ADVERSE REACTIONS SECTION.

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)] . 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 to 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 Accord Healthcare Inc., at 1-866-941-7875 or www.accordhealthcare.us or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The most common adverse reactions (>=20% incidence) are: alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, and convulsions. 6.1) The most common Grade to hematologic laboratory abnormalities (>=10% incidence) in patients with anaplastic astrocytoma are: decreased lymphocytes, decreased platelets, decreased neutrophils, and decreased leukocytes. 6.1) 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 TrialAdverse ReactionsConcomitant PhaseMaintenance PhaseRadiation Therapy and TemozolomideN=288Radiation Therapy AloneN=285TemozolomideN=224All Grades(%)Grade >=3 (%)All Grades(%)Grade >=3 (%)All Grades(%)Grade >=3 (%)Skin and Subcutaneous TissueAlopecia696355Rash19115131Dry Skin225<1Pruritus415Erythema551GeneralFatigue547495619Anorexia1919<1271Headache192174234Weakness323172Dizziness4145Gastrointestinal SystemNausea36116<1491Vomiting20<16<1292Constipation181622Diarrhea63101Stomatitis75<191Abdominal Pain2<115<1EyeVision Blurred91918Injury Radiation Injury NOS74<12Central and Peripheral Nervous SystemConvulsions6373113Memory Impairment3<14<171Confusion414252Special Senses OtherTaste Perversion625Respiratory SystemCoughing5118<1Dyspnea42315<1Psychiatric Insomnia53<14Immune SystemAllergic Reaction52<13Platelet, Bleeding and ClottingThrombocytopenia43184Musculoskeletal SystemArthralgia2<116One patient who was randomized to radiation therapy only arm received radiation therapy and Temozolomide.NOS=not otherwise specified.Note: Grade (fatal) adverse reactions are included in the Grade >=3 column. When laboratory abnormalities and adverse reactions were combined, Grade or Grade neutrophil abnormalities including neutropenic reactions were observed in 8% of the patients, and Grade or Grade 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 to 40 days) and 28 days for neutrophils (range: to 44 days). Only 14% (22/158) of patients had neutrophil nadir and 20% (32/158) of patients had 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 and 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 TrialAdverse ReactionsTemozolomideN=158All Reactions(%)Grade to 4(%)Gastrointestinal SystemNausea5310Vomiting426Constipation331Diarrhea162Abdominal Pain91Anorexia91GeneralHeadache416Fatigue344Asthenia136Fever132Back Pain83Central and Peripheral Nervous SystemConvulsions235Hemiparesis186Dizziness121Coordination abnormal111Amnesia104Insomnia10Paresthesia91Somnolence93Paresis83Urinary incontinence82Ataxia82Dysphasia71Convulsions local6Gait abnormal61Confusion5CardiovascularEdema peripheral111Resistance Mechanism Infection viral11EndocrineAdrenal hypercorticism8Respiratory SystemUpper respiratory tract infection8Pharyngitis8Sinusitis6Coughing5Skin and AppendagesRash8Pruritus81Urinary SystemUrinary tract infection8Micturition increased frequency6Psychiatric DisordersAnxiety71Depression6Reproductive DisordersBreast pain, female6MetabolicWeight increase5Musculoskeletal SystemMyalgia5VisionDiplopia5Vision abnormal5This text includes blurred vision; visual deficit; vision changes; and vision troubles.TABLE 5: Grade to Adverse Hematologic Laboratory Abnormalities in Refractory Anaplastic Astrocytoma TrialTemozolomide Decreased lymphocytes55%Decreased platelets19%Decreased neutrophils14%Decreased leukocytes11%Decreased hemoglobin4% Change from Grade to at baseline to Grade or during treatment.+ Dominator range 142, 158Hematological 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 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 9.5% (6/63) of patients 70 years experienced Grade neutropenia or thrombocytopenia in the first cycle, respectively. For patients <= 70 years, 7% (62/871) and 5.5% (48/879) experienced Grade 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 capsules 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.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. Toxicology studies in rats and dogs identified low incidence of hemorrhage, degeneration, and necrosis of the retina at temozolomide doses equal to or greater than 125 mg/m (0.63 times the human dose of 200 mg/m 2). These changes were most commonly seen at doses where mortality was observed.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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 to 125 mg/m 2) when administered orally on consecutive days every 28 days for 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 cycles of temozolomide at the maximum recommended daily dose. Temozolomide is mutagen and clastogen. In 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 50 and 125 mg/m (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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Temozolomide is not directly active but undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC). The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA. Alkylation (methylation) occurs mainly at the 6 and 7 positions of guanine. 12.3 Pharmacokinetics. Following single oral dose of 150 mg/m 2, the mean 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. Following single 90-minute intravenous infusion of 150 mg/m 2, the mean max value for temozolomide was 7.3 mcg/mL and for MTIC was 276 ng/mL. The mean AUC value for temozolomide was 24.6 mcg.hr/mL and for MTIC was 891 ng.hr/mL. Temozolomide exhibits linear kinetics over the therapeutic dosing range of 75 mg/m 2/day to 250 mg/m 2/day. AbsorptionThe median max is hour. Effect of FoodThe mean max and AUC decreased by 32% and 9%, respectively, and median Tmax increased by 2-fold (from to 2.25 hours) when temozolomide capsules were administered after modified high-fat breakfast (587 calories comprised of fried egg, strips of bacon, slices of toast, pats of butter, and oz whole milk). DistributionTemozolomide has mean apparent volume of distribution of 0.4 L/kg (%CV=13%). The mean percent bound of drug-related total radioactivity is 15%.EliminationClearance of temozolomide is about 5.5 L/hr/m and the mean elimination half-life is 1.8 hours. MetabolismTemozolomide 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 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.ExcretionAbout 38% of the administered temozolomide total radioactive dose is recovered over 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 PopulationsNo clinically meaningful differences in the pharmacokinetics of temozolomide were observed based on age (range: 19 to 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 and B). The pharmacokinetics of temozolomide has not been studies 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 StudiesEffect of Other Drugs on Temozolomide PharmacokineticsIn multiple-dose study, administration of Temozolomide capsules with ranitidine did not change the max or AUC values for temozolomide or MTIC. 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Newly Diagnosed Glioblastoma The efficacy of temozolomide was evaluated in Study MK-7365-051, 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 once daily starting the first day of radiation therapy and continuing until the last day of radiation therapy for 42 days (with maximum of 49 days), followed by temozolomide 150 mg/m or 200 mg/m once daily on Days to of each 28-day cycle, starting weeks after the end of radiation therapy and continuing for 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 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 or less. The major efficacy outcome measure was overall survival. 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 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 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. FIGURE 1: Kaplan-Meier Curves for Overall Survival (ITT Population). 14.2 Refractory Anaplastic Astrocytoma. The efficacy of temozolomide was evaluated in Study MK-7365-006, single-arm, multicenter trial. Eligible patients had anaplastic astrocytoma at first relapse and baseline Karnofsky performance status (KPS) of 70 or greater. Patients had previously received radiation therapy and may also have previously received nitrosourea with or without other chemotherapy. Fifty-four patients had disease progression on prior therapy with both nitrosourea and procarbazine and their malignancy was considered refractory to chemotherapy (refractory anaplastic astrocytoma population). Temozolomide capsules were given on Days to of each 28-day cycle at starting dose of 150 mg/m 2/day. If ANC was >=1.5 10 9/L and platelet count was >=100 10 9/L at the nadir and on Day 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 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 KPS of >80. Sixty-three percent of patients had surgery other than biopsy at the time of initial diagnosis. Of those patients undergoing resection, 73% underwent subtotal resection and 27% underwent 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 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 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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Temozolomide is contraindicated in patients with history of hypersensitivity reactions to:temozolomide or any other ingredients in temozolomide; anddacarbazine, 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)]. 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.. History of hypersensitivity to temozolomide or any other ingredients in temozolomide and dacarbazine. 4.1) History of hypersensitivity to temozolomide or any other ingredients in temozolomide and dacarbazine. 4.1).

DESCRIPTION SECTION.

11 DESCRIPTION. Temozolomide is an alkylating drug. The chemical name of temozolomide is 3,4-dihydro-3-methyl-4-oxoimidazo[5,1d]- as-tetrazine-8-carboxamide. The structural formula of temozolomide is: The material is white to light tan/light pink powder with molecular formula of 6H 6N 6O and molecular weight of 194.15. The molecule is stable at acidic pH (<5) and labile at pH >7; hence temozolomide 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. Chemical Structure. Temozolomide capsules, USPTemozolomide capsules, USP for oral use contains either mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 mg of temozolomide.The inactive ingredients are as follows:Temozolomide capsules USP mg: lactose anhydrous (168 mg), colloidal anhydrous silica (1 mg), sodium starch glycolate (16 mg), tartaric acid (7 mg), and stearic acid (3 mg). Temozolomide capsules USP 20 mg: lactose anhydrous (14.6 mg), colloidal anhydrous silica (0.2 mg), sodium starch glycolate (3.2 mg), tartaric acid (1.4 mg), and stearic acid (0.6 mg). Temozolomide capsules USP 100 mg: lactose anhydrous (73 mg), colloidal anhydrous silica (1 mg), sodium starch glycolate (16 mg), tartaric acid (7 mg), and stearic acid (3 mg). Temozolomide capsules USP 140 mg: lactose anhydrous (102.2 mg), colloidal anhydrous silica (1.4 mg), sodium starch glycolate (22.4 mg), tartaric acid (9.8 mg), and stearic acid (4.2 mg). Temozolomide capsules USP 180 mg: lactose anhydrous (131.4 mg), colloidal anhydrous silica (1.8 mg), sodium starch glycolate (28.8 mg), tartaric acid (12.6 mg), and stearic acid (5.4 mg). Temozolomide capsules USP 250 mg: lactose anhydrous (182.5 mg), colloidal anhydrous silica (2.5 mg), sodium starch glycolate (40 mg), tartaric acid (17.5 mg), and stearic acid (7.5 mg). The body of the capsules is made of gelatin, and is white. The body of 250 mg capsule contain additionally sodium lauryl sulfate. 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 black iron oxide, potassium hydroxide and shellac.Temozolomide capsules USP mg: The green cap contains gelatin, titanium dioxide, iron oxide yellow and FD&C Blue 2. Temozolomide capsules USP 20 mg: The yellow cap contains gelatin, titanium dioxide and iron oxide yellow. Temozolomide capsules USP 100 mg: The pink cap contains gelatin, titanium dioxide and iron oxide red. Temozolomide capsules USP 140 mg: The transparent blue cap contains gelatin and FD&C Blue 2. Temozolomide capsules USP 180 mg: The maroon cap contains gelatin, iron oxide red, iron oxide yellow and titanium dioxide. Temozolomide capsules USP 250 mg: The white cap contains gelatin, titanium dioxide and sodium lauryl sulfate.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administer either orally or intravenously.Newly Diagnosed Glioblastoma: 75 mg/m once daily for 42 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m once daily for Days to of each 28-day cycle for cycles. May increase maintenance dose to 200 mg/m for cycles to based on toxicity. 2.1) Provide Pneumocystis Pneumonia (PCP) prophylaxis during concomitant phase and continue in patients who develop lymphopenia until resolution to grade or less. 2.1) Refractory Anaplastic Astrocytoma: Initial dose of 150 mg/m once daily on Days to of each 28-day cycle. 2.2) Administer either orally or intravenously.. Newly Diagnosed Glioblastoma: 75 mg/m once daily for 42 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m once daily for Days to of each 28-day cycle for cycles. May increase maintenance dose to 200 mg/m for cycles to based on toxicity. 2.1) Provide Pneumocystis Pneumonia (PCP) prophylaxis during concomitant phase and continue in patients who develop lymphopenia until resolution to grade or less. 2.1) 75 mg/m once daily for 42 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m once daily for Days to of each 28-day cycle for cycles. May increase maintenance dose to 200 mg/m for cycles to based on toxicity. 2.1) Provide Pneumocystis Pneumonia (PCP) prophylaxis during concomitant phase and continue in patients who develop lymphopenia until resolution to grade or less. 2.1) Refractory Anaplastic Astrocytoma: Initial dose of 150 mg/m once daily on Days to of each 28-day cycle. 2.2) 2.1 Recommended Dosage and Dosage Modifications for Newly Diagnosed Glioblastoma. Administer temozolomide capsules either orally or intravenously once daily for 42 consecutive days during the concomitant phase with focal radiotherapy and then once daily on Days to of each 28-day cycle for 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 or less [see Warnings and Precautions (5.3)] Concomitant PhaseThe recommended dosage of temozolomide capsules is 75 mg/m 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 2-to 3-cm margin. Obtain 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 PhaseAdverse ReactionInterruptionDiscontinuationAbsolute Neutrophil CountWithhold temozolomide if ANC is greater than or equal to 0.5 10 9/L and less than 1.5 10 9/L. Resume temozolomide when ANC is greater than or equal to 1.5 10 9/L. Discontinue temozolomide if platelet count is less than 0.5 10 9/L. Platelet CountWithhold temozolomide if platelet count is greater than or equal to 10 10 9/L and less than 100 10 9/L. Resume temozolomide when platelet count is greater than or equal to 100 10 9/L. Discontinue temozolomide if platelet count is less than 10 10 9/L. Non-hematological Adverse Reaction (except for alopecia, nausea, vomiting) Withhold temozolomide if Grade adverse reaction occurs.Resume temozolomide when resolution to Grade or less.Discontinue temozolomide if Grade or adverse reaction occurs.Maintenance PhaseBeginning weeks after Concomitant Phase completion, administer temozolomide either orally or intravenously once daily on Days to of each 28-day cycle for cycles. The recommended dosage of temozolomide is as follows:Cycle 1: 150 mg/m per day Cycles to 6: May increase to 200 mg/m 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 to 6. Non-hematologic toxicity is Grade or less (except for alopecia, nausea, vomiting)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. Obtain 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 during the maintenance phase are provided in Table 2. If Temozolomide is withheld, reduce the dose for the next cycle by 50 mg/m per day. Permanently discontinue Temozolomide in patients who are unable to tolerate dose of 100 mg/m per day. TABLE 2: Temozolomide Dosage Modifications During Maintenance TreatmentToxicityInterruption and Dose ReductionDiscontinuationAbsolute Neutrophil CountWithhold temozolomide if ANC less than x 10 9/L. When ANC is above 1.5 10 9/L, resume temozolomide at reduced dose for the next cycle. Unable to tolerate dose of 100 mg/m per day. Platelet CountWithhold temozolomide if platelet less than 50 10 9/L. When platelet count is above 100 10 9/L, resume temozolomide at reduced dose for the next cycle. Unable to tolerate dose of 100 mg/m per day. Non-hematological Adverse Reaction (except for alopecia, nausea, vomiting)Withhold temozolomide if Grade adverse reaction. When resolved to grade or less, resume temozolomide at reduced dose for the next cycle.Recurrent Grade after dose reduction.Grade 4Unable to tolerate dose of 100 mg/m per day. Cycle 1: 150 mg/m per day Cycles to 6: May increase to 200 mg/m 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 to 6. Non-hematologic toxicity is Grade or less (except for alopecia, nausea, vomiting)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. Non-hematologic toxicity is Grade or less (except for alopecia, nausea, vomiting). 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. 2.2 Recommended Dosage and Dosage Modifications for Refractory Anaplastic Astrocytoma. The recommended initial dosage of temozolomide is 150 mg/m once daily on Days to of each 28-day cycle. Increase the temozolomide dose to 200 mg/m per day if the following conditions are met at the nadir and on Day of the next cycle: ANC is greater than or equal 1.5 10 9/L an Platelet count is greater than or equal to 100 10 9/L. Continue temozolomide until disease progression or unacceptable toxicity. In the clinical trial, treatment could be continued for maximum of years, but the optimum duration of therapy is not known.Obtain 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 x 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 per day. Permanently discontinue temozolomide in patients who are unable to tolerate dose of 100 mg/m per day. ANC is greater than or equal 1.5 10 9/L an Platelet count is greater than or equal to 100 10 9/L. 2.3 Preparation and Administration Temozolomide is cytotoxic drug. Follow applicable special handling and disposal procedures.Temozolomide capsulesAdminister 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Temozolomide capsules, USP for oral administration 5-mg capsules have white bodies with green caps. The capsule body is imprinted with 5. The cap is imprinted with TMZ. 20-mg capsules have white bodies with yellow caps. The capsule body is imprinted with 20. The cap is imprinted with TMZ.100-mg capsules have white bodies with pink caps. The capsule body is imprinted with 100. The cap is imprinted with TMZ.140-mg capsules have white bodies with transparent blue caps. The capsule body is imprinted with 140. The cap is imprinted with TMZ.180-mg capsules have white bodies with maroon caps. The capsule body is imprinted with 180. The cap is imprinted with TMZ.250-mg capsules have white bodies with white caps. The capsule body is imprinted with 250. The cap is imprinted with TMZ. Temozolomide capsules, USP for oral administration 5-mg capsules have white bodies with green caps. The capsule body is imprinted with 5. The cap is imprinted with TMZ. 20-mg capsules have white bodies with yellow caps. The capsule body is imprinted with 20. The cap is imprinted with TMZ.100-mg capsules have white bodies with pink caps. The capsule body is imprinted with 100. The cap is imprinted with TMZ.140-mg capsules have white bodies with transparent blue caps. The capsule body is imprinted with 140. The cap is imprinted with TMZ.180-mg capsules have white bodies with maroon caps. The capsule body is imprinted with 180. The cap is imprinted with TMZ.250-mg capsules have white bodies with white caps. The capsule body is imprinted with 250. The cap is imprinted with TMZ. 5-mg capsules have white bodies with green caps. The capsule body is imprinted with 5. The cap is imprinted with TMZ. 20-mg capsules have white bodies with yellow caps. The capsule body is imprinted with 20. The cap is imprinted with TMZ.. 100-mg capsules have white bodies with pink caps. The capsule body is imprinted with 100. The cap is imprinted with TMZ.. 140-mg capsules have white bodies with transparent blue caps. The capsule body is imprinted with 140. The cap is imprinted with TMZ.. 180-mg capsules have white bodies with maroon caps. The capsule body is imprinted with 180. The cap is imprinted with TMZ.. 250-mg capsules have white bodies with white caps. The capsule body is imprinted with 250. The cap is imprinted with TMZ.. Capsules: mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg 3) Capsules: mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg 3).

GERIATRIC USE SECTION.

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 higher incidence of Grade neutropenia (25%) and Grade thrombocytopenia (20%) in the first cycle of therapy than patients less than 70 years of age [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. No dosage adjustment is recommended for patients with mild to moderate hepatic impairment (Child Pugh class and 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).

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Temozolomide is cytotoxic drug. Follow applicable special handling and disposal procedures. Temozolomide capsules, USP Temozolomide capsules, USP are supplied in amber glass bottles with child-resistant polypropylene caps and child-resistant sachet packs containing the following capsule strengths: Temozolomide Capsules USP mg: have white bodies with green caps. The capsule body is imprinted with 5. The cap is imprinted with TMZ. They are supplied as follows: Amber Glass Bottles count NDC 16729-048-53 14 count NDC 16729-048-54 Sachet Packs (Carton Contains Individual Sachet with One Capsule each): count NDC 16729-048-31 14 count NDC 16729-048-04 Temozolomide Capsules USP 20 mg: have white bodies with yellow caps. The capsule body is imprinted with 20. The cap is imprinted with TMZ. They are supplied as follows: Amber Glass Bottles count NDC 16729-049-53 14 count NDC 16729-049-54 Sachet Packs (Carton Contains Individual Sachet with One Capsule each): count NDC 16729-049-31 14 count NDC 16729-049-04 Temozolomide Capsules USP 100 mg: have white bodies with pink caps. The capsule body is imprinted with 100. The cap is imprinted with TMZ. They are supplied as follows: Amber Glass Bottles count NDC 16729-050-53 14 count NDC 16729-050-54 Sachet Packs (Carton Contains Individual Sachet with One Capsule each): count NDC 16729-050-31 14 count NDC 16729-050-04 Temozolomide Capsules USP 140 mg: have white bodies with transparent blue caps. The capsule body is imprinted with 140. The cap is imprinted with TMZ. They are supplied as follows: Amber Glass Bottles count NDC 16729-129-53 14 count NDC 16729-129-54 Sachet Packs (Carton Contains Individual Sachet with One Capsule each): count NDC 16729-129-31 14 count NDC 16729-129-04 Temozolomide Capsules USP 180 mg: have white bodies with maroon caps. The capsule body is imprinted with 180. The cap is imprinted with TMZ. They are supplied as follows: Amber Glass Bottles count NDC 16729-130-53 14 count NDC 16729-130-54 Sachet Packs (Carton Contains Individual Sachet with One Capsule each): count NDC 16729-130-31 14 count NDC 16729-130-04 Temozolomide Capsules USP 250 mg: have white bodies with white caps. The capsule body is imprinted with 250. The cap is imprinted with TMZ. They are supplied as follows: Amber Glass Bottles count NDC 16729-051-53 Sachet Packs (Carton Contains Individual Sachet with One Capsule each): count NDC 16729-051-31 Store temozolomide capsules, USP at 25C (77F) [see USP Controlled Room Temperature]; excursions permitted to 15C to 30C (59F to 86F).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Temozolomide 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 drug regimen containing nitrosourea and procarbazine. 1.2) Newly diagnosed glioblastoma concomitantly with radiotherapy and then as maintenance treatment. 1.1) Refractory anaplastic astrocytoma who have experienced disease progression on drug regimen containing nitrosourea and procarbazine. 1.2) 1.1 Newly Diagnosed Glioblastoma. Temozolomide capsule 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 capsule is indicated for the treatment of adult patients with refractory anaplastic astrocytoma who have experienced disease progression on drug regimen containing nitrosourea and procarbazine.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).MyelosuppressionInform 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 MalignanciesAdvise patients of the increased risk of myelodysplastic syndrome and secondary malignancies [see Warnings and Precautions (5.2)] Pneumocystis PneumoniaAdvise 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)] HepatotoxicityAdvise 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 InstructionsAdvise 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 ToxicityAdvise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of 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 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 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 months after the final dose [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)] LactationAdvise women not to breastfeed during treatment with temozolomide and for at least week after the final dose [see Use in Specific Populations (8.2)] InfertilityAdvise males of reproductive potential that temozolomide may impair fertility [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)] Manufactured For: Accord Healthcare, Inc., 1009 Slater Road, Suite 210-B, Durham, NC 27703, USA. Manufactured By:Intas Pharmaceuticals Limited, Ahmedabad 380 054, India. 10 1475 6011995Issued October 2021.

LACTATION SECTION.

8.2 Lactation There are no data on the presence of temozolomide or its metabolites in human milk, the effects on 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 week after the final dose.

MECHANISM OF ACTION SECTION.

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 6 and 7 positions of guanine.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Temozolomide is carcinogenic in rats at doses less than the maximum recommended human dose. Temozolomide induced mammary carcinomas in both males and females at doses 0.13 to 0.63 times the maximum human dose (25 to 125 mg/m 2) when administered orally on consecutive days every 28 days for 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 cycles of temozolomide at the maximum recommended daily dose. Temozolomide is mutagen and clastogen. In 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 50 and 125 mg/m (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 low incidence of hemorrhage, degeneration, and necrosis of the retina at temozolomide doses equal to or greater than 125 mg/m (0.63 times the human dose of 200 mg/m 2). These changes were most commonly seen at doses where mortality was observed.

NURSING MOTHERS SECTION.

8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating temozolomide [see Use in Specific Population (8.1)]. ContraceptionFemalesTemozolomide can cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Population (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with temozolomide and for at least months after the last dose. MalesBecause 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 months after the final dose [see Use in Specific Population (8.1), Nonclinical Toxicology (13.1)]. Advise male patients not to donate semen during treatment with temozolomide and for at least months after the final dose. InfertilityTemozolomide 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.

OVERDOSAGE SECTION.

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 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 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANELPrincipal Display Panel- mg CapsulesAmber Glass Bottle CartonNDC 16729- 048-53 Temozolomide Capsules mgRx only5 capsulesPrincipal Display Panel- 20 mg CapsulesAmber Glass Bottle CartonNDC 16729- 049-53 Temozolomide Capsules 20 mgRx only5 capsulesPrincipal Display Panel- 100 mg CapsulesAmber Glass Bottle CartonNDC 16729- 050-53 Temozolomide Capsules 100 mgRx only5 capsulesPrincipal Display Panel- 140 mg CapsulesAmber Glass Bottle CartonNDC 16729- 129-53 Temozolomide Capsules 140 mgRx only5 capsulesPrincipal Display Panel- 180 mg CapsulesAmber Glass Bottle CartonNDC 16729- 130-53 Temozolomide Capsules 180 mgRx only5 capsulesPrincipal Display Panel- 250 mg CapsulesAmber Glass Bottle CartonNDC 16729- 051-53 Temozolomide Capsules 250 mgRx only5 capsulesPrincipal Display Panel- mg CapsulesSachet Pack CartonNDC 16729- 048-31 Temozolomide Capsules mgRx onlyTHIS PACKAGE CONTAINS INDIVIDUAL SACHETSEach Individual Sachet Contains One Capsule EachPrincipal Display Panel- 20 mg CapsulesSachet Pack CartonNDC 16729- 049-31 Temozolomide Capsules 20 mgRx onlyTHIS PACKAGE CONTAINS INDIVIDUAL SACHETSEach Individual Sachet Contains One Capsule EachPrincipal Display Panel- 100 mg CapsulesSachet Pack CartonNDC 16729- 050-31 Temozolomide Capsules 100 mgRx onlyTHIS PACKAGE CONTAINS INDIVIDUAL SACHETSEach Individual Sachet Contains One Capsule EachPrincipal Display Panel- 140 mg CapsulesSachet Pack CartonNDC 16729- 129-31 Temozolomide Capsules 140 mgRx onlyTHIS PACKAGE CONTAINS INDIVIDUAL SACHETSEach Individual Sachet Contains One Capsule EachPrincipal Display Panel- 180 mg CapsulesSachet Pack CartonNDC 16729- 130-31 Temozolomide Capsules 180 mgRx onlyTHIS PACKAGE CONTAINS INDIVIDUAL SACHETSEach Individual Sachet Contains One Capsule EachPrincipal Display Panel- 250 mg CapsulesSachet Pack CartonNDC 16729- 051-31 Temozolomide Capsules 250 mgRx onlyTHIS PACKAGE CONTAINS INDIVIDUAL SACHETSEach Individual Sachet Contains One Capsule Each. PRINCIPAL DISPLAY PANEL. PRINCIPAL DISPLAY PANEL. PRINCIPAL DISPLAY PANEL. PRINCIPAL DISPLAY PANEL. PRINCIPAL DISPLAY PANEL. PRINCIPAL DISPLAY PANEL. PRINCIPAL DISPLAY PANEL. PRINCIPAL DISPLAY PANEL. PRINCIPAL DISPLAY PANEL. PRINCIPAL DISPLAY PANEL. PRINCIPAL DISPLAY PANEL. PRINCIPAL DISPLAY PANEL.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of temozolomide have not been established in pediatric patients. Safety and effectiveness of temozolomide capsules were assessed, but not established, in open-label studies in pediatric patients aged to18 years. In one study, 29 patients with recurrent brain stem glioma and 34 patients with recurrent high-grade astrocytoma were enrolled. In second study conducted by the Childrens 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Following single oral dose of 150 mg/m 2, the mean 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. Following single 90-minute intravenous infusion of 150 mg/m 2, the mean max value for temozolomide was 7.3 mcg/mL and for MTIC was 276 ng/mL. The mean AUC value for temozolomide was 24.6 mcg.hr/mL and for MTIC was 891 ng.hr/mL. Temozolomide exhibits linear kinetics over the therapeutic dosing range of 75 mg/m 2/day to 250 mg/m 2/day. AbsorptionThe median max is hour. Effect of FoodThe mean max and AUC decreased by 32% and 9%, respectively, and median Tmax increased by 2-fold (from to 2.25 hours) when temozolomide capsules were administered after modified high-fat breakfast (587 calories comprised of fried egg, strips of bacon, slices of toast, pats of butter, and oz whole milk). DistributionTemozolomide has mean apparent volume of distribution of 0.4 L/kg (%CV=13%). The mean percent bound of drug-related total radioactivity is 15%.EliminationClearance of temozolomide is about 5.5 L/hr/m and the mean elimination half-life is 1.8 hours. MetabolismTemozolomide 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 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.ExcretionAbout 38% of the administered temozolomide total radioactive dose is recovered over 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 PopulationsNo clinically meaningful differences in the pharmacokinetics of temozolomide were observed based on age (range: 19 to 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 and B). The pharmacokinetics of temozolomide has not been studies 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 StudiesEffect of Other Drugs on Temozolomide PharmacokineticsIn multiple-dose study, administration of Temozolomide capsules with ranitidine did not change the max or AUC values for temozolomide or MTIC. 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on its mechanism of action [see Clinical Pharmacology (12.1)] and findings from animal studies, temozolomide can cause fetal harm when administered to 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 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.DataAnimal DataFive consecutive days of oral administration of temozolomide at doses of 75 and 150 mg/m (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 to 12) caused numerous malformations of the external and internal organs and skeleton in both species. In rabbits, temozolomide at the 150 mg/m dose (0.75 times the human dose of 200 mg/m 2) caused embryolethality as indicated by increased resorptions.

REFERENCES SECTION.

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

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. No dosage adjustment is recommended for patients with creatinine clearance (CLcr) of 36 to 130 mL/min/m [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.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Patient InformationTemozolomide capsules (TEM-oh-ZOE-loe-mide) What is the most important information should know about temozolomide capsulesTemozolomide capsules may cause birth defects.Females and female partners of male patients who take temozolomide capsules:Avoid becoming pregnant while taking temozolomide capsules.Females who can become pregnant should use an effective form of birth control (contraception) during treatment and for at least months after your last dose of temozolomide capsules. Your doctor should to do pregnancy test to make sure that you are not pregnant before you start taking temozolomide capsules.Tell your doctor right away if you become pregnant or think you are pregnant during treatment with temozolomide capsules.Males taking temozolomide capsules and have female partner who is pregnant or who can become pregnant:Use condom for birth control (contraception) during treatment and for at least months after taking your final dose of temozolomide capsules.Do not donate semen during treatment and for at least months after your final dose of temozolomide capsules.See the section What are the possible side effects of temozolomide capsules for more information about side effects. What is temozolomide capsuleTemozolomide capsule is prescription medicine used to treat adults with certain brain cancer tumors.It is not known if temozolomide capsule is safe and effective in children.Who should not take temozolomide capsules Do not take temozolomide capsule if you:have had an allergic reaction to temozolomide or any of the other ingredients in temozolomide capsules. See the end of this leaflet for list of ingredients in temozolomide capsules. Symptoms of an allergic reaction with temozolomide capsules may include: red itchy rash, or severe allergic reaction, such as trouble breathing, swelling of the face, throat, or tongue, or severe skin reaction. If you are not sure, ask your doctor.have had an allergic reaction to dacarbazine (DTIC), another cancer medicine.What should tell my doctor before taking temozolomide capsules Tell your doctor about all of your medical conditions, including if you: have kidney problemshave liver problemsare pregnant or plan to become pregnant. See What is the most important information should know about temozolomide capsulesare breast-feeding or plan to breastfeed. It is not known if temozolomide passes into your breast milk. Do not breastfeed during treatment and for at least week after your last dose of temozolomide capsules.Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take medicine that contains valproic acid. Know the medicines you take. Keep list of them and show it to your doctor and pharmacist when you get new medicine.How should take temozolomide capsules Temozolomide capsules may be taken by mouth as capsule.Your doctor will decide the best way for you to take temozolomide capsules. Take temozolomide capsules exactly as prescribed by your doctor.There are common dosing schedules for taking temozolomide capsules depending on the type of brain cancer tumor that you have.People with certain brain can cancer tumors take or receive temozolomide capsules: time each day for 42 days in row (possibly 49 days depending on side effects) along with receiving radiation treatment. This is cycle of treatment. After this, your doctor may prescribe more cycles of temozolomide capsules as maintenance treatment. For each of these cycles, you take or receive temozolomide capsules time each day for days in row and then you stop taking it for the next 23 days. This is 28-day maintenance treatment cycle. People with certain other brain cancer tumors take or receive temozolomide capsules: time each day for days in row only, and then stop taking it for the next 23 days. This is cycle of treatment (28 days). Your doctor will watch your progress on temozolomide capsules and decide how long you should take it. You might take temozolomide capsules until your tumor gets worse or for possibly up to years. If your doctor prescribes treatment regimen that is different from the information in this leaflet, make sure you follow the instructions given to you by your doctor.Your doctor may change your dose of temozolomide capsules, or tell you to stop temozolomide capsules for short period of time or permanently if you have certain side effects.Your doctor will decide how many treatment cycles of temozolomide capsules that you will receive, depending on how you respond to and tolerate treatment.Temozolomide capsules:Take temozolomide capsules exactly as your doctor tells you to.Temozolomide capsules come in different strengths. Each strength has different color cap. Your doctor may prescribe more than strength of temozolomide capsules for you, so it is important that you understand how to take your medicine the right way. Be sure that you understand exactly how many capsules you need to take on each day of your treatment, and what strengths to take. This may be different whenever you start new cycle. Do not take more temozolomide capsules than prescribed. Talk to your doctor or pharmacist before taking your dose if you are not sure how much temozolomide capsules to take. This will help to prevent taking too much temozolomide capsules and decrease your chances of getting serious side effects.Take each days dose of temozolomide capsules at one time, with full glass of water.Swallow temozolomide capsules whole. Do not chew, open, or split the capsules. Take temozolomide capsules at the same time each day.Take temozolomide capsules the same way each time, either with food or without food.If temozolomide capsules are accidentally opened or damaged, be careful not to breathe in (inhale) the powder from the capsules or get the powder on your skin or mucous membranes (for example, in your nose or mouth). If contact with any of these areas happens, flush the area with water.To help reduce nausea and vomiting, try to take temozolomide capsules on an empty stomach or at bedtime. Your doctor may prescribe medicine to help prevent or treat nausea, or other medicines to reduce side effects with temozolomide capsules.See your doctor regularly to check your progress. Your doctor will check you for side effects.If you take more temozolomide capsules than prescribed, call your doctor or get emergency medical help right away.What are the possible side effects of temozolomide capsulesTemozolomide capsules can cause serious side effects, including: See What is the most important information should know about temozolomide capsules Decreased blood cell counts.Temozolomide capsules can affect your bone marrow and cause you to have decreased blood cell counts. Decreased white blood cell count, red blood cell count and platelet count are common with temozolomide capsules but it can also be severe and lead to death. Your doctor will do blood tests regularly to check your blood cell counts before you start and during treatment with temozolomide capsules.Your doctor may need to change the dose of temozolomide capsules, or when you get it depending on your blood cell counts.People who are age 70 or older and women have higher risk for developing decreased blood cell counts during treatment with temozolomide capsules.Secondary cancers. Blood problems such as myelodysplastic syndrome (MDS) and new cancers (secondary cancers), including certain kind of leukemia, can happen in people who take temozolomide capsules. Your doctor will monitor you for this. Pneumocystis pneumonia (PCP).PCP is an infection that people can get when their immune system is weak. Temozolomide capsules decreases white blood cells, which makes your immune system weaker and can increase your risk of getting PCP. People who are taking steroid medicines or who stay on temozolomide capsules for longer period of time may have an increased risk of getting PCP infection.Anyone who takes temozolomide capsules will be watched carefully by their doctor for low blood cell counts and this infection.Tell your doctor if you have any of the following signs and symptoms of PCP infection: shortness of breath, or fever, chills, dry cough.Liver problems. Liver problems can happen with temozolomide capsules and can sometimes be severe and lead to death. Your doctor will do blood tests to check your liver function before you start taking temozolomide capsules, during treatment, and about to weeks after your last dose of temozolomide capsules. Common side effects of temozolomide capsules include:hair lossfeeling tirednausea and vomiting.headacheconstipationloss of appetiteconvulsionsrashdiarrheaunable to move (paralysis) on one side of the bodyweaknessfeverdizzinesscoordination problemsviral infectionmemory losssleep problemsTemozolomide capsules can affect fertility in males and may affect your ability to father child. Talk with your doctor if fertility is concern for you.These are not all the possible side effects with temozolomide capsules. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store temozolomide capsulesStore temozolomide capsules at 77F (controlled room temperature). Storage at 59F to 86F (15C to 30C) is permitted occasionally.Temozolomide capsules comes in child-resistant package.Keep temozolomide capsules and all medicines out of the reach of children.General information about the safe and effective use of temozolomide capsules. Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use temozolomide capsules for condition for which it was not prescribed. Do not give temozolomide capsules to other people, even if they have the same symptoms that you have. It may harm them.This leaflet summarizes the most important information about temozolomide capsules. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about temozolomide capsules that is written for health professionals.For more information, go to www.accordhealthcare.us or call Accord Healthcare at 1-866-941-7875.What are the ingredients in temozolomide capsules Temozolomide capsules: Active ingredient: temozolomide.Inactive ingredients: lactose anhydrous, colloidal anhydrous silica, sodium starch glycolate, tartaric acid, stearic acid.The body of the capsules is made of gelatin and is white. The body of 250 mg capsule contain additionally sodium lauryl sulfate. 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 black iron oxide, potassium hydroxide and shellac.Temozolomide capsules mg: The green cap contains gelatin, titanium dioxide, iron oxide yellow and FD&C Blue 2.Temozolomide capsules 20 mg: The yellow cap contains gelatin, iron oxide yellow and titanium dioxide.Temozolomide capsules 100 mg: The pink cap contains gelatin, titanium dioxide and iron oxide red.Temozolomide capsules 140 mg: The transparent blue cap contains gelatin and FD&C Blue 2.Temozolomide capsules 180 mg: The maroon cap contains gelatin, iron oxide red, iron oxide yellow and titanium dioxide.Temozolomide capsules 250 mg: The white cap contains gelatin, titanium dioxide and sodium lauryl sulfate.(R)The brands listed are trademarks of their respective owners. Manufactured For:Accord Healthcare, Inc., 1009 Slater Road, Suite 210-B, Durham, NC 27703, USA Manufactured By:Intas Pharmaceuticals Limited, Ahmedabad -380 054, India. 10 1475 6011995Issued october 2021. Avoid becoming pregnant while taking temozolomide capsules.. Females who can become pregnant should use an effective form of birth control (contraception) during treatment and for at least months after your last dose of temozolomide capsules. Your doctor should to do pregnancy test to make sure that you are not pregnant before you start taking temozolomide capsules.. Tell your doctor right away if you become pregnant or think you are pregnant during treatment with temozolomide capsules.. Use condom for birth control (contraception) during treatment and for at least months after taking your final dose of temozolomide capsules.. Do not donate semen during treatment and for at least months after your final dose of temozolomide capsules.. have had an allergic reaction to temozolomide or any of the other ingredients in temozolomide capsules. See the end of this leaflet for list of ingredients in temozolomide capsules. Symptoms of an allergic reaction with temozolomide capsules may include: red itchy rash, or severe allergic reaction, such as trouble breathing, swelling of the face, throat, or tongue, or severe skin reaction. If you are not sure, ask your doctor.. have had an allergic reaction to dacarbazine (DTIC), another cancer medicine.. have kidney problems. have liver problems. are pregnant or plan to become pregnant. See What is the most important information should know about temozolomide capsules. are breast-feeding or plan to breastfeed. It is not known if temozolomide passes into your breast milk. Do not breastfeed during treatment and for at least week after your last dose of temozolomide capsules.. People with certain brain can cancer tumors take or receive temozolomide capsules: time each day for 42 days in row (possibly 49 days depending on side effects) along with receiving radiation treatment. This is cycle of treatment. After this, your doctor may prescribe more cycles of temozolomide capsules as maintenance treatment. For each of these cycles, you take or receive temozolomide capsules time each day for days in row and then you stop taking it for the next 23 days. This is 28-day maintenance treatment cycle. 1 time each day for 42 days in row (possibly 49 days depending on side effects) along with receiving radiation treatment. This is cycle of treatment. After this, your doctor may prescribe more cycles of temozolomide capsules as maintenance treatment. For each of these cycles, you take or receive temozolomide capsules time each day for days in row and then you stop taking it for the next 23 days. This is 28-day maintenance treatment cycle. People with certain other brain cancer tumors take or receive temozolomide capsules: time each day for days in row only, and then stop taking it for the next 23 days. This is cycle of treatment (28 days). Your doctor will watch your progress on temozolomide capsules and decide how long you should take it. You might take temozolomide capsules until your tumor gets worse or for possibly up to years. 1 time each day for days in row only, and then stop taking it for the next 23 days. This is cycle of treatment (28 days). Your doctor will watch your progress on temozolomide capsules and decide how long you should take it. You might take temozolomide capsules until your tumor gets worse or for possibly up to years.. If your doctor prescribes treatment regimen that is different from the information in this leaflet, make sure you follow the instructions given to you by your doctor.. Your doctor may change your dose of temozolomide capsules, or tell you to stop temozolomide capsules for short period of time or permanently if you have certain side effects.. Your doctor will decide how many treatment cycles of temozolomide capsules that you will receive, depending on how you respond to and tolerate treatment.. Take temozolomide capsules exactly as your doctor tells you to.. Temozolomide capsules come in different strengths. Each strength has different color cap. Your doctor may prescribe more than strength of temozolomide capsules for you, so it is important that you understand how to take your medicine the right way. Be sure that you understand exactly how many capsules you need to take on each day of your treatment, and what strengths to take. This may be different whenever you start new cycle. Do not take more temozolomide capsules than prescribed. Talk to your doctor or pharmacist before taking your dose if you are not sure how much temozolomide capsules to take. This will help to prevent taking too much temozolomide capsules and decrease your chances of getting serious side effects.. Take each days dose of temozolomide capsules at one time, with full glass of water.. Swallow temozolomide capsules whole. Do not chew, open, or split the capsules. Take temozolomide capsules at the same time each day.. Take temozolomide capsules the same way each time, either with food or without food.. If temozolomide capsules are accidentally opened or damaged, be careful not to breathe in (inhale) the powder from the capsules or get the powder on your skin or mucous membranes (for example, in your nose or mouth). If contact with any of these areas happens, flush the area with water.. To help reduce nausea and vomiting, try to take temozolomide capsules on an empty stomach or at bedtime. Your doctor may prescribe medicine to help prevent or treat nausea, or other medicines to reduce side effects with temozolomide capsules.. See your doctor regularly to check your progress. Your doctor will check you for side effects.. If you take more temozolomide capsules than prescribed, call your doctor or get emergency medical help right away.. See What is the most important information should know about temozolomide capsules Decreased blood cell counts.Temozolomide capsules can affect your bone marrow and cause you to have decreased blood cell counts. Decreased white blood cell count, red blood cell count and platelet count are common with temozolomide capsules but it can also be severe and lead to death. Your doctor will do blood tests regularly to check your blood cell counts before you start and during treatment with temozolomide capsules.Your doctor may need to change the dose of temozolomide capsules, or when you get it depending on your blood cell counts.People who are age 70 or older and women have higher risk for developing decreased blood cell counts during treatment with temozolomide capsules.. Your doctor will do blood tests regularly to check your blood cell counts before you start and during treatment with temozolomide capsules.. Your doctor may need to change the dose of temozolomide capsules, or when you get it depending on your blood cell counts.. People who are age 70 or older and women have higher risk for developing decreased blood cell counts during treatment with temozolomide capsules.. Secondary cancers. Blood problems such as myelodysplastic syndrome (MDS) and new cancers (secondary cancers), including certain kind of leukemia, can happen in people who take temozolomide capsules. Your doctor will monitor you for this. Pneumocystis pneumonia (PCP).PCP is an infection that people can get when their immune system is weak. Temozolomide capsules decreases white blood cells, which makes your immune system weaker and can increase your risk of getting PCP. People who are taking steroid medicines or who stay on temozolomide capsules for longer period of time may have an increased risk of getting PCP infection.Anyone who takes temozolomide capsules will be watched carefully by their doctor for low blood cell counts and this infection.Tell your doctor if you have any of the following signs and symptoms of PCP infection: shortness of breath, or fever, chills, dry cough.. People who are taking steroid medicines or who stay on temozolomide capsules for longer period of time may have an increased risk of getting PCP infection.. Anyone who takes temozolomide capsules will be watched carefully by their doctor for low blood cell counts and this infection.. Tell your doctor if you have any of the following signs and symptoms of PCP infection: shortness of breath, or fever, chills, dry cough.. Liver problems. Liver problems can happen with temozolomide capsules and can sometimes be severe and lead to death. Your doctor will do blood tests to check your liver function before you start taking temozolomide capsules, during treatment, and about to weeks after your last dose of temozolomide capsules. hair loss. feeling tired. nausea and vomiting.. headache. constipation. loss of appetite. convulsions. rash. diarrhea. unable to move (paralysis) on one side of the body. weakness. fever. dizziness. coordination problems. viral infection. memory loss. sleep problems. Store temozolomide capsules at 77F (controlled room temperature). Storage at 59F to 86F (15C to 30C) is permitted occasionally.. Temozolomide capsules comes in child-resistant package.. Keep temozolomide capsules and all medicines out of the reach of children.

SPL UNCLASSIFIED SECTION.

1.1 Newly Diagnosed Glioblastoma. Temozolomide capsule is indicated for the treatment of adult patients with newly diagnosed glioblastoma concomitantly with radiotherapy and then as maintenance treatment.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. 8.2) Lactation: Advise not to breastfeed. 8.2) 8.1 Pregnancy. Risk SummaryBased on its mechanism of action [see Clinical Pharmacology (12.1)] and findings from animal studies, temozolomide can cause fetal harm when administered to 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 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.DataAnimal DataFive consecutive days of oral administration of temozolomide at doses of 75 and 150 mg/m (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 to 12) caused numerous malformations of the external and internal organs and skeleton in both species. In rabbits, temozolomide at the 150 mg/m 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 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 week after the final dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating temozolomide [see Use in Specific Population (8.1)]. ContraceptionFemalesTemozolomide can cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Population (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with temozolomide and for at least months after the last dose. MalesBecause 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 months after the final dose [see Use in Specific Population (8.1), Nonclinical Toxicology (13.1)]. Advise male patients not to donate semen during treatment with temozolomide and for at least months after the final dose. InfertilityTemozolomide 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 were assessed, but not established, in open-label studies in pediatric patients aged to18 years. In one study, 29 patients with recurrent brain stem glioma and 34 patients with recurrent high-grade astrocytoma were enrolled. In second study conducted by the Childrens 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 higher incidence of Grade neutropenia (25%) and Grade thrombocytopenia (20%) in the first cycle of therapy than patients less than 70 years of age [see Warnings and Precautions (5.1) and 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 [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 and 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).

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Myelosuppression: Monitor absolute neutrophil count (ANC) and platelet count prior to each cycle and during treatment. Geriatric patients and women have higher risk of developing myelosuppression. 5.1) Myelodysplastic Syndrome and Secondary Malignancies, including myeloid leukemia, have been observed. 5.2) Pneumocystis Pneumonia (PCP): Closely monitor all patients, particularly those receiving steroids, for the development of lymphopenia and PCP. 5.3) Hepatotoxicity: Fatal and severe hepatotoxicity have been reported. Perform liver tests at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately to weeks after the last dose of temozolomide 5.4) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. Advise male patients with pregnant partners or female partners of reproductive potential to use condoms. 5.5, 8.1, 8.3) Myelosuppression: Monitor absolute neutrophil count (ANC) and platelet count prior to each cycle and during treatment. Geriatric patients and women have higher risk of developing myelosuppression. 5.1) Myelodysplastic Syndrome and Secondary Malignancies, including myeloid leukemia, have been observed. 5.2) Pneumocystis Pneumonia (PCP): Closely monitor all patients, particularly those receiving steroids, for the development of lymphopenia and PCP. 5.3) Hepatotoxicity: Fatal and severe hepatotoxicity have been reported. Perform liver tests at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately to weeks after the last dose of temozolomide 5.4) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. Advise male patients with pregnant partners or female partners of reproductive potential to use condoms. 5.5, 8.1, 8.3) 5.1 Myelosuppression. Myelosuppression, including pancytopenia, leukopenia and anemia, some with fatal outcomes, have occurred with temozolomide [see Adverse Reactions (6.1, 6.2)]. Geriatric patients and women have been shown in clinical trials to have higher risk of developing myelosuppression. Prior to dosing, patients must have an ANC of 1.5 10 9/L or greater and platelet count of 100 10 9/L or greater. For the concomitant phase with radiotherapy, obtain complete blood count prior to initiation of treatment and weekly during treatment [see Dosage and Administration (2.1)]. For the 28-day treatment cycles, obtain complete blood count prior to treatment on Day and on Day 22 of each cycle. Perform complete blood counts weekly until recovery if the ANC falls below 1.5 10 9/L and the platelet count falls below 100 10 9/L [see Dosage and Administration (2.1, 2.2)]. 5.2 Myelodysplastic Syndrome and Secondary Malignancies. Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed following temozolomide administration.. 5.3 Pneumocystis Pneumonia. Pneumocystis pneumonia (PCP) can occur in patients receiving temozolomide. The risk of PCP is increased in patients receiving steroids or with longer treatment regimens.For patients with newly diagnosed glioblastoma, provide PCP prophylaxis for all patients during the concomitant phase. Continue in patients who experience lymphopenia until resolution to grade or less [see Dosage and Administration (2.1)]. Monitor all patients receiving temozolomide for the development of lymphopenia and PCP.. 5.4 Hepatotoxicity. Fatal and severe hepatotoxicity have been reported in patients receiving temozolomide. Perform liver tests at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately two to four weeks after the last dose of temozolomide.. 5.5 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, temozolomide can cause fetal harm when administered to pregnant woman. Adverse developmental outcomes have been reported in both pregnant patients and pregnant partners of male patients. Oral administration of temozolomide to rats and rabbits during the period of organogenesis resulted in embryolethality and polymalformations at doses less than the maximum human dose based on body surface area.Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with temozolomide and for at least months after the final dose. Because of potential risk of genotoxic effects on sperm, advise male patients with female partners of reproductive potential to use condoms during treatment with temozolomide and for at least months after the final dose. Advise male patients not to donate semen during treatment with temozolomide and for at least months after the final dose [see Use in Specific Populations (8.1, 8.3)].