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 to 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 for injection plus cisplatin without vitamin supplementation as compared to patients who were fully supplemented with folic acid and vitamin B12 prior to and throughout pemetrexed for injection plus cisplatin treatment.

Initiate supplementation with oral folic acid and intramuscular vitamin B12 prior to the first dose of pemetrexed for injection; continue vitamin supplementation during treatment and for 21 days after the last dose of pemetrexed for injection to reduce the severity of hematologic and gastrointestinal toxicity of pemetrexed for injection [see 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 1,500 cells/mm3 and platelet count is at least 100,000 cells/mm3. Permanently reduce pemetrexed for injection in patients with an ANC of less than 500 cells/mm3 or platelet count of less than 50,000 cells/mm3 in previous cycles [see Dosage and Administration (2.6)].

In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3 to 4 neutropenia was 15% and 23%, the incidence of Grade 3 to 4 anemia was 6% and 4%, and incidence of Grade 3 to 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 to 4 neutropenia ranged from 3% to 5%, and incidence of Grade 3 to 4 anemia ranged from 3% to 5%.