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…

5. WARNINGS AND PRECAUTIONS Myelosuppression: Monitor absolute neutrophil count (ANC) and platelet count prior to each cycle and during treatment. Geriatric patients and women have a higher risk of developing myelosuppression. ( 5.1 , 8.5 ) Hepatotoxicity : Fatal and severe hepatotoxicity have been reported. Perform liver tests at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately 2 to 4 weeks after the last dose of TEMOZOLOMIDE ( 5.2 ) Pneumocystis Pneumonia (PCP): Closely monitor all patients, particularly those receiving steroids, for the development of lymphopenia and PCP.( 5.3 ) Secondary Malignancies : Myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed. ( 5.4 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. Advise male patients with pregnant partners or female partners of reproductive potential to use condoms. ( 5.5 , 8.1 , 8.3 ) Exposure to Opened Capsules : TEMOZOLOMIDE capsules should not be opened, chewed, or dissolved but should be swallowed whole with a glass of water. ( 5.6 ) 5.1 Myelosuppression Myelosuppression, including pancytopenia, leukopenia and anemia, some with fatal outcomes, have occurred with TEMOZOLOMIDE [see Adverse Reactions ( 6.1 , 6.2 )] . In MK-7365-006, myelosuppression usually occurred during the first few cycles of therapy and was generally not cumulative. The median nadirs occurred at 26 days for platelets (range: 21 to 40 days) and 28 days for neutrophils (range: 1 to 44 days). Approximately 10% of patients required hospitalization, blood transfusion, or discontinuation of therapy due to myelosuppression. Geriatric patients and women have been shown in clinical trials to have a higher risk of developing myelosuppression. Obtain a complete blood count and monitor ANC and platelet counts before initiation of treatment and as clinically indicated during treatment. When TEMOZOLOMIDE is used in combination with radiotherapy, obtain a complete blood count prior to initiation of treatment, weekly during treatment, and as clinically indicated [see Dosage and Administration ( 2.1 , 2.2 , 2.3 )] . For severe myelosuppression, withhold TEMOZOLOMIDE and then resume at same or reduced dose, or permanently discontinue, based on occurrence [see Dosage and Administration ( 2.1 , 2.2 , 2.3 )]. 5.2 Hepatotoxicity Fatal and severe hepatotoxicity have been reported in patients receiving TEMOZOLOMIDE. Perform liver tests at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately two to four weeks after the last dose of TEMOZOLOMIDE. 5.3 Pneumocystis Pneumonia Pneumocystis pneumonia (PCP) can occur in patients receiving TEMOZOLOMIDE. The risk of PCP is increased in patients receiving steroids or with longer treatment regimens of TEMOZOLOMIDE. For patients with newly diagnosed glioblastoma, provide PCP prophylaxis for all patients during the concomitant phase. Continue in patients who experience lymphopenia until resolution to Grade 1 or less [see Dosage and Administration ( 2.1 )]. Monitor all patients receiving TEMOZOLOMIDE for the development of lymphopenia and PCP. 5.4 Secondary Malignancies The incidence of secondary malignancies is increased in patients treated with TEMOZOLOMIDE containing regimens. Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed following TEMOZOLOMIDE administration. 5.5 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, TEMOZOLOMIDE can cause fetal harm when administered to a pregnant woman. Adverse developmental outcomes have been reported in both pregnant patients and pregnant partners of male patients. Oral administration of temozolomide to rats and rabbits during the period of organogenesis resulted in embryolethality and polymalformations at doses less than…

4. CONTRAINDICATIONS TEMOZOLOMIDE is contraindicated in patients with a history of hypersensitivity reactions to: • temozolomide or any other ingredients in TEMOZOLOMIDE; and • dacarbazine, since both temozolomide and dacarbazine are metabolized to the same active metabolite 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide. Reactions to TEMOZOLOMIDE have included anaphylaxis [see Adverse Reactions ( 6.2 )]. History of hypersensitivity to temozolomide or any other ingredients in TEMOZOLOMIDE capsules and dacarbazine. ( 4 )

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology ( 12.1 )] TEMOZOLOMIDE can cause fetal harm when administered to a pregnant woman. Available postmarketing reports describe cases of spontaneous abortions and congenital malformations, including polymalformations with central nervous system, facial, cardiac, skeletal, and genitourinary system anomalies with exposure to TEMOZOLOMIDE during pregnancy. These cases report similar adverse developmental outcomes to those observed in animal studies. Administration of TEMOZOLOMIDE to rats and rabbits during the period of organogenesis caused numerous external, internal, and skeletal malformations at doses less than the maximum human dose based on body surface area (see Data) . Advise pregnant women of the potential risk to a fetus. 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 Five consecutive days of oral administration of temozolomide at doses of 75 and 150 mg/m 2 (0.38 and 0.75 times the human dose of 200 mg/m 2 ) in rats and rabbits, respectively, during the period of organogenesis (Gestation Days 8-12) caused numerous malformations of the external and internal organs and skeleton in both species. In rabbits, temozolomide at the 150 mg/m 2 dose (0.75 times the human dose of 200 mg/m 2 ) caused embryolethality as indicated by increased resorptions.

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 <1 27 1 Headache 19 2 17 4 23 4 Gastrointestinal System Nausea 36 1 16 <1 49 1 Vomiting 20 <1 6 <1 29 2 Constipation 18 1 6 0 22 0 Diarrhea 6 0 3 0 10 1 Central and Peripheral Nervous System Convulsions 6 3 7 3 11 3 NOS=not otherwise specified. Note : Grade 5 (fatal) adverse reactions are included in the Grade ≥3 column. * One patient who was randomized to radiation therapy-only arm received radiation therapy and TEMOZOLOMIDE. Clinically relevant adverse reactions in <10% of patients are presented below: Central & Peripheral Nervous System : memory impairment, confusion Eye : vision blurred Gastrointestinal System : stomatitis, abdominal pain General : weakness, dizziness Immune System : allergic reaction Injury : radiation injury not otherwise specified Musculoskeletal System : arthralgia Platelet, Bleeding, & Clotting : thrombocytopenia Psychiatric : insomnia Respiratory System : coughing, dyspnea Special Senses Other : taste perversion Skin & Subcutaneous Tissue : dry skin, pruritus, erythema When laboratory abnormalities and adverse reactions were combined, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic reactions were observed in 8% of patients, and Grade 3 or Grade 4 platelet abnormalities including thrombocytopenic reactions, were observed in 14% of patients. Newly Diagnosed Anaplastic Astrocytoma The safety of TEMOZOLOMIDE for the adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma was derived from published literature [see Clinical Studies ( 14.2 )]. The safety of TEMOZOLOMIDE for the adjuvant treatment of patients with newly diagnosed anaplastic astrocytoma was consistent with the known safety profile of TEMOZOLOMIDE. Refractory Anaplastic Astrocytoma The safety of TEMOZOLOMIDE was evaluated in Study MK-7365-006 [see Clinical Studies ( 14.2 )]. …