HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Safe Handling and Disposal Care should be exercised in the handling and preparation of temozolomide. Vials and capsules should not be opened. If vials or capsules are accidentally opened or damaged, rigorous precautions should be taken with the contents to avoid inhalation or contact with the skin or mucous membranes. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or capsules. Procedures for proper handling and disposal of anticancer drugs should be considered {1-4}. Several guidelines on this subject have been published. 16.2 How Supplied Temozolomide Capsules: Temozolomide capsules are supplied in amber glass bottles with child-resistant polypropylene caps containing the following capsule strengths: Temozolomide Capsules 5 mg: have opaque white bodies with opaque white caps. The capsule is imprinted with the dosage strength and "Temozolomide". They are supplied as follows: 5-count NDC 0781-2691-75 14-count NDC 0781-2691-44 Temozolomide Capsules 20 mg: have opaque white bodies with opaque white caps. The capsule is imprinted with the dosage strength and "Temozolomide". They are supplied as follows: 5-count NDC 0781-2692-75 14-count NDC 0781-2692-44 Temozolomide Capsules 100 mg: have opaque white bodies with opaque white caps. The capsule is imprinted with the dosage strength and "Temozolomide". They are supplied as follows: 5-count NDC 0781-2693-75 14-count NDC 0781-2693-44 Temozolomide Capsules 140 mg: have opaque white bodies with opaque white caps. The capsule is imprinted with the dosage strength and "Temozolomide". They are supplied as follows: 5-count NDC 0781-2694-75 14-count NDC 0781-2694-44 Temozolomide Capsules 180 mg: have opaque white bodies with opaque white caps. The capsule is imprinted with the dosage strength and "Temozolomide". They are supplied as follows: 5-count NDC 0781-2695-75 14-count NDC 0781-2695-44 Temozolomide Capsules 250 mg: have opaque white bodies with opaque white caps. The capsule is imprinted with the dosage strength and "Temozolomide". They are supplied as follows: 5-count NDC 0781-2696-75 16.3 Storage Store temozolomide capsules at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature]. Store temozolomide for injection refrigerated at 2-8C (36-46F). After reconstitution, store reconstituted product at room temperature (25C [77F]). Reconstituted product must be used within 14 hours, including infusion time.

SPL UNCLASSIFIED SECTION.


Manufactured for: Sandoz Inc., Princeton, NJ 08540 Revised: 10/2018 usphi-g-mk7365-cp-1810r003

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS Temozolomide Capsules for oral administration 5-mg capsules have opaque white bodies with opaque white caps. The capsule is imprinted with the dosage strength and "Temozolomide". 20-mg capsules have opaque white bodies with opaque white caps. The capsule is imprinted with the dosage strength and "Temozolomide". 100-mg capsules have opaque white bodies with opaque white caps. The capsule is imprinted with the dosage strength and "Temozolomide". 140-mg capsules have opaque white bodies with opaque white caps. The capsule is imprinted with the dosage strength and "Temozolomide". 180-mg capsules have opaque white bodies with opaque white caps. The capsule is imprinted with the dosage strength and "Temozolomide". 250-mg capsules have opaque white bodies with opaque white caps. The capsule is imprinted with the dosage strength and "Temozolomide". 5-mg, 20-mg, 100-mg, 140-mg, 180-mg, and 250-mg capsules. (3)

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL - 250 mg Capsule Bottle Carton NDC 0781-2696-75 250 mg per capsule Temozolomide Capsules For Oral Administration Rx only This package contains 5 Capsules SANDOZ a Novartis company

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS The most common adverse reactions (10% incidence) are: alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, convulsions, rash, hemiparesis, diarrhea, asthenia, fever, dizziness, coordination abnormal, viral infection, amnesia, and insomnia. (6.1) The most common Grade 3 to 4 hematologic laboratory abnormalities (10% incidence) that have developed during treatment with temozolomide are: lymphopenia, thrombocytopenia, neutropenia, and leukopenia. (6.1) Allergic reactions have also been reported. (6) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 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 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 Multiforme: During the concomitant phase (temozolomide+radiotherapy), adverse reactions including thrombocytopenia, nausea, vomiting, anorexia, and constipation were more frequent in the temozolomide+RT arm. The incidence of other adverse reactions was comparable in the two arms. The most common adverse reactions across the cumulative temozolomide experience were alopecia, nausea, vomiting, anorexia, headache, and constipation (see Table 7 ). Forty-nine percent (49%) of patients treated with temozolomide reported one or more severe or life-threatening reactions, most commonly fatigue (13%), convulsions (6%), headache (5%), and thrombocytopenia (5%). Overall, the pattern of reactions during the maintenance phase was consistent with the known safety profile of temozolomide. TABLE 7: Number (%) of Patients with Adverse Reactions: All and Severe/Life Threatening (Incidence of 5% or Greater) Concomitant Phase RT Alone (n=285) Concomitant Phase RT+TMZ (n=288)One patient who was randomized to RT only arm received RT+temozolomide. Maintenance Phase TMZ (n=224) All Grade 3 All Grade 3 All Grade 3 RT+TMZ=radiotherapy plus temozolomide; NOS=not otherwise specified. Note: Grade 5 (fatal) adverse reactions are included in the Grade 3 column. Subjects Reporting any Adverse Reaction 258 (91) 74 (26) 266 (92) 80 (28) 206 (92) 82 (37) Body as a Whole General Disorders Anorexia 25 (9) 1 (<1) 56 (19) 2 (1) 61 (27) 3 (1) Dizziness 10 (4) 0 12 (4) 2 (1) 12 (5) 0 Fatigue 139 (49) 15 (5) 156 (54) 19 (7) 137 (61) 20 (9) Headache 49 (17) 11 (4) 56 (19) 5 (2) 51 (23) 9 (4) Weakness 9 (3) 3 (1) 10 (3) 5 (2) 16 (7) 4 (2) Central and Peripheral Nervous System Disorders Confusion 12 (4) 6 (2) 11 (4) 4 (1) 12 (5) 4 (2) Convulsions 20 (7) 9 (3) 17 (6) 10 (3) 25 (11) 7 (3) Memory Impairment 12 (4) 1 (<1) 8 (3) 1 (<1) 16 (7) 2 (1) Disorders of the Eye Vision Blurred 25 (9) 4 (1) 26 (9) 2 (1) 17 (8) 0 Disorders of the Immune System Allergic Reaction 7 (2) 1 (<1) 13 (5) 0 6 (3) 0 Gastrointestinal System Disorders Abdominal Pain 2 (1) 0 7 (2) 1 (<1) 11 (5) 1 (<1) Constipation 18 (6) 0 53 (18) 3 (1) 49 (22) 0 Diarrhea 9 (3) 0 18 (6) 0 23 (10) 2 (1) Nausea 45 (16) 1 (<1) 105 (36) 2 (1) 110 (49) 3 (1) Stomatitis 14 (5) 1 (<1) 19 (7) 0 20 (9) 3 (1) Vomiting 16 (6) 1 (<1) 57 (20) 1 (<1) 66 (29) 4 (2) Injury and Poisoning Radiation Injury NOS 11 (4) 1 (<1) 20 (7) 0 5 (2) 0 Musculoskeletal System Disorders Arthralgia 2 (1) 0 7 (2) 1 (<1) 14 (6) 0 Platelet, Bleeding and Clotting Disorders Thrombocytopenia 3 (1) 0 11 (4) 8 (3) 19 (8) 8 (4) Psychiatric Disorders Insomnia 9 (3) 1 (<1) 14 (5) 0 9 (4) 0 Respiratory System Disorders Coughing 3 (1) 0 15 (5) 2 (1) 19 (8) 1 (<1) Dyspnea 9 (3) 4 (1) 11 (4) 5 (2) 12 (5) 1 (<1) Skin and Subcutaneous Tissue Disorders Alopecia 179 (63) 0 199 (69) 0 124 (55) 0 Dry Skin 6 (2) 0 7 (2) 0 11 (5) 1 (<1) Erythema 15 (5) 0 14 (5) 0 2 (1) 0 Pruritus 4 (1) 0 11 (4) 0 11 (5) 0 Rash 42 (15) 0 56 (19) 3 (1) 29 (13) 3 (1) Special Senses Other, Disorders Taste Perversion 6 (2) 0 18 (6) 0 11 (5) 0 Myelosuppression (neutropenia and thrombocytopenia), which is a known dose-limiting toxicity for most cytotoxic agents, including temozolomide, was observed. When laboratory abnormalities and adverse reactions were combined, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic reactions were observed in 8% of the patients, and Grade 3 or Grade 4 platelet abnormalities, including thrombocytopenic reactions, were observed in 14% of the patients treated with temozolomide. Refractory Anaplastic Astrocytoma: Tables 8 and 9 show the incidence of adverse reactions in the 158 patients in the anaplastic astrocytoma study for whom data are available. In the absence of a control group, it is not clear in many cases whether these reactions should be attributed to temozolomide or the patients' underlying conditions, but nausea, vomiting, fatigue, and hematologic effects appear to be clearly drug-related. The most frequently occurring adverse reactions were nausea, vomiting, headache, and fatigue. The adverse reactions were usually NCI Common Toxicity Criteria (CTC) Grade 1 or 2 (mild to moderate in severity) and were self-limiting, with nausea and vomiting readily controlled with antiemetics. The incidence of severe nausea and vomiting (CTC Grade 3 or 4) was 10% and 6%, respectively. Myelosuppression (thrombocytopenia and neutropenia) was the dose-limiting adverse reaction. It usually occurred within the first few cycles of therapy and was not cumulative. Myelosuppression occurred late in the treatment cycle and returned to normal, on average, within 14 days of nadir counts. The median nadirs occurred at 26 days for platelets (range: 21-40 days) and 28 days for neutrophils (range: 1-44 days). Only 14% (22/158) of patients had a neutrophil nadir and 20% (32/158) of patients had a platelet nadir, which may have delayed the start of the next cycle. Less than 10% of patients required hospitalization, blood transfusion, or discontinuation of therapy due to myelosuppression. In clinical trial experience with 110 to 111 women and 169 to 174 men (depending on measurements), there were higher rates of Grade 4 neutropenia (ANC less than 500 cells/L) and thrombocytopenia (less than 20,000 cells/L) in women than men in the first cycle of therapy (12% vs. 5% and 9% vs. 3%, respectively). In the entire safety database for which hematologic data exist (N=932), 7% (4/61) and 9.5% (6/63) of patients over age 70 experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. For patients less than or equal to age 70, 7% (62/871) and 5.5% (48/879) experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. Pancytopenia, leukopenia, and anemia have also been reported. TABLE 8: Adverse Reactions in the Anaplastic Astrocytoma Trial in Adults (5%) No. (%) of Temozolomide Patients (N=158) All Reactions Grade 3/4 Any Adverse Reaction 153 (97) 79 (50) Body as a Whole Headache 65 (41) 10 (6) Fatigue 54 (34) 7 (4) Asthenia 20 (13) 9 (6) Fever 21 (13) 3 (2) Back pain 12 (8) 4 (3) Cardiovascular Edema peripheral 17 (11) 1 (1) Central and Peripheral Nervous System Convulsions 36 (23) 8 (5) Hemiparesis 29 (18) 10 (6) Dizziness 19 (12) 1 (1) Coordination abnormal 17 (11) 2 (1) Amnesia 16 (10) 6 (4) Insomnia 16 (10) 0 Paresthesia 15 (9) 1 (1) Somnolence 15 (9) 5 (3) Paresis 13 (8) 4 (3) Urinary incontinence 13 (8) 3 (2) Ataxia 12 (8) 3 (2) Dysphasia 11 (7) 1 (1) Convulsions local 9 (6) 0 Gait abnormal 9 (6) 1 (1) Confusion 8 (5) 0 Endocrine Adrenal hypercorticism 13 (8) 0 Gastrointestinal System Nausea 84 (53) 16 (10) Vomiting 66 (42) 10 (6) Constipation 52 (33) 1 (1) Diarrhea 25 (16) 3 (2) Abdominal pain 14 (9) 2 (1) Anorexia 14 (9) 1 (1) Metabolic Weight increase 8 (5) 0 Musculoskeletal System Myalgia 8 (5) Psychiatric Disorders Anxiety 11 (7) 1 (1) Depression 10 (6) 0 Reproductive Disorders Breast pain, female 4 (6) Resistance Mechanism Disorders Infection viral 17 (11) 0 Respiratory System Upper respiratory tract infection 13 (8) 0 Pharyngitis 12 (8) 0 Sinusitis 10 (6) 0 Coughing 8 (5) 0 Skin and Appendages Rash 13 (8) 0 Pruritus 12 (8) 2 (1) Urinary System Urinary tract infection 12 (8) 0 Micturition increased frequency 9 (6) 0 Vision Diplopia 8 (5) 0 Vision abnormalBlurred vision; visual deficit; vision changes; vision troubles 8 (5) TABLE 9: Adverse Hematologic Effects (Grade 3 to 4) in the Anaplastic Astrocytoma Trial in Adults TemozolomideChange from Grade 0 to 2 at baseline to Grade 3 or 4 during treatment. Hemoglobin 7/158 (4%) Lymphopenia 83/152 (55%) Neutrophils 20/142 (14%) Platelets 29/156 (19%) WBC 18/158 (11%) Temozolomide for injection delivers equivalent temozolomide dose and exposure to both temozolomide and 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) as the corresponding temozolomide capsules. Adverse reactions probably related to treatment that were reported from the 2 studies with the intravenous formulation (n=35) that were not reported in studies using the temozolomide capsules were: pain, irritation, pruritus, warmth, swelling, and erythema at infusion site as well as the following adverse reactions: petechiae and hematoma. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval 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 disorders: Toxic epidermal necrolysis and Stevens-Johnson syndrome Immune system disorders: Allergic reactions, including anaphylaxis. Erythema multiforme, which resolved after discontinuation of temozolomide and, in some cases, recurred upon rechallenge. Hematopoietic disorders: Prolonged pancytopenia, which may result in aplastic anemia and fatal outcomes [see Warnings and Precautions (5.1)]. Hepatobiliary disorders: Fatal and severe hepatotoxicity, elevation of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis [see Warnings and Precautions (5.5)]. Infections and infestations: Serious opportunistic infections, including some cases with fatal outcomes, can occur with bacterial, viral (primary and reactivated), fungal, and protozoan organisms. Pulmonary disorders: Interstitial pneumonitis, pneumonitis, alveolitis, and pulmonary fibrosis. Endocrine disorders: Diabetes insipidus

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE Temozolomide is an alkylating drug indicated for the treatment of adult patients with: Newly diagnosed glioblastoma multiforme (GBM) concomitantly with radiotherapy and then as maintenance treatment. (1.1) Refractory anaplastic astrocytoma patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine. (1.2) 1.1 Newly Diagnosed Glioblastoma Multiforme Temozolomide is indicated for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment. 1.2 Refractory Anaplastic Astrocytoma Temozolomide is indicated for the treatment of adult patients with refractory anaplastic astrocytoma, i.e., patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION Newly Diagnosed GBM: 75 mg/m2 for 42 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m2 once daily for Days 1-5 of a 28-day cycle of temozolomide for 6 cycles. (2.1) Refractory Anaplastic Astrocytoma: Initial dose 150 mg/m2 once daily for 5 consecutive days per 28-day treatment cycle. (2.1) The recommended dose for temozolomide as an intravenous infusion over 90 minutes is the same as the dose for the oral capsule formulation. Bioequivalence has been established only when temozolomide for injection was given over 90 minutes. (2.1, 12.3) 2.1 Recommended Dosing and Dose Modification Guidelines The recommended dose for temozolomide as an intravenous infusion over 90 minutes is the same as the dose for the oral capsule formulation. Bioequivalence has been established only when temozolomide for injection was given over 90 minutes [see Clinical Pharmacology (12.3)]. Dosage of temozolomide must be adjusted according to nadir neutrophil and platelet counts in the previous cycle and the neutrophil and platelet counts at the time of initiating the next cycle. For temozolomide dosage calculations based on body surface area (BSA) see Table 5 . For suggested capsule combinations on a daily dose see Table 6 . Patients with Newly Diagnosed High Grade Glioma: Concomitant Phase: Temozolomide is administered at 75 mg/m2 daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions) followed by maintenance temozolomide for 6 cycles. Focal RT includes the tumor bed or resection site with a 2- to 3-cm margin. No dose reductions are recommended during the concomitant phase; however, dose interruptions or discontinuation may occur based on toxicity. The temozolomide dose should be continued throughout the 42-day concomitant period up to 49 days if all of the following conditions are met: absolute neutrophil count greater than or equal to 1.5 109/L, platelet count greater than or equal to 100 109/L, common toxicity criteria (CTC) nonhematological toxicity less than or equal to Grade 1 (except for alopecia, nausea, and vomiting). During treatment a complete blood count should be obtained weekly. Temozolomide dosing should be interrupted or discontinued during concomitant phase according to the hematological and nonhematological toxicity criteria as noted in Table 1. Pneumocystis pneumonia (PCP) prophylaxis is required during the concomitant administration of temozolomide and radiotherapy, and should be continued in patients who develop lymphocytopenia until recovery from lymphocytopenia (CTC Grade less than or equal to 1). TABLE 1: Temozolomide Dosing Interruption or Discontinuation During Concomitant Radiotherapy and Temozolomide Toxicity TMZ InterruptionTreatment with concomitant TMZ could be continued when all of the following conditions were met: absolute neutrophil count greater than or equal to 1.5 109/L; platelet count greater than or equal to 100 109/L; CTC nonhematological toxicity less than or equal to Grade 1 (except for alopecia, nausea, vomiting). TMZ Discontinuation TMZ=temozolomide; CTC=Common Toxicity Criteria. Absolute Neutrophil Count greater than or equal to 0.5 and less than 1.5 109/L less than 0.5 109/L Platelet Count greater than or equal to 10 and less than 100 109/L less than 10 109/L CTC Nonhematological Toxicity (except for alopecia, nausea, vomiting) CTC Grade 2 CTC Grade 3 or 4 Maintenance Phase: Cycle 1: Four weeks after completing the temozolomide+RT phase, temozolomide is administered for an additional 6 cycles of maintenance treatment. Dosage in Cycle 1 (maintenance) is 150 mg/m2 once daily for 5 days followed by 23 days without treatment. Cycles 2-6: At the start of Cycle 2, the dose can be escalated to 200 mg/m2, if the CTC nonhematologic toxicity for Cycle 1 is Grade less than or equal to 2 (except for alopecia, nausea, and vomiting), absolute neutrophil count (ANC) is greater than or equal to 1.5 109/L, and the platelet count is greater than or equal to 100 109/L. The dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles. Dose Reduction or Discontinuation During Maintenance: Dose reductions during the maintenance phase should be applied according to Tables 2 and 3. During treatment, a complete blood count should be obtained on Day 22 (21 days after the first dose of temozolomide) or within 48 hours of that day, and weekly until the ANC is above 1.5 109/L (1500/L) and the platelet count exceeds 100 109/L (100,000/L). The next cycle of temozolomide should not be started until the ANC and platelet count exceed these levels. Dose reductions during the next cycle should be based on the lowest blood counts and worst nonhematologic toxicity during the previous cycle. Dose reductions or discontinuations during the maintenance phase should be applied according to Tables 2 and 3. TABLE 2: Temozolomide Dose Levels for Maintenance Treatment Dose Level Dose (mg/m2/day) Remarks -1 100 Reduction for prior toxicity 0 150 Dose during Cycle 1 1 200 Dose during Cycles 2-6 in absence of toxicity TABLE 3: Temozolomide Dose Reduction or Discontinuation During Maintenance Treatment Toxicity Reduce TMZ by 1 Dose LevelTMZ dose levels are listed in Table 2. Discontinue TMZ TMZ=temozolomide; CTC=Common Toxicity Criteria. Absolute Neutrophil Count less than 1.0 109/L See footnoteTMZ is to be discontinued if dose reduction to less than 100 mg/m2 is required or if the same Grade 3 nonhematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction. Platelet Count less than 50 109/L See footnote CTC Nonhematological Toxicity (except for alopecia, nausea, vomiting) CTC Grade 3 CTC Grade 4 Patients with Refractory Anaplastic Astrocytoma: For adults the initial dose is 150 mg/m2 once daily for 5 consecutive days per 28-day treatment cycle. For adult patients, if both the nadir and day of dosing (Day 29, Day 1 of next cycle) ANC are greater than or equal to 1.5 109/L (1500/L) and both the nadir and Day 29, Day 1 of next cycle platelet counts are greater than or equal to 100 109/L (100,000/L), the temozolomide dose may be increased to 200 mg/m2/day for 5 consecutive days per 28-day treatment cycle. During treatment, a complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until the ANC is above 1.5 109/L (1500/L) and the platelet count exceeds 100 109/L (100,000/L). The next cycle of temozolomide should not be started until the ANC and platelet count exceed these levels. If the ANC falls to less than 1.0 109/L (1000/L) or the platelet count is less than 50 109/L (50,000/L) during any cycle, the next cycle should be reduced by 50 mg/m2, but not below 100 mg/m2, the lowest recommended dose (see Table 4 ). Temozolomide therapy can be continued until disease progression. In the clinical trial, treatment could be continued for a maximum of 2 years, but the optimum duration of therapy is not known. TABLE 4: Dosing Modification Table TABLE 5: Daily Dose Calculations by Body Surface Area (BSA) Total BSA (m2) 75 mg/m2 (mg daily) 150 mg/m2 (mg daily) 200 mg/m2 (mg daily) 1.0 75 150 200 1.1 82.5 165 220 1.2 90 180 240 1.3 97.5 195 260 1.4 105 210 280 1.5 112.5 225 300 1.6 120 240 320 1.7 127.5 255 340 1.8 135 270 360 1.9 142.5 285 380 2.0 150 300 400 2.1 157.5 315 420 2.2 165 330 440 2.3 172.5 345 460 2.4 180 360 480 2.5 187.5 375 500 TABLE 6: Suggested Capsule Combinations Based on Daily Dose in Adults Number of Daily Capsules by Strength (mg) Total Daily Dose (mg) 250 mg 180 mg 140 mg 100 mg 20 mg 5 mg 75 0 0 0 0 3 3 82.5 0 0 0 0 4 0 90 0 0 0 0 4 2 97.5 0 0 0 1 0 0 105 0 0 0 1 0 1 112.5 0 0 0 1 0 2 120 0 0 0 1 1 0 127.5 0 0 0 1 1 1 135 0 0 0 1 1 3 142.5 0 0 1 0 0 0 150 0 0 1 0 0 2 157.5 0 0 1 0 1 0 165 0 0 1 0 1 1 172.5 0 0 1 0 1 2 180 0 1 0 0 0 0 187.5 0 1 0 0 0 1 195 0 1 0 0 0 3 200 0 1 0 0 1 0 210 0 0 0 2 0 2 220 0 0 0 2 1 0 225 0 0 0 2 1 1 240 0 0 1 1 0 0 255 1 0 0 0 0 1 260 1 0 0 0 0 2 270 1 0 0 0 1 0 280 0 0 2 0 0 0 285 0 0 2 0 0 1 300 0 0 0 3 0 0 315 0 0 0 3 0 3 320 0 1 1 0 0 0 330 0 1 1 0 0 2 340 0 1 1 0 1 0 345 0 1 1 0 1 1 360 0 2 0 0 0 0 375 0 2 0 0 0 3 380 0 1 0 2 0 0 400 0 0 0 4 0 0 420 0 0 3 0 0 0 440 0 0 3 0 1 0 460 0 2 0 1 0 0 480 0 1 0 3 0 0 500 2 0 0 0 0 0 2.2 Preparation and Administration Temozolomide Capsules: In clinical trials, temozolomide was administered under both fasting and nonfasting conditions; however, absorption is affected by food [see Clinical Pharmacology (12.3)], and consistency of administration with respect to food is recommended. There are no dietary restrictions with temozolomide. To reduce nausea and vomiting, temozolomide should be taken on an empty stomach. Bedtime administration may be advised. Antiemetic therapy may be administered prior to and/or following administration of temozolomide. Temozolomide capsules should not be opened or chewed. They should be swallowed whole with a glass of water. If capsules are accidentally opened or damaged, precautions should be taken to avoid inhalation or contact with the skin or mucous membranes [see How Supplied/Storage and Handling (16.1)]. Temozolomide for Injection: Each vial of temozolomide for injection contains sterile and pyrogen-free temozolomide lyophilized powder. When reconstituted with 41 mL Sterile Water for Injection, the resulting solution will contain 2.5 mg/mL temozolomide. Bring the vial to room temperature prior to reconstitution with Sterile Water for Injection. The vials should be gently swirled and not shaken. Vials should be inspected, and any vial containing visible particulate matter should not be used. Do not further dilute the reconstituted solution. After reconstitution, store at room temperature (25C [77F]). Reconstituted product must be used within 14 hours, including infusion time. Using aseptic technique, withdraw up to 40 mL from each vial to make up the total dose based on Table 5 above and transfer into an empty 250 mL infusion bag {2}. Temozolomide for injection should be infused intravenously using a pump over a period of 90 minutes. Temozolomide for injection should be administered only by intravenous infusion. Flush the lines before and after each temozolomide 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, other medications should not be infused simultaneously through the same intravenous line.

DESCRIPTION SECTION.


11 DESCRIPTION Temozolomide is an imidazotetrazine derivative. The chemical name of temozolomide is 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide. The structural formula is: The material is a white to light tan/light pink powder with a molecular formula of C6H6N6O2 and a molecular weight of 194.15. The molecule is stable at acidic pH (7; hence temozolomide can be administered orally and intravenously. The prodrug, temozolomide, is rapidly hydrolyzed to the active 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) at neutral and alkaline pH values, with hydrolysis taking place even faster at alkaline pH. Temozolomide Capsules: Each capsule for oral use contains either 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 mg of temozolomide, USP. The inactive ingredients for temozolomide capsules are as follows: Temozolomide 5 mg: lactose anhydrous (132.8 mg), colloidal silicon dioxide (0.2 mg), sodium starch glycolate (7.5 mg), tartaric acid (1.5 mg), and stearic acid (3 mg). Temozolomide 20 mg: lactose anhydrous (182.2 mg), colloidal silicon dioxide (0.2 mg), sodium starch glycolate (11 mg), tartaric acid (2.2 mg), and stearic acid (4.4 mg). Temozolomide 100 mg: lactose anhydrous (175.7 mg), colloidal silicon dioxide (0.3 mg), sodium starch glycolate (15 mg), tartaric acid (3 mg), and stearic acid (6 mg). Temozolomide 140 mg: lactose anhydrous (246 mg), colloidal silicon dioxide (0.4 mg), sodium starch glycolate (21 mg), tartaric acid (4.2 mg), and stearic acid (8.4 mg). Temozolomide 180 mg: lactose anhydrous (316.3 mg), colloidal silicon dioxide (0.5 mg), sodium starch glycolate (27 mg), tartaric acid (5.4 mg), and stearic acid (10.8 mg). Temozolomide 250 mg: lactose anhydrous (154.3 mg), colloidal silicon dioxide (0.7 mg), sodium starch glycolate (22.5 mg), tartaric acid (9 mg), and stearic acid (13.5 mg). The body of the capsules and the caps are made of gelatin, and are opaque white. The capsule body and cap are imprinted with pharmaceutical branding ink. Temozolomide 5 mg: The opaque white cap contains gelatin, titanium dioxide, and sodium lauryl sulfate. The capsule is imprinted with green pharmaceutical ink, which contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, titanium dioxide, black iron oxide, FD&C Blue #1, and D&C Yellow #10. Temozolomide 20 mg: The opaque white cap contains gelatin, titanium dioxide, and sodium lauryl sulfate. The capsule is imprinted with black pharmaceutical ink, which contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, purified water, strong ammonia solution, potassium hydroxide, and ferric oxide. Temozolomide 100 mg: The opaque white cap contains gelatin, titanium dioxide, and sodium lauryl sulfate. The capsule is imprinted with pink pharmaceutical ink, which contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, sodium hydroxide, povidone, titanium dioxide, FD&C Red #40. Temozolomide 140 mg: The opaque white cap contains gelatin, titanium dioxide, and sodium lauryl sulfate. The capsule is imprinted with light blue pharmaceutical ink, which contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, titanium dioxide, FD&C Blue #1, and D&C Yellow #10. Temozolomide 180 mg: The opaque white cap contains gelatin, titanium dioxide, and sodium lauryl sulfate. The capsule is imprinted with red pharmaceutical ink, which contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, titanium dioxide, D&C Red #7, and FD&C Yellow #6. Temozolomide 250 mg: The opaque white cap contains gelatin, titanium dioxide, and sodium lauryl sulfate. The capsule is imprinted with brown pharmaceutical ink, which contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, potassium hydroxide, purified water, titanium dioxide, brown iron oxide, black iron oxide, red iron oxide, and yellow iron oxide. Temozolomide for Injection: Each vial contains 100 mg of sterile and pyrogen-free temozolomide lyophilized powder for intravenous injection. The inactive ingredients are: mannitol (600 mg), L-threonine (160 mg), polysorbate 80 (120 mg), sodium citrate dihydrate (235 mg), and hydrochloric acid (160 mg).

OVERDOSAGE SECTION.


10 OVERDOSAGE Doses of 500, 750, 1000, and 1250 mg/m2 (total dose per cycle over 5 days) have been evaluated clinically in patients. Dose-limiting toxicity was hematologic and was reported with any dose but is expected to be more severe at higher doses. An overdose of 2000 mg per day for 5 days was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia, multi-organ failure, and death. There are reports of patients who have taken more than 5 days of treatment (up to 64 days), with adverse reactions reported including bone marrow suppression, which in some cases was severe and prolonged, and infections and resulted in death. In the event of an overdose, hematologic evaluation is needed. Supportive measures should be provided as necessary.

SPL PATIENT PACKAGE INSERT SECTION.


Patient Information Temozolomide (tem" oh zol' oh mide) Capsules Temozolomide (tem" oh zol' oh mide) for Injection marketed as TEMODAR What is the most important information I should know about temozolomide? Temozolomide may cause birth defects. Male and female patients who take temozolomide should use effective birth control. Female patients and female partners of male patients should avoid becoming pregnant while taking temozolomide. See the section "What are the possible side effects of temozolomide?" for more information about side effects. What is temozolomide? Temozolomide is a prescription medicine used to treat adults with certain brain cancer tumors. Temozolomide blocks cell growth, especially cells that grow fast, such as cancer cells. Temozolomide may decrease the size of certain brain tumors in some patients. It is not known if temozolomide is safe and effective in children. Who should not take temozolomide? Do not take temozolomide if you: have had an allergic reaction to dacarbazine (DTIC), another cancer medicine. have had a red itchy rash, or a severe allergic reaction, such as trouble breathing, swelling of the face, throat, or tongue, or severe skin reaction to temozolomide or any of the ingredients in temozolomide. If you are not sure, ask your doctor. See the end of the leaflet for a list of ingredients in temozolomide. What should I tell my doctor before taking temozolomide? Tell your doctor about all your medical conditions, including if you: are allergic to dacarbazine (DTIC) or have had a severe allergic reaction to temozolomide. See "Who should not take temozolomide?" have kidney problems have liver problems are pregnant. See "What is the most important information I should know about temozolomide?" are breast-feeding. It is not known whether temozolomide passes into breast milk. You and your doctor should decide if you will breast-feed or take temozolomide. You should not do both without talking with your doctor. Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take a medicine that contains valproic acid (Stavzor, Depakene). Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine. How should I take temozolomide? Temozolomide may be taken by mouth as a capsule at home, or you may receive temozolomide by injection into a vein (intravenous). Your doctor will decide the best way for you to take temozolomide. There are two common dosing schedules for taking temozolomide. Some people take temozolomide for 42 days in a row (possibly 49 days depending on side effects) with radiation treatment. This is one cycle of treatment. After this, you may have "maintenance" treatment. Your doctor may prescribe 6 more cycles of temozolomide. For each of these cycles, you take temozolomide one time each day for 5 days in a row and then you stop taking it for the next 23 days. This is a 28-day maintenance treatment cycle. Another way to take temozolomide is to take it one time each day for 5 days in a row only, and then you stop taking it for the next 23 days. This is one cycle of treatment (28 days). Your doctor will watch your progress on temozolomide and decide how long you should take it. You might take temozolomide until your tumor gets worse or for possibly up to 2 years. Your dose is based on your height and weight, and the number of treatment cycles will depend on how you respond to and tolerate this treatment. Your doctor may modify your schedule based on how you tolerate the treatment. If your doctor prescribes a treatment regimen that is different from the information in this leaflet, make sure you follow the specific instructions given to you by your doctor. Temozolomide Capsules: Take temozolomide capsules exactly as prescribed. Temozolomide capsules come in different strengths. Each strength is imprinted with a different color pharmaceutical ink. Your doctor may prescribe more than one strength of temozolomide capsules for you, so it is important that you understand how to take your medicine the right way. Be sure that you understand exactly how many capsules you need to take on each day of your treatment, and what strengths to take. This may be different whenever you start a new cycle. Talk to your doctor before you take your dose if you are not sure how much to take. This will help to prevent taking too much temozolomide and decrease your chances of getting serious side effects. Take each day's dose of temozolomide capsules at one time, with a full glass of water. Swallow temozolomide capsules whole. Do not chew, open, or split the capsules. If temozolomide capsules are accidentally opened or damaged, be careful not to breathe in (inhale) the powder from the capsules or get the powder on your skin or mucous membranes (for example, in your nose or mouth). If contact with any of these areas happens, flush the area with water. If you vomit temozolomide capsules, do not take any more capsules. Wait and take your next planned dose. The medicine is used best by your body if you take it at the same time every day in relation to a meal. To lessen nausea, try to take temozolomide on an empty stomach or at bedtime. Your doctor may prescribe medicine to prevent or treat nausea, or other medicines to lessen side effects with temozolomide. See your doctor regularly to check your progress. Your doctor will check you for side effects that you might not notice. If you miss a dose of temozolomide, talk with your doctor for instructions about when to take your next dose of temozolomide. Call your doctor right away if you take more than the prescribed amount of temozolomide. It is important that you do not take more than the amount of temozolomide prescribed for you. Temozolomide for Injection: You will receive temozolomide as an infusion directly into your vein. Your treatment will take about 90 minutes. Your doctor may prescribe medicine to prevent or treat nausea, or other medicines to relieve side effects with temozolomide. What should I avoid while taking temozolomide? Female patients and female partners of male patients should avoid becoming pregnant while taking temozolomide. See "What is the most important information I should know about temozolomide?" What are the possible side effects of temozolomide? Temozolomide can cause serious side effects. See "What is the most important information I should know about temozolomide?" Decreased blood cells. Temozolomide affects cells that grow rapidly, including bone marrow cells. This can cause you to have a decrease in blood cells. Your doctor can monitor your blood for these effects. White blood cells are needed to fight infections. Neutrophils are a type of white blood cell that help prevent bacterial infections. Decreased neutrophils can lead to serious infections that can lead to death. Other white blood cells called lymphocytes may also be decreased. Platelets are blood cells needed for normal blood clotting. Low platelet counts can lead to bleeding. Tell your doctor about any unusual bruising or bleeding. Your doctor will check your blood regularly while you are taking temozolomide to see if these side effects are happening. Your doctor may need to change the dose of temozolomide or when you get it depending on your blood cell counts. People who are age 70 or older and women may be more likely to have their blood cells affected. Pneumocystis pneumonia (PCP). PCP is an infection that people can get when their immune system is weak. Temozolomide decreases white blood cells, which makes your immune system weaker and can increase your risk of getting PCP. All patients taking temozolomide will be watched carefully by their doctor for this infection, especially patients who take steroids. Tell your doctor if you have any of the following signs and symptoms of PCP infection: shortness of breath and/or fever, chills, dry cough. Secondary cancers. Blood problems such as myelodysplastic syndrome and secondary cancers, such as a certain kind of leukemia, can happen in people who take temozolomide. Your doctor will watch you for this. Convulsions. Convulsions may be severe or life-threatening in people who take temozolomide. Liver side effects have been reported, which very rarely included death. Common side effects with temozolomide include: nausea and vomiting. Your doctor can prescribe medicines that may help reduce these symptoms. headache feeling tired loss of appetite hair loss constipation bruising rash paralysis on one side of the body diarrhea weakness fever dizziness coordination problems viral infection sleep problems memory loss pain, irritation, itching, warmth, swelling or redness at the site of infusion bruising or small red or purple spots under the skin Tell your doctor about any side effect that bothers you or that does not go away. These are not all the possible side effects with temozolomide. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store temozolomide capsules? Store temozolomide capsules at 77F (controlled room temperature). Storage at 59F to 86F (15C to 30C) is permitted occasionally. Keep temozolomide capsules out of the reach of children and pets. General information about temozolomide. Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use temozolomide for a condition for which it was not prescribed. Do not give temozolomide to other people, even if they have the same symptoms that you have. It may harm them. This leaflet summarizes the most important information about temozolomide. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about temozolomide that is written for health professionals. How are temozolomide capsules supplied? Temozolomide capsules contain a white capsule body with a white cap. The capsules are available in six different strengths. Each strength is imprinted with a different color pharmaceutical ink. Temozolomide Capsule Strength Color 5 mg Green Ink 20 mg Black Ink 100 mg Pink Ink 140 mg Light Blue Ink 180 mg Red Ink 250 mg Brown Ink What are the ingredients in temozolomide? Temozolomide Capsules: Active ingredient: temozolomide, USP. Inactive ingredients: lactose anhydrous, colloidal silicon dioxide, sodium starch glycolate, tartaric acid, stearic acid. The body of the capsules and caps are made of gelatin and are opaque white. The capsule body and cap are imprinted with pharmaceutical branding ink. Temozolomide 5 mg: The opaque white cap contains gelatin, titanium dioxide, and sodium lauryl sulfate. The capsule is imprinted with green pharmaceutical ink, which contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, titanium dioxide, black iron oxide, FD&C Blue #1, and D&C Yellow #10. Temozolomide 20 mg: The opaque white cap contains gelatin, titanium dioxide, and sodium lauryl sulfate. The capsule is imprinted with black pharmaceutical ink, which contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, purified water, strong ammonia solution, potassium hydroxide, and ferric oxide. Temozolomide 100 mg: The opaque white cap contains gelatin, titanium dioxide, and sodium lauryl sulfate. The capsule is imprinted with pink pharmaceutical ink, which contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, sodium hydroxide, povidone, titanium dioxide, FD&C Red #40. Temozolomide 140 mg: The opaque white cap contains gelatin, titanium dioxide, and sodium lauryl sulfate. The capsule is imprinted with light blue pharmaceutical ink, which contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, titanium dioxide, FD&C Blue #1, and D&C Yellow #10. Temozolomide 180 mg: The opaque white cap contains gelatin, titanium dioxide, and sodium lauryl sulfate. The capsule is imprinted with red pharmaceutical ink, which contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, titanium dioxide, D&C Red #7, and FD&C Yellow #6. Temozolomide 250 mg: The opaque white cap contains gelatin, titanium dioxide, and sodium lauryl sulfate. The capsule is imprinted with brown pharmaceutical ink, which contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, potassium hydroxide, purified water, titanium dioxide, brown iron oxide, black iron oxide, red iron oxide, and yellow iron oxide. Temozolomide for Injection: Active ingredient: temozolomide. Inactive ingredients: mannitol, L-threonine, polysorbate 80, sodium citrate dihydrate, and hydrochloric acid.

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS Myelosuppression monitor Absolute Neutrophil Count (ANC) and platelet count prior to dosing and throughout treatment. Geriatric patients and women have a higher risk of developing myelosuppression. (5.1) Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed. (5.2) Pneumocystis pneumonia (PCP) PCP prophylaxis required for all patients receiving concomitant temozolomide and radiotherapy for the 42-day regimen for the treatment of newly diagnosed glioblastoma multiforme. (5.3) All patients, particularly those receiving steroids, should be observed closely for the development of lymphopenia and PCP. (5.4) Complete blood counts should be obtained throughout the treatment course as specified. (5.4) Hepatotoxicity fatal and severe hepatotoxicity have been reported. Perform liver function 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. (5.5) Fetal harm can occur when administered to a pregnant woman. Women should be advised to avoid becoming pregnant when receiving temozolomide. (5.6) As bioequivalence has been established only when given over 90 minutes, infusion over a shorter or longer period of time may result in suboptimal dosing; the possibility of an increase in infusion-related adverse reactions cannot be ruled out. (5.7) 5.1 Myelosuppression Patients treated with temozolomide may experience myelosuppression, including prolonged pancytopenia, which may result in aplastic anemia, which in some cases has resulted in a fatal outcome. In some cases, exposure to concomitant medications associated with aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to dosing, patients must have an absolute neutrophil count (ANC) greater than or equal to 1.5 109/L and a platelet count greater than or equal to 100 109/L. A complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until the ANC is above 1.5 109/L and platelet count exceeds 100 109/L. Geriatric patients and women have been shown in clinical trials to have a higher risk of developing myelosuppression. 5.2 Myelodysplastic Syndrome Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed. 5.3 Pneumocystis Pneumonia For treatment of newly diagnosed glioblastoma multiforme: Prophylaxis against Pneumocystis pneumonia (PCP) is required for all patients receiving concomitant temozolomide and radiotherapy for the 42-day regimen. There may be a higher occurrence of PCP when temozolomide is administered during a longer dosing regimen. However, all patients receiving temozolomide, particularly patients receiving steroids, should be observed closely for the development of PCP regardless of the regimen. 5.4 Laboratory Tests For the concomitant treatment phase with RT, a complete blood count should be obtained prior to initiation of treatment and weekly during treatment. For the 28-day treatment cycles, a complete blood count should be obtained prior to treatment on Day 1 and on Day 22 (21 days after the first dose) of each cycle. Blood counts should be performed weekly until recovery if the ANC falls below 1.5 109/L and the platelet count falls below 100 109/L [see Dosage and Administration (2.1)]. 5.5 Hepatotoxicity Fatal and severe hepatotoxicity have been reported in patients receiving temozolomide. Perform liver function 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. 5.6 Use in Pregnancy Temozolomide can cause fetal harm when administered to a pregnant woman. Administration of temozolomide to rats and rabbits during organogenesis at 0.38 and 0.75 times the maximum recommended human dose (75 and 150 mg/m2), respectively, caused numerous fetal malformations of the external organs, soft tissues, and skeleton in both species [see Use in Specific Populations (8.1)]. 5.7 Infusion Time As bioequivalence has been established only when temozolomide for injection was given over 90 minutes, infusion over a shorter or longer period of time may result in suboptimal dosing. Additionally, the possibility of an increase in infusion-related adverse reactions cannot be ruled out.

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS Valproic acid: decreases oral clearance of temozolomide. (7.1) 7.1 Valproic Acid Administration of valproic acid decreases oral clearance of temozolomide by about 5%. The clinical implication of this effect is not known [see Clinical Pharmacology (12.3)].

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Temozolomide is carcinogenic in rats at doses less than the maximum recommended human dose. Temozolomide induced mammary carcinomas in both males and females at doses 0.13 to 0.63 times the maximum human dose (25-125 mg/m2) when administered orally on 5 consecutive days every 28 days for 6 cycles. Temozolomide also induced fibrosarcomas of the heart, eye, seminal vesicles, salivary glands, abdominal cavity, uterus, and prostate, carcinomas of the seminal vesicles, schwannomas of the heart, optic nerve, and harderian gland, and adenomas of the skin, lung, pituitary, and thyroid at doses 0.5 times the maximum daily dose. Mammary tumors were also induced following 3 cycles of temozolomide at the maximum recommended daily dose. Temozolomide is a mutagen and a clastogen. In a reverse bacterial mutagenesis assay (Ames assay), temozolomide increased revertant frequency in the absence and presence of metabolic activation. Temozolomide was clastogenic in human lymphocytes in the presence and absence of metabolic activation. Temozolomide impairs male fertility. Temozolomide caused syncytial cells/immature sperm formation at 0.25 and 0.63 times the maximum recommended human dose (50 and 125 mg/m2) in rats and dogs, respectively, and testicular atrophy in dogs at 0.63 times the maximum recommended human dose (125 mg/m2). 13.2 Animal Toxicology and/or Pharmacology Toxicology studies in rats and dogs identified a low incidence of hemorrhage, degeneration, and necrosis of the retina at temozolomide doses equal to or greater than 0.63 times the maximum recommended human dose (125 mg/m2). These changes were most commonly seen at doses where mortality was observed.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS Nursing mothers: Not recommended. (8.3) Pediatric use: No established use. (8.4) Hepatic/Renal Impairment: Caution should be exercised when temozolomide is administered to patients with severe renal or hepatic impairment. (8.6, 8.7) 8.1 Pregnancy Pregnancy Category D. See Warnings and Precautions section. Temozolomide can cause fetal harm when administered to a pregnant woman. Five consecutive days of oral temozolomide administration of 0.38 and 0.75 times the highest recommended human dose (75 and 150 mg/m2) in rats and rabbits, respectively, during the period of organogenesis caused numerous malformations of the external and internal soft tissues and skeleton in both species. Doses equivalent to 0.75 times the highest recommended human dose (150 mg/m2) caused embryolethality in rats and rabbits as indicated by increased resorptions. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with temozolomide. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and tumorigenicity shown for temozolomide in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of temozolomide to the mother. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Temozolomide capsules have been studied in 2 open-label studies in pediatric patients (aged 3-18 years) at a dose of 160 to 200 mg/m2 daily for 5 days every 28 days. In one trial, 29 patients with recurrent brain stem glioma and 34 patients with recurrent high grade astrocytoma were enrolled. All patients had recurrence following surgery and radiation therapy, while 31% also had disease progression following chemotherapy. In a second study conducted by the Children's Oncology Group (COG), 122 patients were enrolled, including patients with medulloblastoma/PNET (29), high grade astrocytoma (23), low grade astrocytoma (22), brain stem glioma (16), ependymoma (14), other CNS tumors (9), and non-CNS tumors (9). The temozolomide toxicity profile in pediatric patients is similar to adults. Table 10 shows the adverse reactions in 122 children in the COG study. TABLE 10: Adverse Reactions Reported in the Pediatric Cooperative Group Trial (10%) No. (%) of Temozolomide Patients (N=122)These various tumors included the following: PNET-medulloblastoma, glioblastoma, low grade astrocytoma, brain stem tumor, ependymoma, mixed glioma, oligodendroglioma, neuroblastoma, Ewing's sarcoma, pineoblastoma, alveolar soft part sarcoma, neurofibrosarcoma, optic glioma, and osteosarcoma. Body System/Organ Class Adverse Reaction All Reactions Grade 3/4 Subjects Reporting an AE 107 (88) 69 (57) Body as a Whole Central and Peripheral Nervous System Central cerebral CNS cortex 22 (18) 13 (11) Gastrointestinal System Nausea 56 (46) 5 (4) Vomiting 62 (51) 4 (3) Platelet, Bleeding and Clotting Thrombocytopenia 71 (58) 31 (25) Red Blood Cell Disorders Decreased Hemoglobin 62 (51) 7 (6) White Cell and RES Disorders Decreased WBC 71 (58) 21 (17) Lymphopenia 73 (60) 48 (39) Neutropenia 62 (51) 24 (20) 8.5 Geriatric Use Clinical studies of temozolomide did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In the anaplastic astrocytoma study population, patients 70 years of age or older had a higher incidence of Grade 4 neutropenia and Grade 4 thrombocytopenia (2/8; 25%, P=0.31 and 2/10; 20%, P=0.09, respectively) in the first cycle of therapy than patients under 70 years of age [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. In newly diagnosed patients with glioblastoma multiforme, the adverse reaction profile was similar in younger patients (<65 years) vs. older (65 years). 8.6 Renal Impairment Caution should be exercised when temozolomide is administered to patients with severe renal impairment [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment Caution should be exercised when temozolomide is administered to patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

REFERENCES SECTION.


15 REFERENCES OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.[3] Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology.

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Physicians should discuss the following with their patients: Nausea and vomiting are the most frequently occurring adverse reactions. Nausea and vomiting are usually either self-limiting or readily controlled with standard antiemetic therapy. Capsules should not be opened. If capsules are accidentally opened or damaged, rigorous precautions should be taken with the capsule contents to avoid inhalation or contact with the skin or mucous membranes. The medication should be kept away from children and pets.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES 14.1 Newly Diagnosed Glioblastoma Multiforme Five hundred and seventy-three patients were randomized to receive either temozolomide (TMZ)+Radiotherapy (RT) (n=287) or RT alone (n=286). Patients in the temozolomide+RT arm received concomitant temozolomide (75 mg/m2) once daily, starting the first day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 6 cycles of temozolomide alone (150 or 200 mg/m2) on Days 1 to 5 of every 28-day cycle, starting 4 weeks after the end of RT. Patients in the control arm received RT only. In both arms, focal radiation therapy was delivered as 60 Gy/30 fractions. Focal RT includes the tumor bed or resection site with a 2- to 3-cm margin. Pneumocystis pneumonia (PCP) prophylaxis was required during the TMZ+RT, regardless of lymphocyte count, and was to continue until recovery of lymphocyte count to less than or equal to Grade 1. At the time of disease progression, temozolomide was administered as salvage therapy in 161 patients of the 282 (57%) in the RT alone arm, and 62 patients of the 277 (22%) in the temozolomide+RT arm. The addition of concomitant and maintenance temozolomide to radiotherapy in the treatment of patients with newly diagnosed GBM showed a statistically significant improvement in overall survival compared to radiotherapy alone (Figure 1). The hazard ratio (HR) for overall survival was 0.63 (95% CI for HR=0.52-0.75) with a log-rank P80. Sixty-three percent of patients had surgery other than a biopsy at the time of initial diagnosis. Of those patients undergoing resection, 73% underwent a subtotal resection and 27% underwent a gross total resection. Eighteen percent of patients had surgery at the time of first relapse. The median time from initial diagnosis to first relapse was 13.8 months (4.2-75.4). Temozolomide capsules were given for the first 5 consecutive days of a 28-day cycle at a starting dose of 150 mg/m2/day. If the nadir and day of dosing (Day 29, Day 1 of next cycle) absolute neutrophil count was greater than or equal to 1.5 109/L (1500/L) and the nadir and Day 29, Day 1 of next cycle platelet count was greater than or equal to 100 109/L (100,000/L), the temozolomide dose was increased to 200 mg/m2/day for the first 5 consecutive days of a 28-day cycle. In the refractory anaplastic astrocytoma population, the overall tumor response rate (CR+PR) was 22% (12/54 patients) and the complete response rate was 9% (5/54 patients). The median duration of all responses was 50 weeks (range: 16-114 weeks) and the median duration of complete responses was 64 weeks (range: 52-114 weeks). In this population, progression-free survival at 6 months was 45% (95% CI: 31%-58%) and progression-free survival at 12 months was 29% (95% CI: 16%-42%). Median progression-free survival was 4.4 months. Overall survival at 6 months was 74% (95% CI: 62%-86%) and 12-month overall survival was 65% (95% CI: 52%-78%). Median overall survival was 15.9 months.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Temozolomide is not directly active but undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC). The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA. Alkylation (methylation) occurs mainly at the O6 and N7 positions of guanine. 12.3 Pharmacokinetics Absorption: Temozolomide is rapidly and completely absorbed after oral administration with a peak plasma concentration (Cmax) achieved in a median Tmax of 1 hour. Food reduces the rate and extent of temozolomide absorption. Mean peak plasma concentration and AUC decreased by 32% and 9%, respectively, and median Tmax increased by 2-fold (from 1-2.25 hours) when temozolomide was administered after a modified high-fat breakfast. A pharmacokinetic study comparing oral and intravenous temozolomide in 19 patients with primary CNS malignancies showed that 150 mg/m2 temozolomide for injection administered over 90 minutes is bioequivalent to 150 mg/m2 temozolomide oral capsules with respect to both Cmax and AUC of temozolomide and MTIC. Following a single 90-minute intravenous infusion of 150 mg/m2, the geometric mean Cmax values for temozolomide and MTIC were 7.3 mcg/mL and 276 ng/mL, respectively. Following a single oral dose of 150 mg/m2, the geometric mean Cmax values for temozolomide and MTIC were 7.5 mcg/mL and 282 ng/mL, respectively. Following a single 90-minute intravenous infusion of 150 mg/m2, the geometric mean AUC values for temozolomide and MTIC were 24.6 mcghr/mL and 891 nghr/mL, respectively. Following a single oral dose of 150 mg/m2, the geometric mean AUC values for temozolomide and MTIC were 23.4 mcghr/mL and 864 nghr/mL, respectively. Distribution: Temozolomide has a mean apparent volume of distribution of 0.4 L/kg (%CV=13%). It is weakly bound to human plasma proteins; the mean percent bound of drug-related total radioactivity is 15%. Metabolism and Elimination: Temozolomide is spontaneously hydrolyzed at physiologic pH to the active species, MTIC and to temozolomide acid metabolite. MTIC is further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC), which is known to be an intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. Cytochrome P450 enzymes play only a minor role in the metabolism of temozolomide and MTIC. Relative to the AUC of temozolomide, the exposure to MTIC and AIC is 2.4% and 23%, respectively. Excretion: About 38% of the administered temozolomide total radioactive dose is recovered over 7 days: 37.7% in urine and 0.8% in feces. The majority of the recovery of radioactivity in urine is unchanged temozolomide (5.6%), AIC (12%), temozolomide acid metabolite (2.3%), and unidentified polar metabolite(s) (17%). Overall clearance of temozolomide is about 5.5 L/hr/m2. Temozolomide is rapidly eliminated, with a mean elimination half-life of 1.8 hours, and exhibits linear kinetics over the therapeutic dosing range of 75 to 250 mg/m2/day. Effect of Age: A population pharmacokinetic analysis indicated that age (range: 19-78 years) has no influence on the pharmacokinetics of temozolomide. Effect of Gender: A population pharmacokinetic analysis indicated that women have an approximately 5% lower clearance (adjusted for body surface area) for temozolomide than men. Effect of Race: The effect of race on the pharmacokinetics of temozolomide has not been studied. Tobacco Use: A population pharmacokinetic analysis indicated that the oral clearance of temozolomide is similar in smokers and nonsmokers. Effect of Renal Impairment: A population pharmacokinetic analysis indicated that creatinine clearance over the range of 36 to 130 mL/min/m2 has no effect on the clearance of temozolomide after oral administration. The pharmacokinetics of temozolomide have not been studied in patients with severely impaired renal function (CLcr <36 mL/min/m2). Caution should be exercised when temozolomide is administered to patients with severe renal impairment [see Use in Special Populations (8.6)]. Temozolomide has not been studied in patients on dialysis. Effect of Hepatic Impairment: A study showed that the pharmacokinetics of temozolomide in patients with mild-to-moderate hepatic impairment (Child-Pugh Class I - II) were similar to those observed in patients with normal hepatic function. Caution should be exercised when temozolomide is administered to patients with severe hepatic impairment [see Use in Specific Populations (8.7)]. Effect of Other Drugs on Temozolomide Pharmacokinetics: In a multiple-dose study, administration of temozolomide capsules with ranitidine did not change the Cmax or AUC values for temozolomide or MTIC. A population analysis indicated that administration of valproic acid decreases the clearance of temozolomide by about 5% [see Drug Interactions (7.1)]. A population analysis did not demonstrate any influence of coadministered dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2-receptor antagonists, or phenobarbital on the clearance of orally administered temozolomide.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS Known hypersensitivity to any temozolomide component or to dacarbazine (DTIC). (4.1) 4.1 Hypersensitivity Temozolomide is contraindicated in patients who have a history of hypersensitivity reaction (such as urticaria, allergic reaction including anaphylaxis, toxic epidermal necrolysis, and Stevens-Johnson syndrome) to any of its components. Temozolomide is also contraindicated in patients who have a history of hypersensitivity to dacarbazine (DTIC), since both drugs are metabolized to 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC).