Pemetrexed

Pemetrexed for Injection is a folate analog metabolic inhibitor indicated:

• in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non-squamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. (
  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 Studies (14.1)]
    .
  )
• in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous NSCLC. (
  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 Studies (14.1)]
    .
  )
• as a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. (
  1.1 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 Studies (14.1)]
    .
  )
• as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy. (
  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 Studies (14.1)]
    .
  )     
  Limitations of Use
  : Pemetrexed for Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer. (
  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 Studies (14.1)]
    .
  )

• initial treatment, in combination with cisplatin, of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. (
  1.2 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.
  )

• The recommended dose of pemetrexed for injection administered with pembrolizumab and platinum chemotherapy in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m² as an intravenous infusion over 10 minutes, administered after pembrolizumab and prior to platinum chemotherapy, on Day 1 of each 21-day cycle. (
  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/m²as 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/m²as 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/m²as 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/m²as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity.
  )
• The recommended dose of pemetrexed for injection, administered as a single agent or with cisplatin, in patients with creatinine clearance of 45 mL/minute or greater is 500 mg/m² as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. (
  2.1 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/m²as 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/m²as 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/m²as 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/m²as 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/m²as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity.
  )
• Initiate folic acid 400 mcg to 1,000 mcg orally, once daily, beginning 7 days prior to the first dose of pemetrexed for injection and continue until 21 days after the last dose of pemetrexed for injection. (
  2.4 Premedication and Concomitant Medications to Mitigate Toxicity

  Vitamin Supplementation

  • Initiate folic acid 400 mcg to 1,000 mcg orally once daily, beginning 7 days before the first dose of pemetrexed for injection and continuing until 21 days after the last dose of pemetrexed for injection
    [see Warnings and Precautions (5.1)]
    .
  • Administer vitamin B₁₂, 1 mg intramuscularly, 1 week prior to the first dose of pemetrexed for injection and every 3 cycles thereafter. Subsequent vitamin B₁₂injections may be given the same day as treatment with pemetrexed for injection
    [see Warnings and Precautions (5.1)]
    .
    Do not substitute oral vitamin B
    ₁₂
    for intramuscular vitamin B
    ₁₂.

  Corticosteroids

  • Administer dexamethasone 4 mg orally twice daily for three consecutive days, beginning the day before each pemetrexed for injection administration.
  )
• Administer vitamin B₁₂, 1 mg intramuscularly, 1 week prior to the first dose of pemetrexed for injection and every 3 cycles. (
  2.4 Premedication and Concomitant Medications to Mitigate Toxicity

  Vitamin Supplementation

  • Initiate folic acid 400 mcg to 1,000 mcg orally once daily, beginning 7 days before the first dose of pemetrexed for injection and continuing until 21 days after the last dose of pemetrexed for injection
    [see Warnings and Precautions (5.1)]
    .
  • Administer vitamin B₁₂, 1 mg intramuscularly, 1 week prior to the first dose of pemetrexed for injection and every 3 cycles thereafter. Subsequent vitamin B₁₂injections may be given the same day as treatment with pemetrexed for injection
    [see Warnings and Precautions (5.1)]
    .
    Do not substitute oral vitamin B
    ₁₂
    for intramuscular vitamin B
    ₁₂.

  Corticosteroids

  • Administer dexamethasone 4 mg orally twice daily for three consecutive days, beginning the day before each pemetrexed for injection administration.
  )
• Administer dexamethasone 4 mg orally, twice daily the day before, the day of, and the day after pemetrexed for injection administration. (
  2.4 Premedication and Concomitant Medications to Mitigate Toxicity

  Vitamin Supplementation

  • Initiate folic acid 400 mcg to 1,000 mcg orally once daily, beginning 7 days before the first dose of pemetrexed for injection and continuing until 21 days after the last dose of pemetrexed for injection
    [see Warnings and Precautions (5.1)]
    .
  • Administer vitamin B₁₂, 1 mg intramuscularly, 1 week prior to the first dose of pemetrexed for injection and every 3 cycles thereafter. Subsequent vitamin B₁₂injections may be given the same day as treatment with pemetrexed for injection
    [see Warnings and Precautions (5.1)]
    .
    Do not substitute oral vitamin B
    ₁₂
    for intramuscular vitamin B
    ₁₂.

  Corticosteroids

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

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

Lactation: Advise not to breastfeed. (

• Myelosuppression: Can cause severe bone marrow suppression resulting in cytopenia and an increased risk of infection. Do not administer pemetrexed when the absolute neutrophil count is less than 1,500 cells/mm³ and platelets are less than 100,000 cells/mm³. Initiate supplementation with oral folic acid and intramuscular vitamin B₁₂ to reduce the severity of hematologic and gastrointestinal toxicity of pemetrexed. (
  2.4 Premedication and Concomitant Medications to Mitigate Toxicity

  Vitamin Supplementation

  • Initiate folic acid 400 mcg to 1,000 mcg orally once daily, beginning 7 days before the first dose of pemetrexed for injection and continuing until 21 days after the last dose of pemetrexed for injection
    [see Warnings and Precautions (5.1)]
    .
  • Administer vitamin B₁₂, 1 mg intramuscularly, 1 week prior to the first dose of pemetrexed for injection and every 3 cycles thereafter. Subsequent vitamin B₁₂injections may be given the same day as treatment with pemetrexed for injection
    [see Warnings and Precautions (5.1)]
    .
    Do not substitute oral vitamin B
    ₁₂
    for intramuscular vitamin B
    ₁₂.

  Corticosteroids

  • Administer dexamethasone 4 mg orally twice daily for three consecutive days, beginning the day before each pemetrexed for injection administration.
  ,
  5.1 Myelosuppression and Increased Risk of Myelosuppression without Vitamin Supplementation

  Pemetrexed can cause severe myelosuppression resulting in a requirement for transfusions and which may lead to neutropenic infection. The risk of myelosuppression is increased in patients who do not receive vitamin supplementation. In Study JMCH, incidences of Grade 3-4 neutropenia (38% versus 23%), thrombocytopenia (9% versus 5%), febrile neutropenia (9% versus 0.6%), and neutropenic infection (6% versus 0) were higher in patients who received pemetrexed plus cisplatin without vitamin supplementation as compared to patients who were fully supplemented with folic acid and vitamin B₁₂prior to and throughout pemetrexed plus cisplatin treatment.

  Initiate supplementation with oral folic acid and intramuscular vitamin B₁₂prior 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

  [see Dosage and Administration (2.4)]

  . Obtain a complete blood count at the beginning of each cycle. Do not administer pemetrexed until the ANC is at least 1,500 cells/mm³and platelet count is at least 100,000 cells/mm³. Permanently reduce pemetrexed in patients with an ANC of less than 500 cells/mm³or platelet count of less than 50,000 cells/mm³in previous cycles

  [see Dosage and Administration (2.6)]

  .

  In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3-4 neutropenia was 15% and 23%, the incidence of Grade 3-4 anemia was 6% and 4%, and incidence of Grade 3-4 thrombocytopenia was 4% and 5%, respectively. In Study JMCH, 18% of patients in the pemetrexed arm required red blood cell transfusions compared to 7% of patients in the cisplatin arm

  [see Adverse Reactions (6.1)]

  . In Studies JMEN, PARAMOUNT, and JMEI, where all patients received vitamin supplementation, incidence of Grade 3-4 neutropenia ranged from 3% to 5%, and incidence of Grade 3-4 anemia ranged from 3% to 5%.
  )
• Renal Failure: Can cause severe, and sometimes fatal, renal failure. Do not administer when creatinine clearance is less than 45 mL/min. (
  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)]
    .
  ,
  5.2 Renal Failure

  Pemetrexed can cause severe, and sometimes fatal, renal toxicity. The incidences of renal failure in clinical studies in which patients received pemetrexed with cisplatin were: 2.1% in Study JMDB and 2.2% in Study JMCH. The incidence of renal failure in clinical studies in which patients received pemetrexed as a single agent ranged from 0.4% to 0.6% (Studies JMEN, PARAMOUNT, and JMEI

  [see Adverse Reactions (6.1)]

  . Determine creatinine clearance before each dose and periodically monitor renal function during treatment with pemetrexed. Withhold pemetrexed in patients with a creatinine clearance of less than 45 mL/minute

  [see Dosage and Administration (2.3)]

  .
  )
• Bullous and Exfoliative Skin Toxicity: Permanently discontinue for severe and life-threatening bullous, blistering or exfoliating skin toxicity. (
  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. Permanently discontinue pemetrexed for severe and life-threatening bullous, blistering or exfoliating skin toxicity.
  )
• Interstitial Pneumonitis: Withhold for acute onset of new or progressive unexplained pulmonary symptoms. Permanently discontinue if pneumonitis is confirmed. (
  5.4 Interstitial Pneumonitis

  Serious interstitial pneumonitis, including fatal cases, can occur with pemetrexed treatment. Withhold pemetrexed 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.
  )
• Radiation Recall: Can occur in patients who received radiation weeks to years previously; permanently discontinue for signs of radiation recall. (
  5.5 Radiation Recall

  Radiation recall can occur with pemetrexed in patients who have received radiation weeks to years previously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue pemetrexed for signs of radiation recall.
  )
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. (
  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/m². 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)]

  .
  ,
  8.1 Pregnancy

  Risk Summary

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

  [see Clinical Pharmacology (12.1)]

  . There are no available data on pemetrexed use in pregnant women. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and malformations at doses lower than the recommended human dose of 500 mg/m²

  [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/m². At doses, based on BSA, greater than or equal to 0.0012 times the 500 mg/m²human dose, pemetrexed administration resulted in dose-dependent increases in developmental delays (incomplete ossification of talus and skull bone; and decreased fetal weight).
  ,
  8.3 Females and Males of Reproductive Potential

  Based on animal data pemetrexed can cause malformations and developmental delays when administered to a pregnant woman

  [see Use in Specific Populations ]

  .

  Pregnancy Testing

  Verify pregnancy status of females of reproductive potential prior to initiating pemetrexed injection

  [see Use in Specific Populations ]

  .

  Contraception

  Females

  Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with pemetrexed 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 and for 3 months after the last dose

  [see Nonclinical Toxicology (13.1)]

  .

  Infertility

  Males

  Pemetrexed may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible

  [see Nonclinical Toxicology (13.1)]

  .
  )