Pemetrexed Injection is a folate analog metabolic inhibitor indicated:
In combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous, non-small cell lung cancer (NSCLC). ( 1.1 )
As a single agent for the maintenance treatment of patients with locally advanced or metastatic, non -squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. ( 1.1 )
As a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy. ( 1.1 )
Limitations of Use : Pemetrexed Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer. ( 1.1 )
Initial treatment, in combination with cisplatin, of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. ( 1.2 )
1.1Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Pemetrexed
Injection is indicated:
In combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous, non-small cell lung cancer (NSCLC).
As a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.
As a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy. Limitations of Use: Pemetrexed Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer [see Clinical Studies 14.1 ].
1.2Mesothelioma Pemetrexed
Injection is indicated, in combination with cisplatin, for the initial treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.
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Pemetrexed Injection is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed [see Adverse Reactions (6.1) ] . History of severe hypersensitivity reaction to pemetrexed. ( 4 )
Warnings and precautions
Myelosuppression: Can cause severe bone marrow suppression resulting in cytopenia and an increased risk of infection. Do not administer Pemetrexed Injection when the absolute neutrophil count is less than 1500 cells/mm 3 and platelets are less than 100,000 cells/mm 3 . Initiate supplementation with oral folic acid and intramuscular vitamin B 12 to reduce the severity of hematologic and gastrointestinal toxicity of Pemetrexed Injection. ( 2.4 , 5.1 )
Renal Failure: Can cause severe, and sometimes fatal, renal failure. Do not administer when creatinine clearance is less than 45 mL/min. ( 2.3 , 5.2 )
Bullous and Exfoliative Skin Toxicity: Permanently discontinue for severe and life-threatening bullous, blistering or exfoliating skin toxicity. ( 5.3 )
Interstitial Pneumonitis: Withhold for acute onset of new or progressive unexplained pulmonary symptoms. Permanently discontinue if pneumonitis is confirmed. ( 5.4 )
Radiation Recall: Can occur in patients who received radiation weeks to years previously; permanently discontinue for signs of radiation recall. ( 5.5 )
Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.7 , 8.1 , 8.3 )
5.1Myelosuppression 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 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 Injection; continue vitamin supplementation during treatment and for 21 days after the last dose of Pemetrexed Injection to reduce the severity of hematologic and gastrointestinal toxicity of Pemetrexed Injection [see Dosage and Administration (2.4) ] . Obtain a complete blood count at the beginning of each cycle.
Do not administer Pemetrexed Injection until the ANC is at least 1500 cells/mm 3 and platelet count is at least 100,000 cells/mm 3 . Permanently reduce Pemetrexed Injection in patients with an ANC of less than 500 cells/mm 3 or platelet count of less than 50,000 cells/mm 3 in previous cycles [see Dosage and Administration (2.6) ] . In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3–4 neutropenia was 15% and 23%, the incidence of Grade 3–4 anemia was 6% and 4%, and incidence of Grade 3–4 thrombocytopenia was 4% and 5%, respectively.
In Study JMCH, 18% of patients in the pemetrexed arm required red blood cell transfusions compared to 7% of patients in the cisplatin arm [see Adverse Reactions (6.1) ] . In Studies JMEN, PARAMOUNT, and JMEI, where all patients received vitamin supplementation, incidence of Grade 3–4 neutropenia ranged from 3% to 5%, and incidence of Grade 3–4 anemia ranged from 3% to 5%.
5.2Renal 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 Injection. Withhold Pemetrexed Injection in patients with a creatinine clearance of less than 45 mL/minute [see Dosage and Administration (2.3) ] .
5.3Bullous 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 Injection for severe and life-threatening bullous, blistering or exfoliating skin toxicity.
5.4Interstitial Pneumonitis
Serious interstitial pneumonitis, including fatal cases, can occur with pemetrexed treatment. Withhold Pemetrexed Injection for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation. If pneumonitis is confirmed, permanently discontinue Pemetrexed Injection.
5.5Radiation 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 Injection for signs of radiation recall.
5.6Increased 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 Injection. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for Pemetrexed Injection adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity [see Dosage and Administration (2.5) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ] .
5.7Embryo-Fetal Toxicity Based
on findings from animal studies and its mechanism of action, Pemetrexed Injection can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and increased malformations at doses lower than the recommended human dose of 500 mg/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 Injection and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Pemetrexed Injection and for 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3) and Clinical Pharmacology (12.1) ] .
Interactions
Ibuprofen increased risk of Pemetrexed Injection toxicity in patients with mild to moderate renal impairment. Modify the ibuprofen dosage as recommended for patients with a creatinine clearance between 45 mL/min and 79 mL/min. ( 2.5 , 5.6 , 7 ) 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 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.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary Based
on findings from animal studies and its mechanism of action, Pemetrexed Injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on Pemetrexed 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 2 human dose, pemetrexed administration resulted in dose-dependent increases in developmental delays (incomplete ossification of talus and skull bone; and decreased fetal weight).
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 Warnings and Precautions (5.3) ]
Interstitial pneumonitis [see Warnings and Precautions (5.4) ]
Radiation recall [see Warnings and Precautions (5.5) ]
The most common adverse reactions (incidence ≥20%) of pemetrexed when administered as a single agent are fatigue, nausea, and anorexia. ( 6.1 )
The most common adverse reactions (incidence ≥20%) of pemetrexed when administered with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc., at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. In clinical trials, the most common adverse reactions (incidence ≥20%) of pemetrexed, when administered as a single agent, are fatigue, nausea, and anorexia. The most common adverse reactions (incidence ≥20%) of pemetrexed, when administered in combination with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.
Non-Squamous NSCLC Initial Treatment in Combination with Cisplatin The safety of pemetrexed 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 500 mg/m 2 intravenously and cisplatin 75 mg/m 2 intravenously on Day 1 of each 21-day cycle (n=839) or gemcitabine 1250 mg/m 2 intravenously 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 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 2 provides the frequency and severity of adverse reactions that occurred in ≥5% of 839 patients receiving pemetrexed in combination with cisplatin in Study JMDB.
Study JMDB 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 Table 2. Table 2: Adverse Reactions Occurring in ≥5% of Fully Vitamin-Supplemented Patients Receiving Pemetrexed in Combination with Cisplatin Chemotherapy in Study JMDB Adverse Reaction NCI CTCAE version
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 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 2 or 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 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 and a relative dose intensity of pemetrexed 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. Table 3 provides the frequency and severity of adverse reactions reported in ≥5% of the 438 pemetrexed-treated patients in Study JMEN. Table 3: Adverse Reactions Occurring in ≥5% of Patients Receiving Pemetrexed in Study JMEN Adverse Reaction NCI CTCAE version
3.0 Pemetrexed/Cisplatin (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 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
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