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warnings and cautions
5 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 ) 5.1 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 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...
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adverse reactions
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 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 . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. In clinical trials, the most common adverse reactions (incidence ≥20%) of pemetrexed, when administered as a single agent, are fatigue, nausea, and anorexia. The most common adverse reactions (incidence ≥20%) of pemetrexed, when administered in combination with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. 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. Patien...
adverse reactions table
Table 2: Adverse Reactions Occurring in ≥5% of Fully Vitamin-Supplemented Patients Receiving Pemetrexed in Combination with Cisplatin Chemotherapy in Study JMDBAdverse ReactionNCI CTCAE version 2.0Pemetrexed/Cisplatin (N=839)Gemcitabine/Cisplatin (N=830)All Grades (%)Grade 3–4 (%)All Grades (%)Grade 3–4 (%)All adverse reactions90379153 Laboratory Hematologic Anemia3364610 Neutropenia29153827 Thrombocytopenia1042713RenalElevated creatinine10171Clinical Constitutional symptomsFatigue437455Gastrointestinal Nausea567534 Vomiting406366 Anorexia272241 Constipation211200 Stomatitis/pharyngitis141120 Diarrhea121132 Dyspepsia/heartburn5060Neurology Sensory neuropathy90121 Taste disturbance8090Dermatology/Skin Alopecia120211 Rash/Desquamation7081