TEMOZOLOMIDE

Temozolomide, USP is an alkylating drug. The chemical name of temozolomide, USP is 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]- as -tetrazine-8-carboxamide. The structural formula of temozolomide, USP 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, USP can be administered orally. The prodrug, temozolomide, USP 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, USP. The inactive ingredients for temozolomide capsules, USP are as follows: colloidal silicon dioxide, ethyl alcohol, lactose anhydrous, sodium starch glycolate, stearic acid and tartaric acid. The body of the capsules are made of gelatin and titanium dioxide, and are white opaque color. The cap is also made of gelatin, and the colors vary based on the dosage strength. The capsule body and cap are imprinted with pharmaceutical branding ink, which contains alcohol, D&C Yellow #10, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, iron oxide black, n-butyl alcohol, propylene glycol and shellac. Temozolomide Capsules USP, 5 mg : The green cap contains FD&C Blue #2, gelatin, titanium dioxide and yellow iron oxide. Temozolomide Capsules USP, 20 mg : The yellow cap contains D&C Yellow #10, FD&C Yellow #6, gelatin and titanium dioxide. Temozolomide Capsules USP, 100 mg : The pink cap contains FD&C Blue #1, FD&C Red #3, FD&C Red #40, gelatin and titanium dioxide. Temozolomide Capsules USP, 140 mg : The blue cap contains FD&C Blue #1, gelatin and titanium dioxide. Temozolomide Capsules USP, 180 mg : The red cap contains FD&C Blue #1, FD&C Red #40, gelatin and titanium dioxide. Temozolomide Capsules USP, 250 mg : The white cap contains gelatin and titanium dioxide. 1

Temozolomide capsules are an alkylating drug indicated for the treatment of adults 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 are indicated for the treatment of adults with newly diagnosed glioblastoma, concomitantly with radiotherapy and then as maintenance treatment. 1.2 Anaplastic Astrocytoma Temozolomide capsules are indicated for the: adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma; treatment of adults with refractory anaplastic astrocytoma.

Administer orally. ( 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 to 6 based on toxicity. ( 2.1 ) Provide Pneumocystis pneumonia (PCP) prophylaxis during concomitant phase and continue in patients who develop lymphopenia until resolution to Grade 1 or less. ( 2.1 ) 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 to 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 capsules until patients have an absolute neutrophil count (ANC) of 1.5 x 10 9 /L or greater and a platelet count of 100 x 109/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 capsules orally once daily for 42 to 49 consecutive days during the concomitant use phase with focal radiotherapy and then once daily on Days 1 to 5 of each 28-day cycle for 6 cycles during the maintenance use phase. Provide Pneumocystis pneumonia (PCP) prophylaxis during the concomitant use phase and continue in patients who develop lymphopenia until resolution to Grade 1 or less [see Warnings and Precautions (5.3) ] . Concomitant Use Phase: The recommended dosage of temozolomide capsules is 75 mg/m 2 orally once daily for 42 days 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 to adverse reactions during concomitant use phase are provided in Table 1 . TABLE 1: Dosage Modifications Due to Adverse Reactions During Concomitant Use Phase Adverse Reaction Interruption Discontinuation Absolute Neutrophil Count Withhold temozolomide capsules if ANC is greater than or equal to 0.5 × 10 9 /L and less than 1.5 × 10 9 /L. Resume temozolomide capsules at the same dose when ANC is greater than or equal to 1.5 × 10 9 /L. Discontinue temozolomide capsules if ANC is less than 0.5 × 10 9 /L. Platelet Count Withhold temozolomide capsules if platelet count is greater than or equal to 10 × 10 9 /L and less than 100 × 10 9 /L. Resume temozolomide capsules at the same dose when platelet count is greater than or equal to 100 × 10 9 /L. Discontinue temozolomide capsules if platelet count is less than 10 × 10 9 /L. Non-hematological Adverse Reaction (except for alopecia, nausea, vomiting) Withhold temozolomide capsules if Grade 2 adverse reaction occurs. Resume temozolomide capsules at the same dose when resolution to Grade 1 or less. Discontinue temozolomide capsules if Grade 3 or 4 adverse reaction occurs. Single Agent Maintenance Use Phase: Beginning 4 weeks after concomitant use phase completion, administer temozolomide capsules orally once daily on Days 1 to 5 of each 28-day cycle for 6 cycles. The recommended dosage of temozolomide in the maintenance use phase is: Cycle 1: 150 mg/m 2 per day on days 1 to 5. Cycles 2 to 6: May increase to 200 mg/m 2 per day on days 1 to 5 before starting Cycle 2 if no dosage interruptions or discontinuations are required (Table 1). If the dose is not escalated at the onset of Cycle 2, do not increase the dose for Cycles 3 to 6. Obtain a complete blood count on Day 22 and then weekly until the ANC is above 1.5 × 10 9 /L and the platelet count is above 100 × 10 9 /L. Do not start the next cycle until the ANC and platelet count exceed these levels. The recommended dosage modifications due to adverse reactions during the maintenance use phase are provided in Table 2 . If temozolomide capsules are withheld, reduce the dose for the next cycle by 50 mg/m 2 per day. Permanently discontinue temozolomide capsules in patients who are unable to tolerate a dose of 100 mg/m 2 per day. TABLE 2: Dosage Modifications Due to Adverse Reactions During Maintenance and Adjuvant Treatment Adverse Reactions Interruption and Dose Reduction Discontinuation Absolute Neutrophil Count Withhold temozolomide capsules if ANC less than 1 × 10 9 /L. When ANC is above 1.5 × 10 9 /L, resume temozolomide capsules at reduced dose for the next cycle. Discontinue temozolomide capsules if unable to tolerate a dose of 100 mg/m 2 per day. Platelet Count Withhold temozolomide capsules if platelet less than 50 × 10 9 /L. When platelet count is above 100 × 10 9 /L, resume temozolomide capsules at reduced dose for the next cycle. Discontinue temozolomide capsules if unable to tolerate a dose of 100 mg/m 2 per day. Nonhematological Adverse Reactions (except for alopecia, nausea, vomiting) Withhold temozolomide capsules if Grade 3 adverse reaction occurs. When resolved to Grade 1 or less, resume temozolomide capsules at reduced dose for the next cycle. Discontinue temozolomide capsules if recurrent Grade 3 adverse reaction occurs after dose reduction, if Grade 4 adverse reaction occurs, or if unable to tolerate a dose of 100 mg/m 2 per day. 2.3 Recommended Dosage and Dosage Modifications for Anaplastic Astrocytoma Adjuvant Treatment of Newly Diagnosed Anaplastic Astrocytoma Beginning 4 weeks after the end of radiotherapy, administer temozolomide capsules orally in a single dose on days 1 to 5 of a 28-day cycle for 12 cycles. The recommended dosage of temozolomide capsules are: Cycle 1: 150 mg/m 2 per day on days 1 to 5. Cycles 2 to 12: 200 mg/m 2 per day on days 1 to 5 if patient experienced no or minimal toxicity in Cycle 1. If the dose was not escalated at the onset of Cycle 2, do not increase the dose during Cycles 3 to 6. The recommended complete blood count testing and dosage modifications due to adverse reactions during adjuvant treatment are provided above and in Table 2 [see Dosage and Administration (2.2) ] . Refractory Anaplastic Astrocytoma The recommended initial dosage of temozolomide capsules is 150 mg/m 2 once daily on Days 1 to 5 of each 28-day cycle. Increase the temozolomide capsules dose to 200 mg/m 2 per day if the following conditions are met at the nadir and on Day 1 of the next cycle: ANC is greater than or equal to 1.5 × 10 9 /L, and Platelet count is greater than or equal to 100 × 10 9 /L. Continue temozolomide capsules until disease progression or unacceptable toxicity. Obtain a complete blood count on Day 22 and then weekly until the ANC is above 1.5 × 10 9 /L and the platelet count is above 100 × 10 9 /L. Do not start the next cycle until the ANC and platelet count exceed these levels. If the ANC is less than 1 × 10 9 /L or the platelet count is less than 50 × 10 9 /L during any cycle, reduce the temozolomide dose for the next cycle by 50 mg/m 2 per day. Permanently discontinue temozolomide capsules in patients who are unable to tolerate a dose of 100 mg/m 2 per day. 2.4 Preparation and Administration Temozolomide capsules are a hazardous drug. Follow applicable special handling and disposal procedures. 1 Temozolomide capsules Take temozolomide capsules at the same time each day. Administer temozolomide capsules consistently with respect to food (fasting vs. nonfasting) [see Clinical Pharmacology (12.3) ] . To reduce nausea and vomiting, take temozolomide capsules on an empty stomach or at bedtime and consider antiemetic therapy prior to and following temozolomide capsules administration. Swallow temozolomide capsules whole with water. Advise patients not to open, chew, or dissolve the contents of the capsules [see Warnings and Precautions (5.6) ]. If capsules are accidentally opened or damaged, take precautions to avoid inhalation or contact with the skin or mucous membranes . In case of powder contact, wash the affected area with water immediately.

Temozolomide is contraindicated in patients with a history of serious hypersensitivity reactions to: temozolomide or any other ingredients in temozolomide capsules; 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 serious hypersensitivity to temozolomide or any other ingredients in temozolomide capsules and dacarbazine. ( 4 )

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%) are: alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, and convulsions. ( 6.1 ) The most common Grade 3 to 4 hematologic laboratory abnormalities (≥ 10%) in patients with anaplastic astrocytoma are: decreased lymphocytes, decreased platelets, decreased neutrophils, and decreased leukocytes. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 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) ]. 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 *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. 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) ]. 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 MK-7365-006. TABLE 4: Adverse Reactions (≥ 10%) in Patients with Refractory Anaplastic Astrocytoma Adverse Reactions Temozolomide N=158 All Reactions (%) Grades 3-4 (%) Gastrointestinal System Nausea 53 10 Vomiting 42 6 Constipation 33 1 Diarrhea 16 2 General Headache 41 6 Fatigue 34 4 Asthenia 13 6 Fever 13 2 Central and Peripheral Nervous System Convulsions 23 5 Hemiparesis 18 6 Dizziness 12 1 Coordination abnormal 11 1 Amnesia 10 4 Insomnia 10 0 Cardiovascular Edema peripheral 11 1 Resistance Mechanism Infection viral 11 0 Clinically relevant adverse reactions in < 10% of patients are presented below: Central and Peripheral Nervous System: paresthesia, somnolence, paresis, urinary incontinence, ataxia, dysphasia, convulsions local, gait abnormal, confusion Endocrine: adrenal hypercorticism Gastrointestinal System: abdominal pain, anorexia General: back pain Metabolic: weight increase Musculoskeletal System: myalgia Psychiatric: anxiety, depression Reproductive Disorders: breast pain female Respiratory System: upper respiratory tract infection, pharyngitis, sinusitis, coughing Skin & Appendages: rash, pruritus Urinary System: urinary tract infection, micturition increased frequency Vision: diplopia, vision abnormal * * This term includes blurred vision; visual deficit; vision changes; and vision troubles. TABLE 5: Grade 3 to 4 Hematologic Laboratory Abnormalities That Worsened from Baseline in Patients with Refractory Anaplastic Astrocytoma 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 × 10 9 /L) and thrombocytopenia (< 20 × 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 10% (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 6% (48/879) experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. Pancytopenia, leukopenia, and anemia also occurred. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of temozolomide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug exposure. Dermatologic: Toxic epidermal necrolysis and Stevens-Johnson syndrome. Immune System: Hypersensitivity reactions, including anaphylaxis. Erythema multiforme, which resolved after discontinuation of temozolomide and, in some cases, recurred upon rechallenge. Hematopoietic: Prolonged pancytopenia, which may result in aplastic anemia and fatal outcomes. Hepatobiliary: Fatal and severe hepatotoxicity, elevation of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis. Infections: Serious opportunistic infections, including some cases with fatal outcomes, with bacterial, viral (primary and reactivated), fungal, and protozoan organisms. Pulmonary: Interstitial pneumonitis, pneumonitis, alveolitis, and pulmonary fibrosis. Endocrine: Diabetes insipidus.