2 DOSAGE AND ADMINISTRATION Administer either orally or intravenously. Newly Diagnosed Glioblastoma: 75 mg/m 2 once daily for 42 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m 2 once daily for Days 1 to 5 of each 28-day cycle for 6 cycles. May increase maintenance dose to 200 mg/m 2 for cycles 2 to 6 based on toxicity. ( 2.1 ) Provide Pneumocystis pneumonia (PCP) prophylaxis during concomitant phase and continue in patients who develop lymphopenia until resolution to Grade 1 or less. ( 2.1 ) Refractory Anaplastic Astrocytoma : Initial dose of 150 mg/m 2 once daily on Days 1 to 5 of each 28-day cycle. ( 2.2 ) 2.1 Recommended Dosage and Dosage Modifications for Newly Diagnosed Glioblastoma Administer temozolomide either orally or intravenously once daily for 42 consecutive days during the concomitant phase with focal radiotherapy and then once daily on Days 1 to 5 of each 28-day cycle for 6 cycles during the maintenance phase. Provide Pneumocystis pneumonia (PCP) prophylaxis during the concomitant phase and continue in patients who develop lymphocytopenia until resolution to Grade 1 or less [see Warnings and Precautions (5.3) ] . Concomitant Phase The recommended dosage of temozolomide is 75 mg/m 2 either orally or intravenously once daily for 42 days (up to 49 days) concomitant with focal radiotherapy (60 Gy administered in 30 fractions). Focal radiotherapy includes the tumor bed or resection site with a 2- to 3-cm margin. Obtain a complete blood count weekly. No dose reductions are recommended during the concomitant phase. The recommended dosage modifications during the concomitant phase are provided in Table 1 . TABLE 1: Temozolomide Dosage Modifications During Concomitant Phase Adverse Reaction Interruption Discontinuation Absolute Neutrophil Count Withhold temozolomide if ANC is greater than or equal to 0.5 × 10 9 /L and less than 1.5 × 10 9 /L. Discontinue temozolomide if platelet count is less than 0.5 × 10 9 /L. Resume temozolomide when ANC is greater than or equal to 1.5 × 10 9 /L. Platelet Count Withhold temozolomide if platelet count is greater than or equal to 10 × 10 9 /L and less than 100 × 10 9 /L. Discontinue temozolomide if platelet count is less than 10 × 10 9 /L. Resume temozolomide when platelet count is greater than or equal to 100 × 10 9 /L. Non-hematological Adverse Reaction (except for alopecia, nausea, vomiting) Withhold temozolomide if Grade 2 adverse reaction occurs. Discontinue temozolomide if Grade 3 or 4 adverse reaction occurs. Resume temozolomide when resolution to Grade 1 or less. Maintenance Phase: Beginning 4 weeks after Concomitant Phase completion, administer temozolomide either orally or intravenously once daily on Days 1 to 5 of each 28-day cycle for 6 cycles. The recommended dosage of temozolomide is as follows: Cycle 1: 150 mg/m 2 per day Cycles 2 to 6: May increase to 200 mg/m 2 per day if the following conditions are met before starting cycle 2. If the dose was not escalated at the onset of Cycle 2, do not increase the dose for Cycles 3 to 6. Nonhematologic toxicity is Grade 2 or less (except for alopecia, nausea, and vomiting) ANC is greater than or equal to 1.5 x 10 9 /L, and Platelet count is greater than or equal to 100 x 10 9 /L. Obtain a complete blood count on Day 22 and then weekly until the ANC is above 1.5 x 10 9 /L and the platelet count is above 100 x 10 9 /L. Do not start the next cycle until the ANC and platelet count exceed these levels. The recommended dosage modifications during the maintenance phase are provided in Table 2 . If temozolomide is withheld, reduce the dose for the next cycle by 50 mg/m 2 per day. Permanently discontinue temozolomide in patients who are unable to tolerate a dose of 100 mg/m 2 per day. TABLE 2: Temozolomide Dosage Modifications During Maintenance Treatment Toxicity Interruption and Dose Reduction Discontinuation Absolute Neutrophil Count Withhold temozolomide if ANC less than 1 × 10 9 /L. Unable to tolerate a dose of 100 mg/m 2 per day. When ANC is above 1.5 × 10 9 /L, resume temozolomide at reduced dose for the next cycle. Platelet Count Withhold temozolomide if platelet less than 50 × 10 9 /L. Unable to tolerate a dose of 100 mg/m 2 per day. When platelet count is above 100 × 10 9 /L, resume temozolomide at reduced dose for the next cycle. Nonhematological Adverse Reaction (except for alopecia, nausea, vomiting) Withhold temozolomide if Grade 3 adverse reaction. Recurrent Grade 3 after dose reduction. When resolved to Grade 1 or less, resume temozolomide at reduced dose for the next cycle. Grade 4 Unable to tolerate a dose of 100 mg/m 2 per day. 2.2 Recommended Dosage and Dosage Modifications for Refractory Anaplastic Astrocytoma The recommended initial dosage of temozolomide is 150 mg/m 2 once daily on Days 1 to 5 of each 28-day cycle. Increase the temozolomide dose to 200 mg/m 2 per day if the following conditions are met at the nadir and on Day 1 of the next cycle: ANC is greater than or equal to 1.5 x 10 9 /L, and Platelet count is greater than or equal to 100 x 10 9 /L. Continue temozolomide until disease progression or unacceptable toxicity. In the clinical trial, treatment could be continued for a maximum of 2 years, but the optimum duration of therapy is not known. Obtain a complete blood count on Day 22 and then weekly until the ANC is above 1.5 x 10 9 /L and the platelet count is above 100 x 10 9 /L. Do not start the next cycle until the ANC and platelet count exceed these levels. If the ANC is less than 1 x 10 9 /L or the platelet count is less than 50 x 10 9 /L during any cycle, reduce the temozolomide dose for the next cycle by 50 mg/m 2 per day. Permanently discontinue temozolomide in patients who are unable to tolerate a dose of 100 mg/m 2 per day. 2.3 Preparation and Administration Temozolomide is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 Temozolomide capsules Administer temozolomide consistently with respect to food (fasting vs. nonfasting) [see Clinical Pharmacology (12.3) ] . To reduce nausea and vomiting, take temozolomide on an empty stomach or at bedtime and consider antiemetic therapy prior to and/or following temozolomide administration. Swallow temozolomide capsules whole. Do not open or chew capsules. If capsules are accidentally opened or damaged, take precautions to avoid inhalation or contact with the skin or mucous membranes. In case of powder contact, the hands should be washed. Temozolomide for injection Bring the vial to room temperature prior to reconstitution with Sterile Water for Injection. Reconstitute the vial with 41 mL of Sterile Water for Injection to yield a temozolomide solution with a concentration of 2.5 mg/mL temozolomide. Reconstituted temozolomide is a clear solution and essentially free of visible particles. Gently swirl vial. Do not shake. Visually inspect reconstituted solution for particulate matter and discoloration. Discard if particulate matter or discoloration is observed. Do not further dilute the reconstituted solution. Store reconstituted solution at room temperature (25°C [77°F]). Discard reconstituted solution if not used within 14 hours, including infusion time. Withdraw up to 40 mL from each vial to make up the total dose and discard any unused portion. Transfer reconstituted solution from each vial into an empty 250 mL infusion bag. Administer reconstituted solution using a pump over a period of 90 minutes. Administer temozolomide by intravenous infusion only. Infusion over a shorter or longer period of time may result in suboptimal dosing. Flush the lines before and after each infusion. Temozolomide for injection may be administered in the same intravenous line with 0.9% Sodium Chloride injection only. Because no data are available on the compatibility of temozolomide for injection with other intravenous substances or additives, do not infuse other medications simultaneously through the same intravenous line.