Temozolomide

1. INDICATIONS AND USAGE TEMOZOLOMIDE Capsules are an alkylating drug indicated for the treatment of adult patients with: Newly diagnosed glioblastoma concomitantly with radiotherapy and then as maintenance treatment. ( 1.1 ) Anaplastic astrocytoma ( 1.2 ) Adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma. ( 1.2 ) Treatment of adults with refractory anaplastic astrocytoma. ( 1.2 ) 1.1 Newly Diagnosed Glioblastoma TEMOZOLOMIDE Capsules is indicated for the treatment of adults with newly diagnosed glioblastoma, concomitantly with radiotherapy and then as maintenance treatment. 1.2 Anaplastic Astrocytoma TEMOZOLOMIDE Capsules is indicated for the: adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma; treatment of adults with refractory anaplastic astrocytoma.

2. DOSAGE AND ADMINISTRATION Administer either orally or intravenously. (2.4) Newly Diagnosed Glioblastoma: 75 mg/m 2 once daily for 42 to 49 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 – 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 ) Adjuvant Treatment of Newly Diagnosed Anaplastic Astrocytoma: Beginning 4 weeks after the end of radiotherapy, administer TEMOZOLOMIDE Capsules orally in a single dose on days 1-5 of a 28-day cycle for 12 cycles. The recommended dosage for Cycle 1 is 150 mg/m 2 per day and for Cycles 2 to 12 is 200 mg/m 2 if patient experienced no or minimal toxicity in Cycle 1. ( 2.2 ) 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 Monitoring to Inform Dosage and Administration Prior to dosing, withhold TEMOZOLOMIDE until patients have an absolute neutrophil count (ANC) of 1.5 x 10 9 /L or greater and a platelet count of 100 x 10 9 /L or greater. For concomitant radiotherapy, obtain a complete blood count prior to initiation of treatment and weekly during treatment. For the 28-day treatment cycles, obtain a complete blood count prior to treatment on Day 1 and on Day 22 of each cycle. Perform complete blood counts weekly until recovery if the ANC falls below 1.5 x 10 9 /L and the platelet count falls below 100 x 10 9 /L. For concomitant use with focal radiotherapy, obtain a complete blood count weekly and as clinically indicated. 2.2 Recommended Dosage and Dosage Modifications for Newly Diagnosed Glioblastoma Administer TEMOZOLOMIDE either orally or intravenously once daily for 42 to 49 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 to 49 days in combination with focal radiotherapy. Focal radiotherapy includes the tumor bed or resection site with a 2 to 3 cm margin. Other administration schedules have been used. Obtain a complete blood count weekly. The recommended dosage modifications due toadverse reactions during concomitant use 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 x 10 9 /L and less than 1.5 x 10 9 /L. Resume TEMOZOLOMIDE when ANC is greater than or equal to 1.5 x 10 9 /L. Discontinue TEMOZOLOMIDE if platelet count is less than 0.5 x 10 9 /L. Platelet Count Withhold TEMOZOLOMIDE if platelet count is greater than or equal to 10 x 10 9 /L and less than 100 x 10 9 /L. Resume TEMOZOLOMIDE when platelet count is greater than or equal to 100 x 10 9 /L. Discontinue TEMOZOLOMIDE if platelet count is less than 10 x 10 9 /L. Non-hematological Adverse Reaction (except for alopecia, nausea, vomiting) Withhold TEMOZOLOMIDE if Grade 2 adverse reaction occurs. Resume TEMOZOLOMIDE when resolution to Grade 1 or less. Discontinue TEMOZOLOMIDE if Grade 3 or 4 adverse reaction occurs. Single Agent Maintenance Use 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 on days 1 to 5. Cycles 2 to 6: May increase to 200 mg/m 2 per day on days 1 to 5 before starting Cycle 2 if no dosage interruptions or discontinuations are required (Table 1). If the dose is not escalated at the onset of Cycle 2, do not increase the dose for Cycles 3 to 6 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 due to adverse reactions during the maintenance use 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 Discontinuation Absolute Neutrophil Count Withhold TEMOZOLOMIDE if ANC less than 1 x 10 9 /L. When ANC is above 1.5 x 10 9 /L, resume TEMOZOLOMIDE at reduced dose for the next cycle. Discontinue TEMOZOLOMIDE if unable to tolerate a dose of 100 mg/m 2 per day. Platelet Count Withhold TEMOZOLOMIDE if platelet less than 50 x 10 9 /L. When platelet count is above 100 x 10 9 /L, resume TEMOZOLOMIDE at reduced dose for the next cycle. Discontinue TEMOZOLOMIDE if unable to tolerate a dose of 100 mg/m 2 per day. Non-hematological Adverse Reaction (except for alopecia, nausea, vomiting) Withhold TEMOZOLOMIDE if Grade 3 adverse reaction. When resolved to grade 1 or less, resume TEMOZOLOMIDE at reduced dose for the next cycle. Discontinue TEMOZOLOMIDE if recurrent Grade 3 adverse reaction occurs after dose reduction, if Grade 4 adverse reaction occurs, or if unable to tolerate a dose of 100 mg/m 2 per day. 2.3 Recommended Dosage and Dosage Modifications for Anaplastic Astrocytoma Adjuvant Treatment of Newly Diagnosed Anaplastic Astrocytoma Beginning 4 weeks after the end of radiotherapy, administer TEMOZOLOMIDE orally in a single dose on days 1 to 5 of a 28-day cycle for 12 cycles. The recommended dosage of TEMOZOLOMIDE is: Cycle 1: 150 mg/m 2 per day on days 1 to 5. Cycles 2 to 12: 200 mg/m 2 per day on days 1 to 5 if patient experienced no or minimal toxicity in Cycle 1. If the dose was not escalated at the onset of Cycle 2, do not increase the dose during Cycles 3 to 6. The recommended complete blood count testing and dosage modifications due to adverse reactions during adjuvant treatment are provided above and in Table 2 [see Dosage and Administration ( 2.2 )]. 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 × 10 9 /L, and Platelet count is greater than or equal to 100 × 10 9 /L. Continue TEMOZOLOMIDE until disease progression or unacceptable toxicity. 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 × 10 9 /L or the platelet count is less than 50 × 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. 2.4 Preparation and Administration TEMOZOLOMIDE is a hazardous drug. Follow applicable special handling and disposal procedures. 1 TEMOZOLOMIDE capsules Take TEMOZOLOMIDE at the same time each day. 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 following TEMOZOLOMIDE administration. Swallow TEMOZOLOMIDE capsules whole with water. Advise patients not to open, chew, or dissolve the contents of the capsules [see Warnings and Precautions ( 5.6 )] . 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, wash the affected area with water immediately.

6. ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions ( 5.1 )]. Hepatotoxicity [see Warnings and Precautions ( 5.2 )]. Pneumocystis Pneumonia [see Warnings and Precautions ( 5.3 )]. Secondary Malignancies [see Warnings and Precautions ( 5.4 )]. The most common adverse reactions (≥ 20% incidence) are: alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, and convulsions. ( 6.1 ) The most common Grade 3 to 4 hematologic laboratory abnormalities (≥ 10% incidence) in patients with anaplastic astrocytoma are: decreased lymphocytes, decreased platelets, decreased neutrophils, and decreased leukocytes.( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Devatis Inc. at 1-833-534-4406 or druginfo@devatis.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch or www.devatis.com. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly Diagnosed Glioblastoma The safety of TEMOZOLOMIDE was evaluated in Study MK-7365-051 [see Clinical Studies ( 14.1 )]. Severe or life-threatening adverse reactions occurred in 49% of patients treated with TEMOZOLOMIDE; the most common were fatigue (13%), convulsions (6%), headache (5%), and thrombocytopenia (5%). The most common adverse reactions (≥20%) in patients treated with TEMOZOLOMIDE were alopecia, fatigue, nausea, anorexia, headache, constipation, and vomiting. Table 3 summarizes the adverse reactions in MK-7365-051 TABLE 3: Adverse Reactions (≥10%) in Patients with Newly Diagnosed Glioblastoma Adverse Reactions Concomitant Use Phase Maintenance Use Phase Radiation Therapy and TEMOZOLOMIDE N=288* Radiation Therapy Alone N=285 TEMOZOLOMIDE N=224 All Grades (%) Grade ≥3 (%) All Grades (%) Grades ≥3 (%) All Grades (%) Grade ≥3 (%) Skin and Subcutaneous Tissue Alopecia 69 0 63 0 55 0 Rash 19 1 15 0 13 1 General Fatigue 54 7 49 5 61 9 Anorexia 19 1 9 70 years experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. For patients ≤ 70 years, 7% (62/871) and 6% (48/879) experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. Pancytopenia, leukopenia, and anemia also occurred. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TEMOZOLOMIDE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug exposure. Dermatologic: Toxic epidermal necrolysis and Stevens-Johnson syndrome Immune System: Hypersensitivity reactions, including anaphylaxis. Erythema multiforme, which resolved after discontinuation of TEMOZOLOMIDE and, in some cases, recurred upon rechallenge. Hematopoietic: Prolonged pancytopenia, which may result in aplastic anemia and fatal outcomes. Hepatobiliary : Fatal and severe hepatotoxicity, elevation of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis Infections: Serious opportunistic infections, including some cases with fatal outcomes, with bacterial, viral (primary and reactivated), fungal, and protozoan organisms. Pulmonary: Interstitial pneumonitis, pneumonitis, alveolitis, and pulmonary fibrosis. Endocrine : Diabetes insipidus

No interactions listed. Consult your pharmacist.

16. HOW SUPPLIED/STORAGE AND HANDLING TEMOZOLOMIDE is a hazardous drug. Follow applicable special handling and disposal procedures TEMOZOLOMIDE Capsules, USP are supplied in amber glass bottles, with child-resistant polypropylene caps (not supplied in sachets) containing the following capsule strengths: TEMOZOLOMIDE Capsules USP, 250 mg: Have opaque white bodies with opaque white caps. The capsule body is imprinted with the dosage strength. They are supplied as follows: Bottles: 5-count – NDC 72162-2664-2 Store TEMOZOLOMIDE Capsules, USP at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Repackaged/Relabeled by: Bryant Ranch Prepack Burbank, CA 91504