluid collections. The effect of severe third space fluid on pharmacokinetics is not known.

    Drug Interaction Studies

    Drugs Inhibiting OAT3 Transporter

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

    In Vitro Studies

    Pemetrexed is a substrate for OAT3. Ibuprofen, an OAT3 inhibitor inhibited the uptake of pemetrexed in OAT3-expressing cell cultures with an average [I u]/IC 50ratio of 0.38. In vitro data predict that at clinically relevant concentrations, other NSAIDs (naproxen, diclofenac, celocoxib) would not inhibit the uptake of pemetrexed by OAT3 and would not increase the AUC of pemetrexed to a clinically significant extent. [see Drug Interactions ( 7)] .

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

    Aspirin

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

    Cisplatin

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

    Vitamins

    Neither folic acid nor vitamin B 12affect the pharmacokinetics of pemetrexed.

    Drugs Metabolized by Cytochrome P450 Enzymes

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

  • 13 NONCLINICAL TOXICOLOGY

    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 CLINICAL STUDIES

    14.1 Non-Squamous NSCLC

    Initial Treatment in Combination with Pembrolizumab and Platinum


    The efficacy of pemetrexed for injection 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 for injection 500 mg/m 2, pembrolizumab 200 mg, and investigators 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 IMTA 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  for injection 500 mg/m 2, and investigators 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  for injection 500 mg/m 2 intravenously every 3 weeks.


    Treatment with pemetrexed for injection 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  for injection,  pembrolizumab,  and  platinum chemotherapy  arm  and  206  to  the  placebo,  pemetrexed  for injection,  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 for injection, 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 for injection, and platinum chemotherapy (see Table 10 and Figure 1).


    Table 10: Efficacy Results of KEYNOTE-189


  • * Based on the stratified Cox proportional hazard model.
  • † Based on stratified log-rank test.
  • ‡ Response: Best objective response as confirmed complete response or partial response.
  • § Based on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy and smoking status.
    		•
    Endpoint

    Pemetrexed for injection
    Pembrolizumab
    Platinum Chemotherapy n=410
    Placebo
    Pemetrexed for injection 
    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 *(95% CI) 

    0.49 (0.38, 0.64) 
    p-value †

    <0.0001 
    PFS
    Number of patients with event (%) 

    245 (60%) 

    166 (81%) 
    Median in months (95% CI) 

    8.8 (7.6, 9.2) 
    4.9 (4.7, 5.5) 
    Hazard ratio * (95% CI)

    0.52 (0.43, 0.64) 
    p-value †

    <0.0001 
    ORR
    Overall response rate ‡ (95% CI) 

    48% (43, 53) 

    19% (14, 25) 
    Complete response 

    0.5%

    0.5% 
    Partial response 

    47%

    18% 
    p-value §

    <0.0001 
    Duration of Response
    Median in months (range) 

    11.2 (1.1+, 18.0+) 

    7.8 (2.1+, 16.4+) 


    NR = not reached

    At the protocol specified final OS analysis, the median in the pemetrexed  for injection in combination with pembrolizumab and platinum chemotherapy arm was 22.0 months (95% CI: 19.5, 24.5) compared to 10.6 months (95% CI: 8.7, 13.6) in the placebo with pemetrexed  for injection and platinum chemotherapy arm, with an HR of 0.56 (95% CI: 0.46, 0.69).

    Figure 1

    Figure 1 : Kaplan-Meier Curve for Overall Survival in KEYNOTE-189

    *Based on the protocol –specified final OS analysis

    Initial Treatment in Combination with Cisplatin

    The efficacy of pemetrexed for injection 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 for injection 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 2on  Day 1 of each 21-day cycle. Cisplatin was administered intravenously at a dose of 75 mg/m 2approximately 30 minutes after pemetrexed for injection administration on Day 1 of each cycle, gemcitabine was administered at a dose of 1250 mg/m 2on Day 1 and Day 8, and cisplatin was administered intravenously at a dose of 75 mg/m 2approximately 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 for injection  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

    Figure 2

    Figure 2 : Kaplan-Meier Curves for Overall Survival in Study JMDB


    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 12and Figures 3and 4. This  difference in treatment effect for pemetrexed for injection 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
    Table-12

    Figure 3

    Figure 3: Kaplan-Meier Curves for Overall Survival in Non-squamous NSCLC in Study JMDB

    Figure 4

    Figure 4 : Kaplan-Meier Curves for Overall Survival in Squamous NSCLC in Study JMDB

    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


    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

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

    Figure 7

    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


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

    Treatment of Recurrent Disease After Prior Chemotherapy



    The efficacy of pemetrexed for injection was evaluated in Study JMEI (NCT00004881), a multicenter, randomized (1:1),  open-  label  study  conducted  in  patients  with  Stage  III  or  IV  NSCLC  that  had  recurred  or  progressed following one prior  chemotherapy regimen for advanced disease. Patients were randomized to  receive  pemetrexed  500  mg/m 2intravenously  or  docetaxel  75  mg/m 2as  a  1-hour  intravenous infusion  once  every  21  days.  Patients  randomized  to  pemetrexed  also  received  folic  acid  and vitamin  B 12.  The  study  was  designed  to  show  that  overall  survival  with  pemetrexed for injection  was  non- inferior to  docetaxel,  as the major efficacy  outcome measure, and  that overall survival was superior for patients randomized to pemetrexed compared to docetaxel, as a secondary outcome measure.


    A   total   of   571   patients   were   enrolled   with   283   patients   randomized   to   pemetrexed for injection and   288   patients randomized to  docetaxel. The median age was 58 years (range 22 to 87 years); 72% were male; 71% were White, 24% were  Asian, 2.8% were Black or African American, 1.8% were Hispanic or Latino, and <2% were other ethnicities; 88%  had an ECOG PS of 0 or 1. With regard to tumor characteristics, 75% had Stage IV disease; 53% had  adenocarcinoma, 30% had squamous histology;  8%  large  cell;  and 9%  had other  histologic  subtypes  of NSCLC.

     The efficacy results in  the  overall population and in  subgroup analyses based  on histologic subtype are provided  in  Tables  16  and  17,  respectively.  Study  JMEI  did  not  show  an  improvement  in  overall  survival in the intent-to-treat  population. In subgroup analyses, there was no evidence of a treatment effect  on survival in  patients with  squamous NSCLC; the absence of a treatment effect in  patients with NSCLC of squamous histology was also  observed Studies JMDB and JMEN [ see Clinical Studies (14.1)].

    Table 16: Efficacy Results in Study JMEI
    Efficacy Parameter
    		Pemetrexed for injection
    (N=283)
    		Docetaxel
    (N=288)
    Overall survival
    Median (months)
            (95% CI)
    		8.3
    (7.0-9.4)
    		7.9
    (6.3-9.2)
    Hazard ratio a
            (95% CI)
    		0.99
    (0.82-1.20)
    Progression-free survival
    Median (months)
            (95% CI)
    		2.9
    (2.4-3.1)
    		2.9
    (2.7-3.4)
    Hazard ratio a
            (95% CI)

     0.97
    (0.82-1.16)
    Overall response rate
            (95% CI)
    		8.5%
    (5.2-11.7)
    		8.3%
    (5.1-11.5)

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

    Table 17: Exploratory Efficacy Analyses by Histologic Subgroup in Study JMEI
    Histologic Subgroups
    		Pemetrexed for injection
    (N=283)
    		Docetaxel
    (N=288)
    Non-squamous NSCLC (N=399)
    Median (months)
            (95% CI)
    		9.3
    (7.8-9.7)
    		8.0
    (6.3-9.3)
    HR a
            (95% CI)
    		0.89
    (0.71-1.13)
    Adenocarcinoma (N=301)
    Median (months)
            (95% CI)
    		9.0
    (7.6-9.6)
    		9.2
    (7.5-11.3)
    HR a
            (95% CI)
    		1.09
    (0.83-1.44)
    Large Cell (N=47)
    Median (months)
            (95% CI)
    		12.8
    (5.8-14.0)
    		4.5
    (2.3-9.1)
    HR a
            (95% CI)
    		0.38
    (0.18-0.78)
    Other b(N=51)
    Median (months)
            (95% CI)
    		9.4
    (6.0-10.1)
    		7.9
    (4.0-8.9)
    HR a
            (95% CI)
    		0.62
    (0.32-1.23)
    Squamous NSCLC (N=172)
    Median (months)
            (95% CI)
    		6.2
    (4.9-8.0)
    		7.4
    (5.6-9.5)
    HR a
            (95% CI)
    		1.32
    (0.93-1.86)

    a Hazard ratio unadjusted for multiple comparisons

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

    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.

    Table 18: Efficacy Results in Study JMCH
    Efficacy Parameter
    		All Randomized and Treated Patients
    (N=448)
    		Fully Supplemented
    Patients
    (N=331)
    Pemetrexed for injection /Cisplatin
    (N=226)
    		Cisplatin
    (N=222)
    		Pemetrexed for injection /Cisplatin
    (N=168)
    		Cisplatin
    (N=163)
    Median overall survival (months)
    		12.1
    		9.3
    		13.3
    		10.0
    (95% CI)
    		(10.0-14.4)
    		(7.8-10.7)
    		(11.4-14.9)
    		(8.4-11.9)
    Hazard ratio a
    		0.77
    		0.75
    Log rank p-value
    		0.020
    		NA b

    a Hazard ratios are not adjusted for stratification variables.

    bNot a pre-specified analysis.

    Figure 9

    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.

  • 15 REFERENCES

    1. “OSHA Hazardous Drugs.” OSHA. [https://www.osha.gov/hazardous-drugs]
  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    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

  • 17 PATIENT COUNSELING INFORMATION

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

    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

  • PATIENT PACKAGE INSERT

    PATIENT INFORMATION
    Pemetrexed for injection (pem-e-TREX-ed for in-jec-tion)
    for Intravenous Use
    What is Pemetrexed for injection?
    Pemetrexed for injection is a prescription medicine used to treat:
    • a kind of lung cancer called non-squamous non-small cell lung cancer (NSCLC).Pemetrexed for injection is used:
      • as the first treatment in combination with pembrolizumab and platinum chemotherapy when your lung cancer with no abnormal EGFR or ALK gene has spread (advanced NSCLC).
      • as the first treatment in combination with cisplatin when your lung cancer has spread (advanced NSCLC).
      • alone as maintenance treatment after you have received 4 cycles of chemotherapy that contains platinum for first treatment of your advanced NSCLC and your cancer has not progressed.
      • alone when your lung cancer has returned or spread after prior chemotherapy.

                Pemetrexed for injection is not for use for the treatment of people with squamous cell non-small cell lung cancer. 
    • a kind of cancer called malignant pleural mesothelioma. This cancer affects the lining of the lungs and chest wall. Pemetrexed for injection is used in combination with cisplatin as the first treatment for malignant pleural mesothelioma that cannot be removed by surgery or you are not able to have surgery.

    Pemetrexed for injection has not been shown to be safe and effective in children. 
    Do not take pemetrexed for injection if you have had a severe allergic reaction to any medicine that contains pemetrexed.
    Before taking pemetrexed for injection, tell your healthcare provider about all of your medical conditions, including if you:
    • have kidney problems.
    • have had radiation therapy.
    • are pregnant or plan to become pregnant. Pemetrexed for injection can harm your unborn baby.

                    Females who are able to become pregnant:
    Your healthcare provider will check to see if you are pregnant before you start treatment with pemetrexed for injection. You should use effective birth control (contraception) during treatment with pemetrexed for injection and for 6 months after the last dose. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with pemetrexed for injection.
    Maleswith female partners who are able to become pregnant should use effective birth control (contraception) during treatment with pemetrexed for injection and for 3 months after the last dose. 
    • are breastfeeding or plan to breastfeed. It is not known if pemetrexed for injection passes into breast milk. Do not breastfeed during treatment with pemetrexed for injection and for 1 week after the last dose.
    Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
    Tell your healthcare provider if you have kidney problems and take a medicine that contains ibuprofen. You should avoid taking ibuprofen for 2 days before, the day of, and 2 days after receiving treatment with pemetrexed for injection.

    How is pemetrexed for injection given?

    • It is very important to take folic acid and vitamin B 12 during your treatment with pemetrexed for injection to lower your risk of harmful side effects.
      • Take folic acid exactly as prescribed by your healthcare provider 1 time a day, beginning 7 days (1 week) before your first dose of pemetrexed for injection and continue taking folic acid until 21 days (3 weeks) after your last dose of pemetrexed for injection.
      • Your healthcare provider will give you vitamin B 12 injections during treatment with pemetrexed for injection. You will get your first vitamin B 12 injection 7 days (1 week) before your first dose of pemetrexed for injection, and then every 3 cycles.
      • Your healthcare provider will prescribe a medicine called corticosteroid for you to take 2 times a day for 3 days, beginning the day before each treatment with pemetrexed for injection.
      • Pemetrexed for injection is given to you by intravenous (IV) infusion into your vein. The infusion is given over 10 minutes.
      • Pemetrexed for injection is usually given 1 time every 21 days (3 weeks).

    What are the possible side effects of pemetrexed for injection?
    Pemetrexed for injection can cause serious side effects, including:
    • Low blood cell counts. Low blood cell counts can be severe, including low white blood cell counts (neutropenia), low platelet counts (thrombocytopenia), and low red blood cell counts (anemia). Your healthcare provider will do blood test to check your blood cell counts regularly during your treatment with pemetrexed for injection.  Tell your healthcare provider right away if you have any signs of infection, fever, bleeding, or severe tiredness during your treatment with pemetrexed for injection.
    • Kidney problems, including kidney failure. Pemetrexed for injection can cause severe kidney problems that can lead to death. Severe vomiting or diarrhea can lead to loss of fluids (dehydration) which may cause kidney problems to become worse. Tell your healthcare provider right away if you have a decrease in amount of urine.
    • Severe skin reactions. Severe skin reactions that may lead to death can happen with pemetrexed for injection. Tell your healthcare provider right away if you develop blisters, skin sores, skin peeling, or painful sores, or ulcers in your mouth, nose, throat or genital area.
    • Lung problems (pneumonitis). Pemetrexed for injection can cause serious lung problems that can lead to death. Tell your healthcare provider right away if you get any new or worsening symptoms of shortness of breath, cough, or fever.
    • Radiation recall. Radiation recall is a skin reaction that can happen in people who have received radiation treatment in the past and are treated with pemetrexed for injection. Tell your healthcare provider if you get swelling, blistering, or a rash that looks like a sunburn in an area that was previously treated with radiation.
    The most common side effects of pemetrexed for injection when given alone are:
    • tiredness
    • nausea
    • loss of appetite
    The most common side effects of pemetrexed for injection when given with cisplatin are:
    • vomiting
    • swelling or sores in your mouth or sore throat
    • constipation
    • low white blood cell counts (neutropenia)
    • low platelet counts (thrombocytopenia)
    • low red blood cell counts (anemia)
    The most common side effects of pemetrexed for injection when given with pembrolizumab and platinum chemotherapy are:
    • tiredness/weakness
    • constipation
    • loss of appetite
    • vomiting
    • shortness of breath
    • nausea
    • diarrhea
    • rash
    • cough
    • fever
    Pemetrexed for injection may cause fertility problems in males. This may affect your ability to father a child. It is not known if these effects are reversible. Talk to your healthcare provider if this is a concern for you.
    Your healthcare provider will do blood test to check for side effects during treatment with pemetrexed for injection. Your healthcare provider may change your dose of pemetrexed for injection, delay treatment, or stop treatment if you have certain side effects.
    Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
    These are not all the side effects of pemetrexed for injection. For more information, ask your healthcare provider or pharmacist.
    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088

    General information about the safe and effective use of pemetrexed for injection.
    Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.
    You can ask your pharmacist or healthcare provider for information about pemetrexed for injection that is written for health professionals.

    What are the ingredients in pemetrexed for injection?
    Active ingredient: pemetrexed
    Inactive ingredients: mannitol, hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.


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

    This Patient Information has been approved by the U.S. Food and Drug Administration.        Revised: March 2025 
  • PRINCIPAL DISPLAY PANEL

    Label – Pemetrexed for Injection 100 mg single-dose vial

    NDC: 70069-834-01

    Single-Dose Vial

    Pemetrexed for Injection, USP

    100 mg/vial

    For intravenous use only.

    Rx only
    Manufactured for:

    Somerset Therapeutics LLC

    Label_Pemetrexed 100 mg


  • PRINCIPAL DISPLAY PANEL

    PACKAGE CARTON – Pemetrexed for Injection 100 mg single-dose vial

    NDC: 70069-834-01

    Single-Dose Vial

    Pemetrexed for Injection, USP

    100 mg/vial

    For intravenous use only.

    Rx only

    Manufactured for:

    Somerset Therapeutics, LLC.


    Pemetrexed100 mg_Carton

    Carton_Pemetrexed 100 mg

  • PRINCIPAL DISPLAY PANEL

    Label Pemetrexed for Injection 500 mg single-dose vial

    Single-Dose Vial

    NDC: 70069-835-01

    Pemetrexed for Injection, USP

    500 mg/vial

    For intravenous use only.

    Rx only

    Manufactured for:

    Somerset Therapeutics, LLC.


    Pemetrexed 500 mg_Label

    Label_Pemetrexed 500 mg

  • PRINCIPAL DISPLAY PANEL

    PACKAGE CARTON – Pemetrexed for Injection 500 mg single-dose vial

    Single-Dose Vial

    NDC: 70069-835-01

    Pemetrexed for Injection, USP

    500 mg/vial

    For intravenous use only.

    Rx only

    Manufactured for:

    Somerset Therapeutics, LLC.


    Pemetrexed 500 mg_Carton

    Carton_Pemetrexed 500 mg

  • INGREDIENTS AND APPEARANCE
    PEMETREXED 
    pemetrexed disodium injection, powder, lyophilized, for solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 70069-834
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    PEMETREXED DISODIUM HEPTAHYDRATE (UNII: 9T47E4OM16) (PEMETREXED - UNII:04Q9AIZ7NO) PEMETREXED DISODIUM HEPTAHYDRATE100 mg  in 4 mL
    Inactive Ingredients
    Ingredient NameStrength
    MANNITOL (UNII: 3OWL53L36A) 106 mg  in 4 mL
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 70069-834-011 in 1 CARTON04/15/2025
    14 mL in 1 VIAL; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21189904/15/2025
    PEMETREXED 
    pemetrexed disodium injection, powder, lyophilized, for solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 70069-835
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    PEMETREXED DISODIUM HEPTAHYDRATE (UNII: 9T47E4OM16) (PEMETREXED - UNII:04Q9AIZ7NO) PEMETREXED DISODIUM HEPTAHYDRATE500 mg  in 20 mL
    Inactive Ingredients
    Ingredient NameStrength
    MANNITOL (UNII: 3OWL53L36A) 500 mg  in 20 mL
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 70069-835-011 in 1 CARTON04/15/2025
    120 mL in 1 VIAL; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21189904/15/2025
    Labeler - Somerset Therapeutics LLC (079947873)
    Establishment
    NameAddressID/FEIBusiness Operations
    Reliance Life Sciences Private Limited650213072analysis(70069-834, 70069-835) , label(70069-834, 70069-835) , manufacture(70069-834, 70069-835) , pack(70069-834, 70069-835) , api manufacture(70069-834, 70069-835)
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