TEMOZOLOMIDE

Temozolomide is an alkylating drug. The chemical name of temozolomide is 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]- as -tetrazine-8-carboxamide. The structural formula of temozolomide is: The material is a white to light tan/light pink powder with a molecular formula of C 6 H 6 N 6 O 2 and a molecular weight of 194.15. The molecule is stable at acidic pH (<5) and labile at 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, USP: Each capsule for oral use contains either 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 mg of temozolomide. The inactive ingredients for TEMOZOLOMIDE Capsules, USP 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 (3.0 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 (3.0 mg), and stearic acid (6.0 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 (9.0 mg), and stearic acid (13.5 mg). The body of the capsules is made of gelatin and titanium dioxide and is opaque white. The cap is also made of gelatin and the colors may vary based on the dosage strength. The capsule body and cap are imprinted with pharmaceutical branding ink, which contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, purified water, strong ammonia solution, potassium hydroxide, and ferric oxide. · TEMOZOLOMIDE 5 mg: The opaque green cap contains gelatin, titanium dioxide, iron oxide yellow and FD&C Blue 2. · TEMOZOLOMIDE 20 mg: The opaque yellow cap contains gelatin, titanium dioxide and iron oxide yellow. · TEMOZOLOMIDE 100 mg: The opaque flesh cap contains gelatin, titanium dioxide and iron oxide red. · TEMOZOLOMIDE 140 mg: The transparent blue cap contains gelatin, FD&C Blue #2, and titanium dioxide. · TEMOZOLOMIDE 180 mg: The opaque orange cap contains gelatin, titanium dioxide and iron oxide red. · TEMOZOLOMIDE 250 mg: The opaque white cap contains gelatin and titanium dioxide. chemical-structure

TEMOZOLOMIDE Capsules, USP 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 ) • Refractory anaplastic astrocytoma who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine. ( 1.2 ) 1.1 Newly Diagnosed Glioblastoma TEMOZOLOMIDE Capsules, USP is indicated for the treatment of adult patients with newly diagnosed glioblastoma concomitantly with radiotherapy and then as maintenance treatment. 1.2 Refractory Anaplastic Astrocytoma TEMOZOLOMIDE Capsules , USP is indicated for the treatment of adult patients with refractory anaplastic astrocytoma who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.

Administer either orally or intravenously. Newly Diagnosed Glioblastoma: o 75 mg/m 2 once daily for 42 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m 2 once daily for Days 1 to 5 of each 28-day cycle for 6 cycles. May increase maintenance dose to 200 mg/ m 2 for cycles 2 – 6 based on toxicity. ( 2.1 ) o Provide Pneumocystis pneumonia (PCP) prophylaxis during concomitant phase and continue in patients who develop lymphopenia until resolution to grade 1 or less. ( 2.1 ) Refractory Anaplastic Astrocytoma: Initial dose of 150 mg/m 2 once daily on Days 1 to 5 of each 28-day cycle. ( 2.2 ) 2.1 Recommended Dosage and Dosage Modifications for Newly Diagnosed Glioblastoma Administer TEMOZOLOMIDE either orally once daily for 42 consecutive days during the concomitant phase with focal radiotherapy and then once daily on Days 1 to 5 of each 28-day cycle for 6 cycles during the maintenance phase. Provide Pneumocystis pneumonia (PCP) prophylaxis during the concomitant phase and continue in patients who develop lymphocytopenia until resolution to grade 1 or less [see Warnings and Precautions ( 5.3 )]. Concomitant Phase The recommended dosage of TEMOZOLOMIDE is 75 mg/m 2 either orally or intravenously once daily for 42 days (up to 49 days) concomitant with focal radiotherapy (60 Gy administered in 30 fractions). Focal radiotherapy includes the tumor bed or resection site with a 2- to 3-cm margin. Obtain a complete blood count weekly. No dose reductions are recommended during the concomitant phase. The recommended dosage modifications during the concomitant phase are provided in Table 1 . TABLE 1: Temozolomide Dosage Modifications During Concomitant Phase Adverse Reaction Interruption Discontinuation Absolute Neutrophil Count Withhold TEMOZOLOMIDE if ANC is greater than or equal to 0.5 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. Maintenance Phase Beginning 4 weeks after Concomitant Phase completion, administer TEMOZOLOMIDE either orally or intravenously once daily on Days 1 to 5 of each 28-day cycle for 6 cycles. The recommended dosage of TEMOZOLOMIDE is as follows: • Cycle 1: 150 mg/m 2 per day • Cycles 2 to 6: May increase to 200 mg/m 2 per day if the following conditions are met before starting cycle 2. If the dose was not escalated at the onset of Cycle 2, do not increase the dose for Cycles 3 to 6. o Nonhematologic toxicity is grade 2 or less (except for alopecia, nausea, and vomiting) o ANC is greater than or equal to 1.5 x 10 9 /L and o Platelet count is greater than or equal to 100 x 10 9 /L. Obtain a complete blood count on Day 22 and then weekly until the ANC is above 1.5 x 10 9 /L and the platelet count is above 100 x 10 9 /L. Do not start the next cycle until the ANC and platelet count exceed these levels. The recommended dosage modifications during the maintenance phase are provided in Table 2. If TEMOZOLOMIDE is withheld, reduce the dose for the next cycle by 50 mg/m 2 per day. Permanently discontinue TEMOZOLOMIDE in patients who are unable to tolerate a dose of 100 mg/m 2 per day. TABLE 2: Temozolomide Dosage Modifications During Maintenance Treatment Toxicity Interruption 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. 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. 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. Recurrent Grade 3 after dose reduction. Grade 4 Unable to tolerate a dose of 100 mg/m 2 per day. 2.2 Recommended Dosage and Dosage Modifications for Refractory Anaplastic Astrocytoma The recommended initial dosage of TEMOZOLOMIDE is 150 mg/m 2 once daily on Days 1 to 5 of each 28-day cycle. Increase the TEMOZOLOMIDE dose to 200 mg/m 2 per day if the following conditions are met at the nadir and on Day 1 of the next cycle: • ANC is greater than or equal to 1.5 x 10 9 /L and • Platelet count is greater than or equal to 100 x 10 9 /L Continue TEMOZOLOMIDE until disease progression or unacceptable toxicity. In the clinical trial, treatment could be continued for a maximum of 2 years, but the optimum duration of therapy is not known. Obtain a complete blood count on Day 22 and then weekly until the ANC is above 1.5 x 10 9 /L and the platelet count is above 100 x 10 9 /L. Do not start the next cycle until the ANC and platelet count exceed these levels. If the ANC is less than 1 x 10 9 /L or the platelet count is less than 50 x 10 9 /L during any cycle, reduce the TEMOZOLOMIDE dose for the next cycle by 50 mg/m 2 per day. Permanently discontinue TEMOZOLOMIDE in patients who are unable to tolerate a dose of 100 mg/m 2 per day. 2.3 Preparation and Administration TEMOZOLOMIDE is a cytotoxic drug. Follow applicable special handling and disposal procedures 1 . TEMOZOLOMIDE capsules Administer TEMOZOLOMIDE consistently with respect to food (fasting vs.nonfasting) [see Clinical Pharmacology 12.3 )] . To reduce nausea and vomiting, take TEMOZOLOMIDE on an empty stomach or at bedtime and consider antiemetic therapy prior to and/or following TEMOZOLOMIDE administration. Swallow TEMOZOLOMIDE capsules whole. Do not open or chew capsules. If capsules are accidentally opened or damaged, take precautions to avoid inhalation or contact with the skin or mucous membranes. In case of powder contact, the hands should be washed.

TEMOZOLOMIDE 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, USP and dacarbazine.

The following clinically significant adverse reactions are described elsewhere in the labeling: • Myelosuppression [see Warnings and Precautions ( 5.1 )]. • Myelodysplastic Syndrome and Secondary Malignancies [see Warnings and Precautions ( 5.2 )]. • Pneumocystis Pneumonia [see Warnings and Precautions ( 5.3 )]. • Hepatotoxicity [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 Ascend Laboratories LLC at 1-877-ASC-RX01 (877-272-7901) 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 The safety of TEMOZOLOMIDE was evaluated in Study MK-7365-051 [see Clinical Studies ( 14.1 )]. 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%). The most common adverse reactions (≥20%) across the cumulative TEMOZOLOMIDE experience were alopecia, fatigue, nausea, and vomiting. Table 3 summarizes the adverse reactions in Newly Diagnosed Glioblastoma Trial. Overall, the pattern of reactions during the maintenance phase was consistent with the known safety profile of TEMOZOLOMIDE. TABLE 3: Adverse Reactions (≥5%) in Patients Receiving TEMOZOLOMIDE in Newly Diagnosed Glioblastoma Trial Adverse Reactions Concomitant Phase Maintenance Phase Radiation Therapy and TEMOZOLAMIDE N=288* Radiation Therapy Alone N=285 TEMOZOLOMIDE N=224 All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%) All Grades (%) Grade ≥3 (%) Skin and Subcutaneous Tissue Alopecia 69 63 55 Rash 19 1 15 13 1 Dry Skin 2 2 5 <1 Pruritus 4 1 5 Erythema 5 5 1 General Fatigue 54 7 49 5 61 9 Anorexia 19 1 9 <1 27 1 Headache 19 2 17 4 23 4 Weakness 3 2 3 1 7 2 Dizziness 4 1 4 5 Gastrointestinal System Nausea 36 1 16 <1 49 1 Vomiting 20 <1 6 <1 29 2 Constipation 18 1 6 22 Diarrhea 6 3 10 1 Stomatitis 7 5 <1 9 1 Abdominal Pain 2 <1 1 5 <1 Eye Vision Blurred 9 1 9 1 8 Injury Radiation Injury NOS 7 4 <1 2 Central and Peripheral Nervous System Convulsions 6 3 7 3 11 3 Memory Impairment 3 <1 4 <1 7 1 Confusion 4 1 4 2 5 2 Special Senses Other Taste Perversion 6 2 5 Respiratory System Coughing 5 1 1 8 <1 Dyspnea 4 2 3 1 5 <1 Psychiatric Insomnia 5 3 <1 4 Immune System Allergic Reaction 5 2 <1 3 Platelet, Bleeding and Clotting Thrombocytopenia 4 3 1 8 4 Musculoskeletal System Arthralgia 2 <1 1 6 *One patient who was randomized to radiation therapy only arm received radiation therapy and TEMOZOLOMIDE. NOS=not otherwise specified. Note : Grade 5 (fatal) adverse reactions are included in the Grade ≥3 column. 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. Refractory Anaplastic Astrocytoma The safety of TEMOZOLOMIDE was evaluated in Study MK-7365-006 [see Clinical Studies ( 14.2 )]. 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. The most common adverse reactions (≥20%) were nausea, vomiting, headache, fatigue, constipation, and convulsions. Tables 4 and 5 summarize the adverse reactions and hematological laboratory abnormalities in Refractory Anaplastic Astrocytoma Trial. TABLE 4: Adverse Reactions (≥5%) in Patients Receiving TEMOZOLOMIDE in Refractory Anaplastic Astrocytoma Trial Adverse Reactions TEMOZOLOMIDE N=158 All Reactions (%) Grades 3-4 (%) Gastrointestinal System Nausea 53 10 Vomiting 42 6 Constipation 33 1 Diarrhea 16 2 Abdominal pain 9 1 Anorexia 9 1 General Headache 41 6 Fatigue 34 4 Asthenia 13 6 Fever 13 2 Back pain 8 3 Central and Peripheral Nervous System Convulsions 23 5 Hemiparesis 18 6 Dizziness 12 1 Coordination abnormal 11 1 Amnesia 10 4 Insomnia 10 Paresthesia 9 1 Somnolence 9 3 Paresis 8 3 Urinary incontinence 8 2 Ataxia 8 2 Dysphasia 7 1 Convulsions local 6 Gait abnormal 6 1 Confusion 5 Cardiovascular Edema peripheral 11 1 Resistance Mechanism Infection viral 11 Endocrine Adrenal hypercorticism 8 Respiratory System Upper respiratory tract infection 8 Pharyngitis 8 Sinusitis 6 Coughing 5 Skin and Appendages Rash 8 Pruritus 8 1 Urinary System Urinary tract infection 8 Micturition increased frequency 6 Psychiatric Anxiety 7 1 Depression 6 Reproductive Disorders Breast pain, female 6 Metabolic Weight increase 5 Musculoskeletal System Myalgia 5 Vision Diplopia 5 Vision abnormal* 5 *This term includes blurred vision; visual deficit; vision changes; and vision troubles. TABLE 5: Grade 3 to 4 Adverse Hematologic Laboratory Abnormalities in Refractory Anaplastic Astrocytoma Trial TEMOZOLOMIDE *,† Decreased lymphocytes 55% Decreased platelets 19% Decreased neutrophils 14% Decreased leukocytes 11% Decreased hemoglobin 4% *Change from Grade 0 to 2 at baseline to Grade 3 or 4 during treatment. †Denominator range= 142, 158 Hematological Toxicities for Advanced Gliomas: In clinical trial experience with 110 to 111 females and 169 to 174 males (depending on measurements), females experienced higher rates of Grade 4 neutropenia (ANC < 0.5 x 10 9 /L) and thrombocytopenia (< 20 x 10 9 /L) than males 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 > 70 years experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. For patients ≤ 70 years, 7% (62/871) and 5.5% (48/879) experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. Pancytopenia, leukopenia, and anemia also occurred. Adverse reactions with TEMOZOLOMIDE for injection Adverse reactions that were reported in 35 patients who received TEMOZOLOMIDE for injection that were not reported in patients who received TEMOZOLOMIDE capsules were pain, irritation, pruritus, warmth, swelling, and erythema at infusion site; petechiae; and hematoma. 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