Temozolomide

6 ADVERSE REACTIONS 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 Nivagen Pharmaceutical, Inc., at 1-877­-977-0687 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 s ummarizes 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 Temozolomide N=288 One patient who was randomized to radiation therapy only arm received radiation therapy and Temozolomide. 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 NOS=not otherwise specified. Not e : 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 This term includes blurred vision; visual deficit; vision changes; and vision troubles. 5 TABLE 5: Grade 3 to 4 Adverse Hematologic Laboratory Abnormalities in Refractory Anaplastic Astrocytoma Trial Temozolomide Change from Grade 0 to 2 at baseline to Grade 3 or 4 during treatment. ' Denominator range= 142, 158 Decreased lymphocytes 55% Decreased platelets 19% Decreased neutrophils 14% Decreased leukocytes 11% Decreased hemoglobin 4% 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. 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

4 CONTRAINDICATIONS Temozolomide capsules, USP is contraindicated in patients with a history of hypersensitivity reactions to: temozolomide or any other ingredients in Temozolomide capsules, USP; 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. ( 4.1 )

11 DESCRIPTION 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 capsules, USP can be administered orally. 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: Temozolomide capsules, USP for oral use contains either 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 mg of temozolomide. The inactive ingredients are as follows: Temozolomide capsules, USP, 5 mg: lactose anhydrous (103.52 mg), colloidal silicon dioxide (0.180 mg), sodium starch glycolate (5.650 mg), tartaric acid (2.260 mg), and stearic acid (3.390 mg). Temozolomide capsules, USP, 20 mg: lactose anhydrous (179.0 mg), colloidal silicon dioxide (0.320 mg), sodium starch glycolate (10.350 mg), tartaric acid (4.140 mg), and stearic acid (6.210 mg). Temozolomide capsules, USP, 100 mg: lactose anhydrous (73.0 mg), colloidal silicon dioxide (0.280 mg), sodium starch glycolate (9.00 mg), tartaric acid (3.60 mg), and stearic acid (5.40 mg). Temozolomide capsules, USP, 140 mg: lactose anhydrous (102.2 mg), colloidal silicon dioxide (0.390 mg), sodium starch glycolate (12.60 mg), tartaric acid (5.040 mg), and stearic acid (7.560 mg). Temozolomide capsules, USP, 180 mg: lactose anhydrous (131.4 mg), colloidal silicon dioxide (0.500 mg), sodium starch glycolate (16.20 mg), tartaric acid (6.480 mg), and stearic acid (9.720 mg). Temozolomide capsules, USP, 250 mg: lactose anhydrous (182.5 mg), colloidal silicon dioxide (0.700 mg), sodium starch glycolate (22.50 mg), tartaric acid (9.000 mg), and stearic acid (13.50 mg). The body of the capsules for 5 mg, 20 mg, 140 mg, 180 mg and 250 mg strengths is made of gelatin, and titanium dioxide and is white opaque. The body of the capsules for 100 mg strengths is made of gelatin, titanium dioxide and ferric oxide yellow and is buff opaque. 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 shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, purified water, strong ammonia solution, potassium hydroxide, and Black Iron Oxide. Temozolomide capsules, USP, 5 mg: The green opaque cap contains gelatin, titanium dioxide, FDA/E172 yellow iron oxide, and FD&C Blue #2. Temozolomide capsules, USP, 20 mg: The rich yellow opaque cap contains gelatin, titanium dioxide, and FDA/E172 yellow iron oxide. Temozolomide capsules, USP, 100 mg: The peach opaque cap contains gelatin, titanium dioxide, ferric oxide yellow, and ferric oxide red. Temozolomide capsules, USP, 140 mg: The blue opaque cap contains gelatin, titanium dioxide, and FD&C Blue#2. Temozolomide capsules, USP, 180 mg: The red opaque cap contains gelatin, titanium dioxide, and ferric oxide red. Temozolomide capsules, USP, 250 mg: The white opaque cap contains gelatin, and titanium dioxide. structure

2 DOSAGE AND ADMINISTRATION Administer orally. Newly Diagnosed Glioblastoma : 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 ) 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 capsules, USP 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 capsules, USP is 75 mg/m 2 orally 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 capsules, USP orally once daily on Days 1 to 5 of each 28-day cycle for 6 cycles. The recommended dosage of Temozolomide capsules, USP 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. Nonhematologic toxicity is grade 2 or less (except for alopecia, nausea, and vomiting) 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. 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 and Dose Reduction 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. Nonhematological 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, USP 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, USP 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.

1 INDICATIONS AND USAGE Temozolomide capsules, USP is 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.

10 OVERDOSAGE Dose-limiting toxicity was myelosuppression 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 myelosuppression, which in some cases was severe and prolonged, and infections and resulted in death. In the event of an overdose, monitor complete blood count and provide supportive measures as necessary.

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 O 6 and N 7 positions of guanine. 12.3 Pharmacokinetics Following a single oral dose of 150 mg/m 2 , the mean C max value for temozolomide was 7.5 mcg/mL and for MTIC was 282 ng/mL. The mean AUC value for temozolomide was 23.4 mcg·hr/mL and for MTIC was 864 ng·hr/mL. Temozolomide exhibits linear kinetics over the therapeutic dosing range of 75 mg/m 2 /day to 250 mg/m 2 /day. Absorption The median T max is 1 hour. Effect of Food The mean C max and AUC decreased by 32% and 9%, respectively, and median T max increased by 2-fold (from 1-2.25 hours) when Temozolomide capsules, USP were administered after a modified high-fat breakfast (587 calories comprised of 1 fried egg, 2 strips of bacon, 2 slices of toast, 2 pats of butter, and 8 oz whole milk). Distribution Temozolomide has a mean apparent volume of distribution of 0.4 L/kg (%CV=13%). The mean percent bound of drug-related total radioactivity is 15%. Elimination Clearance of temozolomide is about 5.5 L/hr/m 2 and the mean elimination half-life is 1.8 hours. Metabolism 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: 38% in urine and 0.8% in feces. The majority of the recovery of radioactivity in urine is unchanged temozolomide (6%), AIC (12%), temozolomide acid metabolite (2.3%), and unidentified polar metabolite(s) (17%). Specific Populations No clinically meaningful differences in the pharmacokinetics of temozolomide were observed based on age (range: 19-78 years), gender, smoking status (smoker vs. non-smoker), creatinine clearance (CLcr) of 36 to 130 mL/min/m 2 , or mild to moderate hepatic impairment (Child Pugh class A and B). The pharmacokinetics of temozolomide has not been studied in patients with CLcr < 36 mL/min/m 2 , end-stage renal disease on dialysis, or severe hepatic impairment (Child-Pugh class C). Drug Interaction Studies Effect of Other Drugs on Temozolomide Pharmacokinetics In a multiple-dose study, administration of Temozolomide capsules, USP with ranitidine did not change the C max or AUC values for temozolomide or MTIC. A population analysis indicated that administration of valproic acid decreases the clearance of temozolomide by about 5%. A population analysis did not demonstrate any influence of coadministered dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, histamine-2-receptor antagonists, or phenobarbital on the clearance of orally administered Temozolomide capsules, USP.

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 O 6 and N 7 positions of guanine.

12.3 Pharmacokinetics Following a single oral dose of 150 mg/m 2 , the mean C max value for temozolomide was 7.5 mcg/mL and for MTIC was 282 ng/mL. The mean AUC value for temozolomide was 23.4 mcg·hr/mL and for MTIC was 864 ng·hr/mL. Temozolomide exhibits linear kinetics over the therapeutic dosing range of 75 mg/m 2 /day to 250 mg/m 2 /day. Absorption The median T max is 1 hour. Effect of Food The mean C max and AUC decreased by 32% and 9%, respectively, and median T max increased by 2-fold (from 1-2.25 hours) when Temozolomide capsules, USP were administered after a modified high-fat breakfast (587 calories comprised of 1 fried egg, 2 strips of bacon, 2 slices of toast, 2 pats of butter, and 8 oz whole milk). Distribution Temozolomide has a mean apparent volume of distribution of 0.4 L/kg (%CV=13%). The mean percent bound of drug-related total radioactivity is 15%. Elimination Clearance of temozolomide is about 5.5 L/hr/m 2 and the mean elimination half-life is 1.8 hours. Metabolism 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: 38% in urine and 0.8% in feces. The majority of the recovery of radioactivity in urine is unchanged temozolomide (6%), AIC (12%), temozolomide acid metabolite (2.3%), and unidentified polar metabolite(s) (17%). Specific Populations No clinically meaningful differences in the pharmacokinetics of temozolomide were observed based on age (range: 19-78 years), gender, smoking status (smoker vs. non-smoker), creatinine clearance (CLcr) of 36 to 130 mL/min/m 2 , or mild to moderate hepatic impairment (Child Pugh class A and B). The pharmacokinetics of temozolomide has not been studied in patients with CLcr < 36 mL/min/m 2 , end-stage renal disease on dialysis, or severe hepatic impairment (Child-Pugh class C). Drug Interaction Studies Effect of Other Drugs on Temozolomide Pharmacokinetics In a multiple-dose study, administration of Temozolomide capsules, USP with ranitidine did not change the C max or AUC values for temozolomide or MTIC. A population analysis indicated that administration of valproic acid decreases the clearance of temozolomide by about 5%. A population analysis did not demonstrate any influence of coadministered dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, histamine-2-receptor antagonists, or phenobarbital on the clearance of orally administered Temozolomide capsules, USP.

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3 DOSAGE FORMS AND STRENGTHS Capsules: - 5 mg: white opaque bodies with green opaque caps. The capsule body is imprinted with “5 mg”. The cap is imprinted with “NIV-132.” - 20 mg: white opaque bodies with rich yellow opaque caps. The capsule body is imprinted with “20 mg”. The cap is imprinted with “NIV-142.” - 100 mg: buff opaque bodies with peach opaque caps. The capsule body is imprinted with “100 mg”. The cap is imprinted with “NIV-143.” - 140 mg: white opaque bodies with blue opaque caps. The capsule body is imprinted with “140 mg”. The cap is imprinted with “NIV-144.” - 180 mg: white opaque bodies with red opaque caps. The capsule body is imprinted with “180 mg”. The cap is imprinted with “NIV-145.” - 250 mg: white opaque bodies with white opaque caps. The capsule body is imprinted with “250 mg”. The cap is imprinted with “NIV-146.” • Capsules : 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg ( 3 )

temozolomide temozolomide TEMOZOLOMIDE TEMOZOLOMIDE GELATIN TITANIUM DIOXIDE FERRIC OXIDE YELLOW FD&C BLUE NO. 2 SHELLAC BUTYL ALCOHOL ISOPROPYL ALCOHOL PROPYLENE GLYCOL AMMONIA POTASSIUM HYDROXIDE FERROSOFERRIC OXIDE WATER ALCOHOL opaque opaque NIV132;5mg temozolomide temozolomide TEMOZOLOMIDE TEMOZOLOMIDE GELATIN TITANIUM DIOXIDE FERRIC OXIDE YELLOW SHELLAC BUTYL ALCOHOL ISOPROPYL ALCOHOL PROPYLENE GLYCOL AMMONIA POTASSIUM HYDROXIDE FERROSOFERRIC OXIDE WATER ALCOHOL opaque opaque NIV142;20mg temozolomide temozolomide TEMOZOLOMIDE TEMOZOLOMIDE ANHYDROUS LACTOSE SILICON DIOXIDE SODIUM STARCH GLYCOLATE TYPE A POTATO TARTARIC ACID STEARIC ACID GELATIN TITANIUM DIOXIDE FERRIC OXIDE YELLOW FERRIC OXIDE RED SHELLAC BUTYL ALCOHOL ISOPROPYL ALCOHOL PROPYLENE GLYCOL AMMONIA POTASSIUM HYDROXIDE FERROSOFERRIC OXIDE WATER ALCOHOL opaque opaque NIV143;100mg temozolomide temozolomide TEMOZOLOMIDE TEMOZOLOMIDE ANHYDROUS LACTOSE SILICON DIOXIDE SODIUM STARCH GLYCOLATE TYPE A POTATO TARTARIC ACID STEARIC ACID GELATIN TITANIUM DIOXIDE FD&C BLUE NO. 2 SHELLAC BUTYL ALCOHOL ISOPROPYL ALCOHOL PROPYLENE GLYCOL AMMONIA POTASSIUM HYDROXIDE FERROSOFERRIC OXIDE WATER ALCOHOL opaque opaque NIV144;140mg temozolomide temozolomide TEMOZOLOMIDE TEMOZOLOMIDE ANHYDROUS LACTOSE SILICON DIOXIDE SODIUM STARCH GLYCOLATE TYPE A POTATO TARTARIC ACID STEARIC ACID GELATIN TITANIUM DIOXIDE FERRIC OXIDE RED SHELLAC BUTYL ALCOHOL ISOPROPYL ALCOHOL PROPYLENE GLYCOL AMMONIA POTASSIUM HYDROXIDE FERROSOFERRIC OXIDE WATER ALCOHOL opaque opaque NIV145;180mg temozolomide temozolomide TEMOZOLOMIDE TEMOZOLOMIDE ANHYDROUS LACTOSE SILICON DIOXIDE SODIUM STARCH GLYCOLATE TYPE A POTATO TARTARIC ACID STEARIC ACID GELATIN TITANIUM DIOXIDE SHELLAC BUTYL ALCOHOL ISOPROPYL ALCOHOL PROPYLENE GLYCOL AMMONIA POTASSIUM HYDROXIDE FERROSOFERRIC OXIDE WATER ALCOHOL opaque NIV146;250mg

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 125 mg/m 2 (0.63 times the human dose of 200 mg/m 2 ). These changes were most commonly seen at doses where mortality was observed.

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/m 2 ) 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 doses of 50 and 125 mg/m 2 (0.25 and 0.63 times the human dose of 200 mg/m 2 ) in rats and dogs, respectively, and testicular atrophy in dogs at 125 mg/m 2 .

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/m 2 ) 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 doses of 50 and 125 mg/m 2 (0.25 and 0.63 times the human dose of 200 mg/m 2 ) in rats and dogs, respectively, and testicular atrophy in dogs at 125 mg/m 2 . 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 125 mg/m 2 (0.63 times the human dose of 200 mg/m 2 ). These changes were most commonly seen at doses where mortality was observed.

ANDA213328

Temozolomide

temozolomide

75834-146

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 75834-132-05 Temozolomide 5mg per Capsule Bottle Label - 5 Capsules Count NDC 75834-132-05 Temozolomide 5mg per Capsule Bottle Carton - 5 Capsules Count NDC 75834-132-14 Temozolomide 5mg per Capsule Bottle Label - 14 Capsules Count NDC 75834-132-14 Temozolomide 5mg per Capsule Bottle Carton - 14 Capsules Count NDC 75834-142-05 Temozolomide 20mg per Capsule Bottle Label - 5 Capsules Count NDC 75834-142-05 Temozolomide 20mg per Capsule Bottle Carton - 5 Capsules Count NDC 75834-142-14 Temozolomide 20mg per Capsule Bottle Label - 14 Capsules Count NDC 75834-142-14 Temozolomide 20mg per Capsule Bottle Carton - 14 Capsules Count NDC 75834-143-05 Temozolomide 100mg per Capsule Bottle Label - 5 Capsules Count NDC 75834-143-05 Temozolomide 100mg per Capsule Bottle Carton - 5 Capsules Count NDC 75834-143-14 Temozolomide 100mg per Capsule Bottle Label - 14 Capsules Count NDC 75834-143-14 Temozolomide 100mg per Capsule Bottle Carton - 14 Capsules Count NDC 75834-144-05 Temozolomide 140mg per Capsule Bottle Label - 5 Capsules Count NDC 75834-144-05 Temozolomide 140mg per Capsule Bottle Carton - 5 Capsules Count NDC 75834-144-14 Temozolomide 140mg per Capsule Bottle Label - 14 Capsules Count NDC 75834-144-14 Temozolomide 140mg per Capsule Bottle Carton - 14 Capsules Count NDC 75834-145-05 Temozolomide 180mg per Capsule Bottle Label - 5 Capsules Count NDC 75834-145-05 Temozolomide 180mg per Capsule Bottle Carton - 5 Capsules Count NDC 75834-145-14 Temozolomide 180mg per Capsule Bottle Label - 14 Capsules Count NDC 75834-145-14 Temozolomide 180mg per Capsule Bottle Carton - 14 Capsules Count NDC 75834-146-05 Temozolomide 250mg per Capsule Bottle Label - 5 Capsules Count NDC 75834-146-05 Temozolomide 250mg per Capsule Bottle Carton - 5 Capsules Count 5mg-5count-label.jpg 5mg5c-carton.jpg 5mg-14count-label.jpg 5mg14c-carton.jpg 20mg-5count-label.jpg 20mg5c-carton.jpg 20mg-14count-label.jpg 20mg14c-carton.jpg 100mg-5count-label.jpg 100mg5c-carton.jpg 100mg-14count-label.jpg 100mg14c-carton.jpg 140mg-5count-label.jpg 140mg5c-carton.jpg 140mg-14count-label.jpg 140mg14c-carton.jpg 180mg-5count-label.jpg 180mg5c-carton.jpg 180mg-14count-label.jpg 180mg14c-carton.jpg 250mg-5count-label.jpg 250mg5c-carton.jpg

Warnings and Precautions ( 5.5 ) 11/2019

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Myelosuppression Inform patients that Temozolomide can cause low blood cell counts and the need for frequent monitoring of blood cell counts. Advise patients to contact their healthcare provider immediately for bleeding, fever, or other signs of infection [see Warnings and Precautions (5.1) ]. Myelodysplastic Syndrome and Secondary Malignancies Advise patients of the increased risk of myelodysplastic syndrome and secondary malignancies [see Warnings and Precautions (5.2) ]. Pneumocystis Pneumonia Advise patients of the increased risk of Pneumocystis pneumonia and to contact their healthcare provided immediately for new or worsening pulmonary symptoms. Inform patients that prophylaxis for Pneumocystis pneumonia may be needed [see Dosage and Administration (2.1) , Warnings and Precautions (5.3) ]. Hepatotoxicity Advise patients of the increased risk of hepatotoxicity and to contact their healthcare provider immediately for signs or symptoms of hepatoxicity [see Warnings and Precautions (5.4) ]. Administration Instructions Advise patient to not open capsules. If capsules are accidentally opened or damaged, advise patients to take rigorous precautions with capsule contents to avoid inhalation or contact with the skin or mucous membranes. In case of powder contact, the hands should be washed. [see Dosage and Administration (2.3) ]. Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.5) , Use in Specific Populations (8.1) ]. Advise females of reproductive potential to use effective contraception during treatment with Temozolomide and for at least 6 months after the last dose [see Use in Specific Populations (8.3) ]. Advise male patients with pregnant partners or female partners of reproductive potential to use condoms during treatment with Temozolomide and for at least 3 months after the final dose [see Use in Specific Populations (8.3) , Nonclinical Toxicology (13.1) ]. Advise male patients not to donate semen during treatment with Temozolomide and for at least 3 months after the final dose [see Use in Specific Populations (8.3) , Nonclinical Toxicology (13.1) ]. Lactation Advise women not to breastfeed during treatment with Temozolomide and for at least 1 week after the final dose [see Use in Specific Populations (8.2) ]. Infertility Advise males of reproductive potential that Temozolomide may impair fertility [see Use in Specific Populations (8.3) , Nonclinical Toxicology (13.1) ]. Manufactured for: Nivagen Pharmaceutical, Inc. Sacramento, CA 95827 USA Toll free number: 1-877-977-0687 Revised: 06/2020

14 CLINICAL STUDIES 14.1 Newly Diagnosed Glioblastoma The efficacy of Temozolomide was evaluated in Study MK-7365-051, a randomized (1:1), multicenter, open-label trial. Eligible patients were required to have newly diagnosed glioblastoma. Patients were randomized to receive either radiation therapy alone or concomitant Temozolomide 75 mg/m 2 once daily starting the first day of radiation therapy and continuing until the last day of radiation therapy for 42 days (with a maximum of 49 days), followed by Temozolomide 150 mg/m 2 or 200 mg/m 2 once daily on Days 1 to 5 of each 28-day cycle, starting 4 weeks after the end of radiation therapy and continuing for 6 cycles. In both arms, focal radiation therapy was delivered as 60 Gy/30 fractions and included radiation to the tumor bed or resection site with a 2- to 3-cm margin. PCP prophylaxis was required during the concomitant phase, regardless of lymphocyte count and continued until recovery of lymphocyte count to grade 1 or less. The major efficacy outcome measure was overall survival. A total of 573 patients were randomized, 287 to Temozolomide and radiation therapy and 286 to radiation therapy alone. At the time of disease progression, Temozolomide was administered as salvage therapy in 161 patients of the 282 (57%) in the radiation therapy alone arm and 62 patients of the 277 (22%) in the Temozolomide and radiation therapy arm. The addition of concomitant and maintenance Temozolomide to radiation therapy for the treatment of patients with newly diagnosed glioblastoma 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: 0.52, 0.75) with a log-rank P <0.0001 in favor of the Temozolomide arm. The median survival was increased by 2.5 months in the Temozolomide arm. FIGURE 1: Kaplan-Meier Curves for Overall Survival (ITT Population) in Newly Diagnosed Glioblastoma Trial figure1 14.2 Refractory Anaplastic Astrocytoma The efficacy of Temozolomide was evaluated in Study MK-7365-006, a single-arm, multicenter trial. Eligible patients had anaplastic astrocytoma at first relapse and a baseline Karnofsky performance status (KPS) of 70 or greater. Patients had previously received radiation therapy and may also have previously received a nitrosourea with or without other chemotherapy. Fifty-four patients had disease progression on prior therapy with both a nitrosourea and procarbazine and their malignancy was considered refractory to chemotherapy (refractory anaplastic astrocytoma population). Temozolomide capsules, USP were given on Days 1 to 5 of each 28-day cycle at a starting dose of 150 mg/m 2 /day. If ANC was ≥1.5 x 10 9 /L and platelet count was ≥100 x 10 9 /L at the nadir and on Day 1 of the next cycle, the Temozolomide dose was increased to 200 mg/m 2 /day. The major efficacy outcome measure was progression-free survival at 6 months and the additional efficacy outcome measures were overall survival and overall response rate. In the refractory anaplastic astrocytoma population (n=54), the median age was 42 years (range: 19 to 76); 65% were male; and 72% had a KPS of >80. 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 (range: 4.2 months to 6.3 years). In the refractory anaplastic astrocytoma population, the overall response rate (CR+PR) was 22% (12 of 54 patients) and the complete response rate was 9% (5 of 54 patients). The median duration of all responses was 50 weeks (range: 16 to 114 weeks) and the median duration of complete responses was 64 weeks (range: 52 to 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.

15 REFERENCES 1. “OSHA Hazardous Drugs.” OSHA . http://www.osha.gov/SLTC/hazardousdrugs/index.

8.5 Geriatric Use In the Newly Diagnosed Glioblastoma trial, Study MK-7365-051, 15% of patients were 65 years and older. This study did not include sufficient numbers of patients aged 65 years and older to determine differences in effectiveness from younger patients. No overall differences in safety were observed between patients ≥65 years and younger patients. In the Refractory Anaplastic Astrocytoma trial, Study MK-7365-0006, 4% of patients were 70 years and older. This study did not include sufficient numbers of patients aged 70 years and older to determine differences in effectiveness from younger patients. Patients 70 years and older had a higher incidence of Grade 4 neutropenia (25%) and Grade 4 thrombocytopenia (20%) in the first cycle of therapy than patients less than 70 years of age [see Warnings and Precautions (5.1) , Adverse Reactions (6.1) ].

8.2 Lactation There are no data on the presence of Temozolomide or its metabolites in human milk, the effects on a breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions, including myelosuppression from temozolomide in the breastfed children, advise women not to breastfeed during treatment with Temozolomide and for at least 1 week after the final dose.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating Temozolomide [see Use in Specific Populations (8.1) ]. Contraception Females Temozolomide can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ]. Advise females of reproductive potential to use effective contraception during treatment with Temozolomide and for at least 6 months after the last dose. Males Because of the potential for embryofetal toxicity and genotoxic effects on sperm cells, advise male patients with pregnant partners or female partners of reproductive potential to use condoms during treatment with Temozolomide and for at least 3 months after the final dose [see Use in Specific Populations (8.1) , Nonclinical Toxicology (13.1) ]. Advise male patients not to donate semen during treatment with Temozolomide and for at least 3 months after the final dose. Infertility Temozolomide may impair male fertility [see Nonclinical Toxicology (13.1) ] . Limited data from male patients show changes in sperm parameters during treatment with Temozolomide; however, no information is available on the duration or reversibility of these changes.

8.4 Pediatric Use Safety and effectiveness of Temozolomide have not been established in pediatric patients. Safety and effectiveness of Temozolomide capsules, USP were assessed, but not established, in 2 open-label studies in pediatric patients aged 3 to18 years. In one study, 29 patients with recurrent brain stem glioma and 34 patients with recurrent high-grade astrocytoma were enrolled. 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 adverse reaction profile in pediatric patients was similar to adults.

8.1 Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1) ] and findings from animal studies, Temozolomide can cause fetal harm when administered to a pregnant woman. Available postmarketing reports describe cases of spontaneous abortions and congenital malformations, including polymalformations with central nervous system, facial, cardiac, skeletal, and genitourinary system anomalies with exposure to Temozolomide during pregnancy. These cases report similar adverse developmental outcomes to those observed in animal studies. Administration of Temozolomide to rats and rabbits during the period of organogenesis caused numerous external, internal, and skeletal malformations at doses less than the maximum human dose based on body surface area (see Data). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Five consecutive days of oral administration of temozolomide at doses of 75 and 150 mg/m 2 (0.38 and 0.75 times the human dose of 200 mg/m 2 ) in rats and rabbits, respectively, during the period of organogenesis (Gestation Days 8-12) caused numerous malformations of the external and internal organs and skeleton in both species. In rabbits, temozolomide at the 150 mg/m 2 dose (0.75 times the human dose of 200 mg/m 2 ) caused embryolethality as indicated by increased resorptions.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to brestfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1) ] and findings from animal studies, Temozolomide can cause fetal harm when administered to a pregnant woman. Available postmarketing reports describe cases of spontaneous abortions and congenital malformations, including polymalformations with central nervous system, facial, cardiac, skeletal, and genitourinary system anomalies with exposure to Temozolomide during pregnancy. These cases report similar adverse developmental outcomes to those observed in animal studies. Administration of Temozolomide to rats and rabbits during the period of organogenesis caused numerous external, internal, and skeletal malformations at doses less than the maximum human dose based on body surface area (see Data). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Five consecutive days of oral administration of temozolomide at doses of 75 and 150 mg/m 2 (0.38 and 0.75 times the human dose of 200 mg/m 2 ) in rats and rabbits, respectively, during the period of organogenesis (Gestation Days 8-12) caused numerous malformations of the external and internal organs and skeleton in both species. In rabbits, temozolomide at the 150 mg/m 2 dose (0.75 times the human dose of 200 mg/m 2 ) caused embryolethality as indicated by increased resorptions. 8.2 Lactation There are no data on the presence of Temozolomide or its metabolites in human milk, the effects on a breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions, including myelosuppression from temozolomide in the breastfed children, advise women not to breastfeed during treatment with Temozolomide and for at least 1 week after the final dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating Temozolomide [see Use in Specific Populations (8.1) ]. Contraception Females Temozolomide can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ]. Advise females of reproductive potential to use effective contraception during treatment with Temozolomide and for at least 6 months after the last dose. Males Because of the potential for embryofetal toxicity and genotoxic effects on sperm cells, advise male patients with pregnant partners or female partners of reproductive potential to use condoms during treatment with Temozolomide and for at least 3 months after the final dose [see Use in Specific Populations (8.1) , Nonclinical Toxicology (13.1) ]. Advise male patients not to donate semen during treatment with Temozolomide and for at least 3 months after the final dose. Infertility Temozolomide may impair male fertility [see Nonclinical Toxicology (13.1) ] . Limited data from male patients show changes in sperm parameters during treatment with Temozolomide; however, no information is available on the duration or reversibility of these changes. 8.4 Pediatric Use Safety and effectiveness of Temozolomide have not been established in pediatric patients. Safety and effectiveness of Temozolomide capsules, USP were assessed, but not established, in 2 open-label studies in pediatric patients aged 3 to18 years. In one study, 29 patients with recurrent brain stem glioma and 34 patients with recurrent high-grade astrocytoma were enrolled. 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 adverse reaction profile in pediatric patients was similar to adults. 8.5 Geriatric Use In the Newly Diagnosed Glioblastoma trial, Study MK-7365-051, 15% of patients were 65 years and older. This study did not include sufficient numbers of patients aged 65 years and older to determine differences in effectiveness from younger patients. No overall differences in safety were observed between patients ≥65 years and younger patients. In the Refractory Anaplastic Astrocytoma trial, Study MK-7365-0006, 4% of patients were 70 years and older. This study did not include sufficient numbers of patients aged 70 years and older to determine differences in effectiveness from younger patients. Patients 70 years and older had a higher incidence of Grade 4 neutropenia (25%) and Grade 4 thrombocytopenia (20%) in the first cycle of therapy than patients less than 70 years of age [see Warnings and Precautions (5.1) , Adverse Reactions (6.1) ]. 8.6 Renal Impairment No dosage adjustment is recommended for patients with creatinine clearance (CLcr) of 36 to 130 mL/min/m 2 [see Clinical Pharmacology (12.3) ]. The recommended dose of Temozolomide has not been established for patients with severe renal impairment (CLcr < 36 mL/min/m 2 ) or for patients with end-stage renal disease on dialysis. 8.7 Hepatic Impairment No dosage adjustment is recommended for patients with mild to moderate hepatic impairment (Child Pugh class Aand B) [see Clinical Pharmacology (12.3 ) ]. The recommended dose of Temozolomide has not been established for patients with severe hepatic impairment (Child-Pugh class C).

16 HOW SUPPLIED/STORAGE AND HANDLING Temozolomide is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 Temozolomide capsules, USP Temozolomide capsules, USP are supplied in HDPE bottle with child-resistant Polypropylene closure containing the following capsule strengths: 5 mg : white opaque bodies with green opaque caps. The capsule body is imprinted with “5 mg”. The cap is imprinted with “NIV-132”. They are supplied as follows: 5-count – NDC 75834-132-05 14-count – NDC 75834-132-14 20 mg : white opaque bodies with rich yellow opaque caps. The capsule body is imprinted with “20 mg”. The cap is imprinted with “NIV-142”. They are supplied as follows: 5-count – NDC 75834-142-05 14-count – NDC 75834-142-14 100 mg : buff opaque bodies with peach opaque caps. The capsule body is imprinted with “100 mg”. The cap is imprinted with “NIV-143”. They are supplied as follows: 5-count – NDC 75834-143-05 14-count – NDC 75834-143-14 140 mg : white opaque bodies with blue opaque caps. The capsule body is imprinted with “140 mg”. The cap is imprinted with “NIV-144”. They are supplied as follows: 5-count – NDC 75834-144-05 14-count – NDC 75834-144-14 180 mg : white opaque bodies with red opaque caps. The capsule body is imprinted with “180 mg”. The cap is imprinted with “NIV-145”. They are supplied as follows: 5-count – NDC 75834-145-05 14-count – NDC 75834-145-14 250 mg : white opaque bodies with white opaque caps. The capsule body is imprinted with “250 mg”. The cap is imprinted with “NIV-146”. They are supplied as follows: 5-count – NDC 75834-146-05 Store Temozolomide capsules, USP at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

IMPORTANT DISPENSING INFORMATION For every patient, dispense Temozolomide capsules, USP in a separate vial or in its original package, making sure each container lists the strength per capsule and that patients take the appropriate number of capsules from each package or vial. Please see the dispensing instructions below for more information.