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 O6 and N7 positions of guanine.

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, TEMODAR 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 TEMODAR during pregnancy. These cases report similar adverse developmental outcomes to those observed in animal studies. Administration of TEMODAR 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.. Data. Animal DataFive consecutive days of oral administration of temozolomide at doses of 75 and 150 mg/m2 (0.38 and 0.75 times the human dose of 200 mg/m2) 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/m2 dose (0.75 times the human dose of 200 mg/m2) caused embryolethality as indicated by increased resorptions.. 8.2 Lactation. There are no data on the presence of TEMODAR 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 TEMODAR 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 TEMODAR [see Use in Specific Populations (8.1)].. Contraception. FemalesTEMODAR can cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with TEMODAR 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 TEMODAR and for at least 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 TEMODAR and for at least months after the final dose.. InfertilityTEMODAR may impair male fertility [see Nonclinical Toxicology (13.1)]. Limited data from male patients show changes in sperm parameters during treatment with TEMODAR; however, no information is available on the duration or reversibility of these changes.. 8.4 Pediatric Use. Safety and effectiveness of TEMODAR have not been established in pediatric patients. Safety and effectiveness of TEMODAR capsules were assessed, but not established, in open-label studies in pediatric patients aged to 18 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), Adverse Reactions (6.1)].. 8.6Renal Impairment. No dosage adjustment is recommended for patients with creatinine clearance (CLcr) of 36 to 130 mL/min/m2 [see Clinical Pharmacology (12.3)]. The recommended dose of TEMODAR has not been established for patients with severe renal impairment (CLcr <36 mL/min/m2) or for patients with end-stage renal disease on dialysis.. 8.7Hepatic 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 TEMODAR has not been established for patients with severe hepatic impairment (Child-Pugh class C).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. TEMODAR is contraindicated in patients with history of hypersensitivity reactions to:temozolomide or any other ingredients in TEMODAR; anddacarbazine, since both temozolomide and dacarbazine are metabolized to the same active metabolite 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide.Reactions to TEMODAR have included anaphylaxis [see Adverse Reactions (6.2)]. temozolomide or any other ingredients in TEMODAR; 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 TEMODAR and dacarbazine.. History of hypersensitivity to temozolomide or any other ingredients in TEMODAR and dacarbazine.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. MyelosuppressionInform patients that TEMODAR 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 provider 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 TEMODAR 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 TEMODAR 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 TEMODAR 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 TEMODAR and for at least week after the final dose [see Use in Specific Populations (8.2)].. InfertilityAdvise males of reproductive potential that TEMODAR may impair fertility [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

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 Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc., at 1-877-888-4231 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). 6.1Clinical 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 GlioblastomaThe safety of TEMODAR was evaluated in Study MK-7365-051 [see Clinical Studies (14.1)]. Forty-nine percent (49%) of patients treated with TEMODAR 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 TEMODAR 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 TEMODAR.TABLE 3: Adverse Reactions (>=5%) in Patients Receiving TEMODAR in Newly Diagnosed Glioblastoma TrialAdverse ReactionsConcomitant PhaseMaintenance PhaseRadiation Therapy and TEMODAR N=288One patient who was randomized to radiation therapy-only arm received radiation therapy and TEMODAR. Radiation Therapy Alone N=285TEMODAR N=224All Grades (%)Grade >=3 (%)All Grades (%)Grades >=3 (%)All Grades (%)Grade >=3 (%)NOS not otherwise specified. Note: Grade (fatal) adverse reactions are included in the Grade >=3 column.Skin and Subcutaneous Tissue Alopecia696355Rash19115131Dry Skin225<1Pruritus415Erythema551General Fatigue547495619Anorexia1919<1271Headache192174234Weakness323172Dizziness4145Gastrointestinal SystemNausea36116<1491Vomiting20<16<1292Constipation181622Diarrhea63101Stomatitis75<191Abdominal Pain2<115<1EyeVision Blurred91918InjuryRadiation 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<116When laboratory abnormalities and adverse reactions were combined, Grade or Grade neutrophil abnormalities including neutropenic reactions were observed in 8% of patients, and Grade or Grade platelet abnormalities including thrombocytopenic reactions were observed in 14% of patients.. Refractory Anaplastic AstrocytomaThe safety of TEMODAR 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 TEMODAR in Refractory Anaplastic Astrocytoma TrialAdverse ReactionsTEMODAR N=158All Reactions (%)Grades 3-4 (%)Gastrointestinal SystemNausea5310Vomiting426Constipation331Diarrhea162Abdominal pain91Anorexia91GeneralHeadache416Fatigue344Asthenia136Fever132Back pain83Central and Peripheral Nervous SystemConvulsions235Hemiparesis186Dizziness121Coordination abnormal111Amnesia104Insomnia10Paresthesia91Somnolence93Paresis83Urinary incontinence82Ataxia82Dysphasia71Convulsions local6Gait abnormal61Confusion5CardiovascularEdema peripheral111Resistance MechanismInfection viral11EndocrineAdrenal hypercorticism8Respiratory SystemUpper respiratory tract infection8Pharyngitis8Sinusitis6Coughing5Skin and AppendagesRash8Pruritus81Urinary SystemUrinary tract infection8Micturition increased frequency6PsychiatricAnxiety71Depression6Reproductive DisordersBreast pain, female6MetabolicWeight increase5Musculoskeletal SystemMyalgia5VisionDiplopia5Vision abnormalThis term includes blurred vision; visual deficit; vision changes; and vision troubles. 5TABLE 5: Grade to Adverse Hematologic Laboratory Abnormalities in Refractory Anaplastic Astrocytoma TrialTEMODARChange from Grade to at baseline to Grade or during treatment. Denominator range= 142, 158 Decreased lymphocytes55%Decreased platelets19%Decreased neutrophils14%Decreased leukocytes11%Decreased hemoglobin4%. 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 neutropenia (ANC <0.5 109/L) and thrombocytopenia (<20 109/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.. Adverse reactions with TEMODAR for injectionAdverse reactions that were reported in 35 patients who received TEMODAR for injection that were not reported in patients who received TEMODAR capsules were pain, irritation, pruritus, warmth, swelling, and erythema at infusion site; petechiae; and hematoma.. 6.2Postmarketing Experience. The following adverse reactions have been identified during post-approval use of TEMODAR. 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 syndromeImmune System: Hypersensitivity reactions, including anaphylaxis. Erythema multiforme, which resolved after discontinuation of TEMODAR 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/m2 (0.63 times the human dose of 200 mg/m2). These changes were most commonly seen at doses where mortality was observed.

BOXED WARNING SECTION.

IMPORTANT DISPENSING INFORMATIONFor every patient, dispense TEMODAR in 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.

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 (25-125 mg/m2) 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 of 50 and 125 mg/m2 (0.25 and 0.63 times the human dose of 200 mg/m2) in rats and dogs, respectively, and testicular atrophy in dogs at 125 mg/m2.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Temozolomide is not directly active but undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC). The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA. Alkylation (methylation) occurs mainly at the O6 and N7 positions of guanine.. 12.3 Pharmacokinetics. Following single oral dose of 150 mg/m2, the mean Cmax value for temozolomide was 7.5 mcg/mL and for MTIC was 282 ng/mL. The mean AUC value for temozolomide was 23.4 mcghr/mL and for MTIC was 864 nghr/mL.Following single 90-minute intravenous infusion of 150 mg/m2, the mean Cmax value for temozolomide was 7.3 mcg/mL and for MTIC was 276 ng/mL. The mean AUC value for temozolomide was 24.6 mcghr/mL and for MTIC was 891 nghr/mL.Temozolomide exhibits linear kinetics over the therapeutic dosing range of 75 mg/m2/day to 250 mg/m2/day.. AbsorptionThe median Tmax is hour.. Effect of FoodThe mean Cmax and AUC decreased by 32% and 9%, respectively, and median Tmax increased by 2-fold (from to 2.25 hours) when TEMODAR 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/m2 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/m2, or mild to moderate hepatic impairment (Child Pugh class and B). The pharmacokinetics of temozolomide has not been studied in patients with CLcr <36 mL/min/m2, 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 multiple-dose study, administration of TEMODAR capsules with ranitidine did not change the Cmax or AUC values for temozolomide or MTIC.A population analysis indicated that administration of valproic acid decreases the clearance of temozolomide by about 5%. 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 TEMODAR.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Newly Diagnosed Glioblastoma. The efficacy of TEMODAR 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 TEMODAR 75 mg/m2 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 TEMODAR 150 mg/m2 or 200 mg/m2 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.A total of 573 patients were randomized, 287 to TEMODAR and radiation therapy and 286 to radiation therapy alone. At the time of disease progression, TEMODAR 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 TEMODAR and radiation therapy arm.The addition of concomitant and maintenance TEMODAR 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 TEMODAR arm. The median survival was increased by 2.5 months in the TEMODAR arm.FIGURE 1: Kaplan-Meier Curves for Overall Survival (ITT Population) in Newly Diagnosed Glioblastoma Trial. Figure 1. 14.2Refractory Anaplastic Astrocytoma. The efficacy of TEMODAR 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). TEMODAR capsules were given on Days to of each 28-day cycle at starting dose of 150 mg/m2/day. If ANC was >=1.5 109/L and platelet count was >=100 109/L at the nadir and on Day of the next cycle, the TEMODAR dose was increased to 200 mg/m2/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.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical 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 GlioblastomaThe safety of TEMODAR was evaluated in Study MK-7365-051 [see Clinical Studies (14.1)]. Forty-nine percent (49%) of patients treated with TEMODAR 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 TEMODAR 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 TEMODAR.TABLE 3: Adverse Reactions (>=5%) in Patients Receiving TEMODAR in Newly Diagnosed Glioblastoma TrialAdverse ReactionsConcomitant PhaseMaintenance PhaseRadiation Therapy and TEMODAR N=288One patient who was randomized to radiation therapy-only arm received radiation therapy and TEMODAR. Radiation Therapy Alone N=285TEMODAR N=224All Grades (%)Grade >=3 (%)All Grades (%)Grades >=3 (%)All Grades (%)Grade >=3 (%)NOS not otherwise specified. Note: Grade (fatal) adverse reactions are included in the Grade >=3 column.Skin and Subcutaneous Tissue Alopecia696355Rash19115131Dry Skin225<1Pruritus415Erythema551General Fatigue547495619Anorexia1919<1271Headache192174234Weakness323172Dizziness4145Gastrointestinal SystemNausea36116<1491Vomiting20<16<1292Constipation181622Diarrhea63101Stomatitis75<191Abdominal Pain2<115<1EyeVision Blurred91918InjuryRadiation 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<116When laboratory abnormalities and adverse reactions were combined, Grade or Grade neutrophil abnormalities including neutropenic reactions were observed in 8% of patients, and Grade or Grade platelet abnormalities including thrombocytopenic reactions were observed in 14% of patients.. Refractory Anaplastic AstrocytomaThe safety of TEMODAR 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 TEMODAR in Refractory Anaplastic Astrocytoma TrialAdverse ReactionsTEMODAR N=158All Reactions (%)Grades 3-4 (%)Gastrointestinal SystemNausea5310Vomiting426Constipation331Diarrhea162Abdominal pain91Anorexia91GeneralHeadache416Fatigue344Asthenia136Fever132Back pain83Central and Peripheral Nervous SystemConvulsions235Hemiparesis186Dizziness121Coordination abnormal111Amnesia104Insomnia10Paresthesia91Somnolence93Paresis83Urinary incontinence82Ataxia82Dysphasia71Convulsions local6Gait abnormal61Confusion5CardiovascularEdema peripheral111Resistance MechanismInfection viral11EndocrineAdrenal hypercorticism8Respiratory SystemUpper respiratory tract infection8Pharyngitis8Sinusitis6Coughing5Skin and AppendagesRash8Pruritus81Urinary SystemUrinary tract infection8Micturition increased frequency6PsychiatricAnxiety71Depression6Reproductive DisordersBreast pain, female6MetabolicWeight increase5Musculoskeletal SystemMyalgia5VisionDiplopia5Vision abnormalThis term includes blurred vision; visual deficit; vision changes; and vision troubles. 5TABLE 5: Grade to Adverse Hematologic Laboratory Abnormalities in Refractory Anaplastic Astrocytoma TrialTEMODARChange from Grade to at baseline to Grade or during treatment. Denominator range= 142, 158 Decreased lymphocytes55%Decreased platelets19%Decreased neutrophils14%Decreased leukocytes11%Decreased hemoglobin4%. 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 neutropenia (ANC <0.5 109/L) and thrombocytopenia (<20 109/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.. Adverse reactions with TEMODAR for injectionAdverse reactions that were reported in 35 patients who received TEMODAR for injection that were not reported in patients who received TEMODAR capsules were pain, irritation, pruritus, warmth, swelling, and erythema at infusion site; petechiae; and hematoma.

DESCRIPTION SECTION.

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 white to light tan/light pink powder with molecular formula of C6H6N6O2 and molecular weight of 194.15. The molecule is stable at acidic pH (<5) and labile at pH >7; hence TEMODAR can be administered orally and intravenously. The prodrug, temozolomide, is rapidly hydrolyzed to the active 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) at neutral and alkaline pH values, with hydrolysis taking place even faster at alkaline pH.. TEMODAR capsulesTEMODAR (temozolomide) capsules 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:TEMODAR mg: lactose anhydrous (132.8 mg), colloidal silicon dioxide (0.2 mg), sodium starch glycolate (7.5 mg), tartaric acid (1.5 mg), and stearic acid (3 mg).TEMODAR 20 mg: lactose anhydrous (182.2 mg), colloidal silicon dioxide (0.2 mg), sodium starch glycolate (11 mg), tartaric acid (2.2 mg), and stearic acid (4.4 mg).TEMODAR 100 mg: lactose anhydrous (175.7 mg), colloidal silicon dioxide (0.3 mg), sodium starch glycolate (15 mg), tartaric acid (3 mg), and stearic acid (6 mg).TEMODAR 140 mg: lactose anhydrous (246 mg), colloidal silicon dioxide (0.4 mg), sodium starch glycolate (21 mg), tartaric acid (4.2 mg), and stearic acid (8.4 mg).TEMODAR 180 mg: lactose anhydrous (316.3 mg), colloidal silicon dioxide (0.5 mg), sodium starch glycolate (27 mg), tartaric acid (5.4 mg), and stearic acid (10.8 mg).TEMODAR 250 mg: lactose anhydrous (154.3 mg), colloidal silicon dioxide (0.7 mg), sodium starch glycolate (22.5 mg), tartaric acid (9 mg), and stearic acid (13.5 mg).The body of the capsules is made of gelatin, and is opaque white. 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 ferric oxide.TEMODAR mg: The green cap contains gelatin, titanium dioxide, iron oxide yellow, sodium lauryl sulfate, and FD&C Blue 2.TEMODAR 20 mg: The yellow cap contains gelatin, sodium lauryl sulfate, and iron oxide yellow.TEMODAR 100 mg: The pink cap contains gelatin, titanium dioxide, sodium lauryl sulfate, and iron oxide red.TEMODAR 140 mg: The blue cap contains gelatin, sodium lauryl sulfate, and FD&C Blue 2.TEMODAR 180 mg: The orange cap contains gelatin, iron oxide red, iron oxide yellow, titanium dioxide, and sodium lauryl sulfate.TEMODAR 250 mg: The white cap contains gelatin, titanium dioxide, and sodium lauryl sulfate.. TEMODAR mg: lactose anhydrous (132.8 mg), colloidal silicon dioxide (0.2 mg), sodium starch glycolate (7.5 mg), tartaric acid (1.5 mg), and stearic acid (3 mg).. TEMODAR 20 mg: lactose anhydrous (182.2 mg), colloidal silicon dioxide (0.2 mg), sodium starch glycolate (11 mg), tartaric acid (2.2 mg), and stearic acid (4.4 mg).. TEMODAR 100 mg: lactose anhydrous (175.7 mg), colloidal silicon dioxide (0.3 mg), sodium starch glycolate (15 mg), tartaric acid (3 mg), and stearic acid (6 mg).. TEMODAR 140 mg: lactose anhydrous (246 mg), colloidal silicon dioxide (0.4 mg), sodium starch glycolate (21 mg), tartaric acid (4.2 mg), and stearic acid (8.4 mg).. TEMODAR 180 mg: lactose anhydrous (316.3 mg), colloidal silicon dioxide (0.5 mg), sodium starch glycolate (27 mg), tartaric acid (5.4 mg), and stearic acid (10.8 mg).. TEMODAR 250 mg: lactose anhydrous (154.3 mg), colloidal silicon dioxide (0.7 mg), sodium starch glycolate (22.5 mg), tartaric acid (9 mg), and stearic acid (13.5 mg).. TEMODAR mg: The green cap contains gelatin, titanium dioxide, iron oxide yellow, sodium lauryl sulfate, and FD&C Blue 2.. TEMODAR 20 mg: The yellow cap contains gelatin, sodium lauryl sulfate, and iron oxide yellow.. TEMODAR 100 mg: The pink cap contains gelatin, titanium dioxide, sodium lauryl sulfate, and iron oxide red.. TEMODAR 140 mg: The blue cap contains gelatin, sodium lauryl sulfate, and FD&C Blue 2.. TEMODAR 180 mg: The orange cap contains gelatin, iron oxide red, iron oxide yellow, titanium dioxide, and sodium lauryl sulfate.. TEMODAR 250 mg: The white cap contains gelatin, titanium dioxide, and sodium lauryl sulfate.. TEMODAR for injectionTEMODAR (temozolomide) for injection is for intravenous use. Each single-dose vial contains 100 mg of sterile and pyrogen-free lyophilized powder. The inactive ingredients are: mannitol (600 mg), L-threonine (160 mg), polysorbate 80 (120 mg), sodium citrate dihydrate (235 mg), and hydrochloric acid (160 mg).. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administer either orally or intravenously.Newly Diagnosed Glioblastoma:75 mg/m2 once daily for 42 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m2 once daily for Days to of each 28-day cycle for cycles. May increase maintenance dose to 200 mg/m2 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/m2 once daily on Days to of each 28-day cycle. (2.2). Administer either orally or intravenously.. Newly Diagnosed Glioblastoma:75 mg/m2 once daily for 42 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m2 once daily for Days to of each 28-day cycle for cycles. May increase maintenance dose to 200 mg/m2 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/m2 once daily for 42 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m2 once daily for Days to of each 28-day cycle for cycles. May increase maintenance dose to 200 mg/m2 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/m2 once daily on Days to of each 28-day cycle. (2.2). 2.1Recommended Dosage and Dosage Modifications for Newly Diagnosed Glioblastoma. Administer TEMODAR 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 TEMODAR is 75 mg/m2 either orally or intravenously once daily for 42 days (up to 49 days) concomitant with focal radiotherapy (60 Gy administered in 30 fractions). Focal radiotherapy includes the tumor bed or resection site with 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 TEMODAR if ANC is greater than or equal to 0.5 109/L and less than 1.5 109/L.Discontinue TEMODAR if platelet count is less than 0.5 109/L.Resume TEMODAR when ANC is greater than or equal to 1.5 109/L.Platelet CountWithhold TEMODAR if platelet count is greater than or equal to 10 109/L and less than 100 109/L.Discontinue TEMODAR if platelet count is less than 10 109/L.Resume TEMODAR when platelet count is greater than or equal to 100 109/L.Non-hematological Adverse Reaction (except for alopecia, nausea, vomiting)Withhold TEMODAR if Grade adverse reaction occurs.Discontinue TEMODAR if Grade or adverse reaction occurs.Resume TEMODAR when resolution to Grade or less.. Maintenance Phase:Beginning weeks after Concomitant Phase completion, administer TEMODAR either orally or intravenously once daily on Days to of each 28-day cycle for cycles. The recommended dosage of TEMODAR is as follows:Cycle 1: 150 mg/m2 per dayCycles to 6: May increase to 200 mg/m2 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.Nonhematologic toxicity is Grade or less (except for alopecia, nausea, and vomiting)ANC is greater than or equal to 1.5 109/L, andPlatelet count is greater than or equal to 100 109/L. Obtain complete blood count on Day 22 and then weekly until the ANC is above 1.5 109/L and the platelet count is above 100 109/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 TEMODAR is withheld, reduce the dose for the next cycle by 50 mg/m2 per day. Permanently discontinue TEMODAR in patients who are unable to tolerate dose of 100 mg/m2 per day.TABLE 2: Temozolomide Dosage Modifications During Maintenance TreatmentToxicityInterruption and Dose ReductionDiscontinuationAbsolute Neutrophil CountWithhold TEMODAR if ANC less than x 109/L.Unable to tolerate dose of 100 mg/m2 per day.When ANC is above 1.5 109/L, resume TEMODAR at reduced dose for the next cycle.Platelet CountWithhold TEMODAR if platelet less than 50 109/L.Unable to tolerate dose of 100 mg/m2 per day.When platelet count is above 100 109/L, resume TEMODAR at reduced dose for the next cycle.Nonhematological Adverse Reaction (except for alopecia, nausea, vomiting)Withhold TEMODAR if Grade adverse reaction.Recurrent Grade after dose reduction.When resolved to Grade or less, resume TEMODAR at reduced dose for the next cycle.Grade Unable to tolerate dose of 100 mg/m2 per day.. Cycle 1: 150 mg/m2 per day. Cycles to 6: May increase to 200 mg/m2 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.Nonhematologic toxicity is Grade or less (except for alopecia, nausea, and vomiting)ANC is greater than or equal to 1.5 109/L, andPlatelet count is greater than or equal to 100 109/L. Nonhematologic toxicity is Grade or less (except for alopecia, nausea, and vomiting). ANC is greater than or equal to 1.5 109/L, and. Platelet count is greater than or equal to 100 109/L.. 2.2 Recommended Dosage and Dosage Modifications for Refractory Anaplastic Astrocytoma. The recommended initial dosage of TEMODAR is 150 mg/m2 once daily on Days to of each 28-day cycle. Increase the TEMODAR dose to 200 mg/m2 per day if the following conditions are met at the nadir and on Day of the next cycle:ANC is greater than or equal to 1.5 109/L, andPlatelet count is greater than or equal to 100 109/L.Continue TEMODAR 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 1.5 109/L and the platelet count is above 100 109/L. Do not start the next cycle until the ANC and platelet count exceed these levels.If the ANC is less than x 109/L or the platelet count is less than 50 109/L during any cycle, reduce the TEMODAR dose for the next cycle by 50 mg/m2 per day. Permanently discontinue TEMODAR in patients who are unable to tolerate dose of 100 mg/m2 per day.. ANC is greater than or equal to 1.5 109/L, and. Platelet count is greater than or equal to 100 109/L.. 2.3Preparation and Administration. TEMODAR is cytotoxic drug. Follow applicable special handling and disposal procedures.1 TEMODAR capsulesAdminister TEMODAR consistently with respect to food (fasting vs. nonfasting) [see Clinical Pharmacology (12.3)]. To reduce nausea and vomiting, take TEMODAR on an empty stomach or at bedtime and consider antiemetic therapy prior to and/or following TEMODAR administration.Swallow TEMODAR 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.. TEMODAR for injectionBring the vial to room temperature prior to reconstitution with Sterile Water for Injection.Reconstitute the vial with 41 mL of Sterile Water for Injection to yield TEMODAR solution with concentration of 2.5 mg/mL temozolomide. Reconstituted TEMODAR is clear solution and essentially free of visible particles.Gently swirl vial. Do not shake.Visually inspect reconstituted solution for particulate matter and discoloration. Discard if particulate matter or discoloration is observed.Do not further dilute the reconstituted solution.Store reconstituted solution at room temperature (25C [77F]). Discard reconstituted solution if not used within 14 hours, including infusion time.Withdraw up to 40 mL from each vial to make up the total dose and discard any unused portion. Transfer reconstituted solution from each vial into an empty 250 mL infusion bag.Administer reconstituted solution using pump over period of 90 minutes. Administer TEMODAR by intravenous infusion only. Infusion over shorter or longer period of time may result in suboptimal dosing. Flush the lines before and after each infusion. TEMODAR for injection may be administered in the same intravenous line with 0.9% Sodium Chloride injection only.Because no data are available on the compatibility of TEMODAR for injection with other intravenous substances or additives, do not infuse other medications simultaneously through the same intravenous line.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Capsules:-5 mg: opaque white bodies with green caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR.-20 mg: opaque white bodies with yellow caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR.-100 mg: opaque white bodies with pink caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR.-140 mg: opaque white bodies with blue caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR.-180 mg: opaque white bodies with orange caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR.-250 mg: opaque white bodies with white caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR. For injection: 100 mg white to light tan/light pink lyophilized powder for reconstitution in single-dose vial.. Capsules:-5 mg: opaque white bodies with green caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR.-20 mg: opaque white bodies with yellow caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR.-100 mg: opaque white bodies with pink caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR.-140 mg: opaque white bodies with blue caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR.-180 mg: opaque white bodies with orange caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR.-250 mg: opaque white bodies with white caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR. -5 mg: opaque white bodies with green caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR.. -20 mg: opaque white bodies with yellow caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR.. -100 mg: opaque white bodies with pink caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR.. -140 mg: opaque white bodies with blue caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR.. -180 mg: opaque white bodies with orange caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR.. -250 mg: opaque white bodies with white caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR.. For injection: 100 mg white to light tan/light pink lyophilized powder for reconstitution in single-dose vial.. Capsules: mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg. (3)For injection: 100 mg as lyophilized powder in single-dose vial for reconstitution. (3). Capsules: mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg. (3). For injection: 100 mg as lyophilized powder in single-dose vial for reconstitution. (3).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating TEMODAR [see Use in Specific Populations (8.1)].. Contraception. FemalesTEMODAR can cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with TEMODAR 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 TEMODAR and for at least 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 TEMODAR and for at least months after the final dose.. InfertilityTEMODAR may impair male fertility [see Nonclinical Toxicology (13.1)]. Limited data from male patients show changes in sperm parameters during treatment with TEMODAR; however, no information is available on the duration or reversibility of these changes.

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), Adverse Reactions (6.1)].

HEPATIC IMPAIRMENT SUBSECTION.

8.7Hepatic 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 TEMODAR has not been established for patients with severe hepatic impairment (Child-Pugh class C).

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. TEMODAR is cytotoxic drug. Follow applicable special handling and disposal procedures.1 TEMODAR capsulesTEMODAR capsules are supplied in child-resistant sachets containing the following capsule strengths:5 mg: opaque white bodies with green caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR. They are supplied as follows: 5-count NDC 0085-3004-03 14-count NDC 0085-3004-0420 mg: opaque white bodies with yellow caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR. They are supplied as follows: 5-count NDC 0085-1519-03 14-count NDC 0085-1519-04100 mg: opaque white bodies with pink caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR. They are supplied as follows: 5-count NDC 0085-1366-03 14-count NDC 0085-1366-04140 mg: opaque white bodies with blue caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR. They are supplied as follows: 5-count NDC 0085-1425-03 14-count NDC 0085-1425-04180 mg: opaque white bodies with orange caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR. They are supplied as follows: 5-count NDC 0085-1430-03 14-count NDC 0085-1430-04250 mg: opaque white bodies with white caps. The capsule body is imprinted with two stripes, the dosage strength, and the Schering-Plough logo. The cap is imprinted with TEMODAR. They are supplied as follows: 5-count NDC 0085-1417-02. 5-count NDC 0085-3004-03. 14-count NDC 0085-3004-04. 5-count NDC 0085-1519-03. 14-count NDC 0085-1519-04. 5-count NDC 0085-1366-03. 14-count NDC 0085-1366-04. 5-count NDC 0085-1425-03. 14-count NDC 0085-1425-04. 5-count NDC 0085-1430-03. 14-count NDC 0085-1430-04. 5-count NDC 0085-1417-02. Store TEMODAR Capsules at 25C (77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].. TEMODAR for injectionTEMODAR for injection is supplied in single-dose glass vials containing 100 mg temozolomide. The lyophilized powder is white to light tan/light pink. NDC 0085-1381-01. NDC 0085-1381-01. Store TEMODAR for injection refrigerated at 2C to 8C (36F to 46F).

INDICATIONS & USAGE SECTION.

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

LACTATION SECTION.

8.2 Lactation. There are no data on the presence of TEMODAR 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 TEMODAR and for at least week after the final dose.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Temozolomide is carcinogenic in rats at doses less than the maximum recommended human dose. Temozolomide induced mammary carcinomas in both males and females at doses 0.13 to 0.63 times the maximum human dose (25-125 mg/m2) when administered orally on 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 of 50 and 125 mg/m2 (0.25 and 0.63 times the human dose of 200 mg/m2) in rats and dogs, respectively, and testicular atrophy in dogs at 125 mg/m2.. 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/m2 (0.63 times the human dose of 200 mg/m2). These changes were most commonly seen at doses where mortality was observed.

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 PANEL 5 mg Capsule Sachet Carton. NDC 0085-3004-035 mgper capsuleTemodar(R) [temozolomide]CapsulesFor Oral AdministrationRx onlyTHIS PACKAGE CONTAINS5 INDIVIDUAL SACHETSEach Individual Sachet ContainsOne Capsule Each. PRINCIPAL DISPLAY PANEL 5 mg Capsule Sachet Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of TEMODAR have not been established in pediatric patients. Safety and effectiveness of TEMODAR capsules were assessed, but not established, in open-label studies in pediatric patients aged to 18 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/m2, the mean Cmax value for temozolomide was 7.5 mcg/mL and for MTIC was 282 ng/mL. The mean AUC value for temozolomide was 23.4 mcghr/mL and for MTIC was 864 nghr/mL.Following single 90-minute intravenous infusion of 150 mg/m2, the mean Cmax value for temozolomide was 7.3 mcg/mL and for MTIC was 276 ng/mL. The mean AUC value for temozolomide was 24.6 mcghr/mL and for MTIC was 891 nghr/mL.Temozolomide exhibits linear kinetics over the therapeutic dosing range of 75 mg/m2/day to 250 mg/m2/day.. AbsorptionThe median Tmax is hour.. Effect of FoodThe mean Cmax and AUC decreased by 32% and 9%, respectively, and median Tmax increased by 2-fold (from to 2.25 hours) when TEMODAR 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/m2 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/m2, or mild to moderate hepatic impairment (Child Pugh class and B). The pharmacokinetics of temozolomide has not been studied in patients with CLcr <36 mL/min/m2, 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 multiple-dose study, administration of TEMODAR capsules with ranitidine did not change the Cmax or AUC values for temozolomide or MTIC.A population analysis indicated that administration of valproic acid decreases the clearance of temozolomide by about 5%. 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 TEMODAR.

POSTMARKETING EXPERIENCE SECTION.

6.2Postmarketing Experience. The following adverse reactions have been identified during post-approval use of TEMODAR. 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 syndromeImmune System: Hypersensitivity reactions, including anaphylaxis. Erythema multiforme, which resolved after discontinuation of TEMODAR 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on its mechanism of action [see Clinical Pharmacology (12.1)] and findings from animal studies, TEMODAR 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 TEMODAR during pregnancy. These cases report similar adverse developmental outcomes to those observed in animal studies. Administration of TEMODAR 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.. Data. Animal DataFive consecutive days of oral administration of temozolomide at doses of 75 and 150 mg/m2 (0.38 and 0.75 times the human dose of 200 mg/m2) 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/m2 dose (0.75 times the human dose of 200 mg/m2) 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.

8.6Renal Impairment. No dosage adjustment is recommended for patients with creatinine clearance (CLcr) of 36 to 130 mL/min/m2 [see Clinical Pharmacology (12.3)]. The recommended dose of TEMODAR has not been established for patients with severe renal impairment (CLcr <36 mL/min/m2) or for patients with end-stage renal disease on dialysis.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information TEMODAR(R) (tem-o-dar) (temozolomide) capsulesTEMODAR(R) (tem-o-dar) (temozolomide) for injection This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: November 2019What is the most important information should know about TEMODARTEMODAR may cause birth defects.Females and female partners of male patients who take TEMODAR:Avoid becoming pregnant while taking TEMODAR.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 TEMODAR. Your doctor should to do pregnancy test to make sure that you are not pregnant before you start taking TEMODAR.Tell your doctor right away if you become pregnant or think you are pregnant during treatment with TEMODAR.Males taking TEMODAR 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 TEMODAR.Do not donate semen during treatment and for at least months after your final dose of TEMODAR.See the section What are the possible side effects of TEMODAR for more information about side effects.What is TEMODARTEMODAR is prescription medicine used to treat adults with certain brain cancer tumors.It is not known if TEMODAR is safe and effective in children.Who should not take TEMODARDo not take TEMODAR if you:have had an allergic reaction to temozolomide or any of the other ingredients in TEMODAR. See the end of this leaflet for list of ingredients in TEMODAR. Symptoms of an allergic reaction with TEMODAR 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 TEMODARTell 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 TEMODAR are breastfeeding or plan to breastfeed. It is not known if TEMODAR passes into your breast milk. Do not breastfeed during treatment and for at least week after your last dose of TEMODAR.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 TEMODARTEMODAR may be taken different ways:you may take TEMODAR by mouth as capsule, or you may receive TEMODAR as an intravenous (IV) injection into your vein.Your doctor will decide the best way for you to take TEMODAR. Take TEMODAR exactly as prescribed by your doctor.There are common dosing schedules for taking TEMODAR depending on the type of brain cancer tumor that you have.People with certain brain cancer tumors take or receive TEMODAR: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 TEMODAR as maintenance treatment. For each of these cycles, you take or receive TEMODAR 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 TEMODAR: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 TEMODAR and decide how long you should take it. You might take TEMODAR 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 TEMODAR, or tell you to stop TEMODAR for short period of time or permanently if you have certain side effects.Your doctor will decide how many treatment cycles of TEMODAR that you will receive, depending on how you respond to and tolerate treatment.TEMODAR capsules:Take TEMODAR capsules exactly as your doctor tells you to.TEMODAR capsules contain white capsule body with color cap and the colors vary based on the dosage strength. Your doctor may prescribe more than strength of TEMODAR 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 TEMODAR than prescribed.Talk to your doctor or pharmacist before taking your dose if you are not sure how much TEMODAR to take. This will help to prevent taking too much TEMODAR and decrease your chances of getting serious side effects.Take each days dose of TEMODAR capsules at one time, with full glass of water.Swallow TEMODAR capsules whole. Do not chew, open, or split the capsules.Take TEMODAR capsules at the same time each day.Take TEMODAR the same way each time, either with food or without food.If TEMODAR 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 TEMODAR 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 TEMODAR.See your doctor regularly to check your progress. Your doctor will check you for side effects.If you take more TEMODAR than prescribed, call your doctor or get emergency medical help right away.TEMODAR for injection:You will receive TEMODAR as an infusion directly into your vein over about 90 minutes.Your doctor may prescribe medicine to prevent or treat nausea, or other medicines to help relieve side effects with TEMODAR.For certain people taking or receiving TEMODAR, your doctor may prescribe an antibiotic to prevent certain infections if you have certain white blood cell counts that are too low.What are the possible side effects of TEMODARTEMODAR can cause serious side effects, including:See What is the most important information should know about TEMODARDecreased blood cell counts. TEMODAR 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 TEMODAR 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 TEMODAR.Your doctor may need to change the dose of TEMODAR 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 TEMODAR.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 TEMODAR. Your doctor will monitor you for this.Pneumocystis pneumonia (PCP). PCP is an infection that people can get when their immune system is weak. TEMODAR 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 TEMODAR for longer period of time may have an increased risk of getting PCP infection.Anyone who takes TEMODAR 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 TEMODAR and can sometimes be severe and lead to death. Your doctor will do blood tests to check your liver function before you start taking TEMODAR, during treatment, and about to weeks after your last dose of TEMODAR.Common side effects of TEMODAR include:hair lossfeeling tirednausea and vomitingheadacheconstipationloss of appetiteconvulsions rashdiarrheaunable to move (paralysis) on one side of the bodyweaknessfeverdizzinesscoordination problemsviral infectionmemory losssleep problemsAdditional side effects seen with TEMODAR for injection:pain, irritation, itching, warmth, swelling, or redness at the site of infusionbruising or small red or purple spots under the skinTEMODAR can affect fertility in males and may affect your ability to father child. Talk with your doctor if fertility is concern for you.Tell your doctor about any side effect that bothers you or that does not go away.These are not all the possible side effects with TEMODAR. 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 TEMODAR capsulesStore TEMODAR capsules at room temperature between 68F to 77F (20C to 25C).Keep TEMODAR and all medicines out of the reach of children.General information about the safe and effective use of TEMODAR.Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use TEMODAR for condition for which it was not prescribed. Do not give TEMODAR 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 TEMODAR. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about TEMODAR that is written for health professionals.For more information, go to www.TEMODAR.com or call 1-877-888-4231.What are the ingredients in TEMODARTEMODAR capsules:Active ingredient: temozolomide.Inactive ingredients: lactose anhydrous, colloidal silicon dioxide, sodium starch glycolate, tartaric acid, stearic acid.The body of the capsules is made of gelatin and is opaque white. 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, potassium hydroxide, and ferric oxide.TEMODAR mg: The green cap contains gelatin, titanium dioxide, iron oxide yellow, sodium lauryl sulfate, and FD&C Blue 2.TEMODAR 20 mg: The yellow cap contains gelatin, sodium lauryl sulfate, and iron oxide yellow.TEMODAR 100 mg: The pink cap contains gelatin, titanium dioxide, sodium lauryl sulfate, and iron oxide red.TEMODAR 140 mg: The blue cap contains gelatin, sodium lauryl sulfate, and FD&C Blue 2.TEMODAR 180 mg: The orange cap contains gelatin, iron oxide red, iron oxide yellow, titanium dioxide, and sodium lauryl sulfate.TEMODAR 250 mg: The white cap contains gelatin, titanium dioxide, and sodium lauryl sulfate.TEMODAR for injection:Active ingredient: temozolomide.Inactive ingredients: mannitol, L-threonine, polysorbate 80, sodium citrate dihydrate, and hydrochloric acid.Distributed by: Merck Sharp Dohme Corp., subsidiary of MERCK CO., INC., Whitehouse Station, NJ 08889, USAFor patent information: www.merck.com/product/patent/home.htmlThe trademarks depicted herein are owned by their respective companies.Copyright (C) 1999-2019 Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc. All rights reserved.Revised: 11/2019usppi-mk7365-mtl-1911r011. Avoid becoming pregnant while taking TEMODAR.. 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 TEMODAR. Your doctor should to do pregnancy test to make sure that you are not pregnant before you start taking TEMODAR.. Tell your doctor right away if you become pregnant or think you are pregnant during treatment with TEMODAR.. Use condom for birth control (contraception) during treatment and for at least months after taking your final dose of TEMODAR.. Do not donate semen during treatment and for at least months after your final dose of TEMODAR.. have had an allergic reaction to temozolomide or any of the other ingredients in TEMODAR. See the end of this leaflet for list of ingredients in TEMODAR. Symptoms of an allergic reaction with TEMODAR 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 TEMODAR are breastfeeding or plan to breastfeed. It is not known if TEMODAR passes into your breast milk. Do not breastfeed during treatment and for at least week after your last dose of TEMODAR.. you may take TEMODAR by mouth as capsule, or you may receive TEMODAR as an intravenous (IV) injection into your vein.. People with certain brain cancer tumors take or receive TEMODAR: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 TEMODAR as maintenance treatment. For each of these cycles, you take or receive TEMODAR 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 TEMODAR as maintenance treatment. For each of these cycles, you take or receive TEMODAR 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 TEMODAR: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 TEMODAR and decide how long you should take it. You might take TEMODAR 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 TEMODAR and decide how long you should take it. You might take TEMODAR 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 TEMODAR, or tell you to stop TEMODAR for short period of time or permanently if you have certain side effects.. Your doctor will decide how many treatment cycles of TEMODAR that you will receive, depending on how you respond to and tolerate treatment.. Take TEMODAR capsules exactly as your doctor tells you to.. TEMODAR capsules contain white capsule body with color cap and the colors vary based on the dosage strength. Your doctor may prescribe more than strength of TEMODAR 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 TEMODAR than prescribed.. Talk to your doctor or pharmacist before taking your dose if you are not sure how much TEMODAR to take. This will help to prevent taking too much TEMODAR and decrease your chances of getting serious side effects.. Take each days dose of TEMODAR capsules at one time, with full glass of water.. Swallow TEMODAR capsules whole. Do not chew, open, or split the capsules.. Take TEMODAR capsules at the same time each day.. Take TEMODAR the same way each time, either with food or without food.. If TEMODAR 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 TEMODAR 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 TEMODAR.. See your doctor regularly to check your progress. Your doctor will check you for side effects.. If you take more TEMODAR than prescribed, call your doctor or get emergency medical help right away.. You will receive TEMODAR as an infusion directly into your vein over about 90 minutes.. Your doctor may prescribe medicine to prevent or treat nausea, or other medicines to help relieve side effects with TEMODAR.. For certain people taking or receiving TEMODAR, your doctor may prescribe an antibiotic to prevent certain infections if you have certain white blood cell counts that are too low.. See What is the most important information should know about TEMODAR. Decreased blood cell counts. TEMODAR 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 TEMODAR 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 TEMODAR.Your doctor may need to change the dose of TEMODAR 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 TEMODAR.. Your doctor will do blood tests regularly to check your blood cell counts before you start and during treatment with TEMODAR.. Your doctor may need to change the dose of TEMODAR 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 TEMODAR.. 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 TEMODAR. Your doctor will monitor you for this.. Pneumocystis pneumonia (PCP). PCP is an infection that people can get when their immune system is weak. TEMODAR 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 TEMODAR for longer period of time may have an increased risk of getting PCP infection.Anyone who takes TEMODAR 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 TEMODAR for longer period of time may have an increased risk of getting PCP infection.. Anyone who takes TEMODAR 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 TEMODAR and can sometimes be severe and lead to death. Your doctor will do blood tests to check your liver function before you start taking TEMODAR, during treatment, and about to weeks after your last dose of TEMODAR.. 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. pain, irritation, itching, warmth, swelling, or redness at the site of infusion. bruising or small red or purple spots under the skin. Store TEMODAR capsules at room temperature between 68F to 77F (20C to 25C).. Keep TEMODAR and all medicines out of the reach of children.

SPL UNCLASSIFIED SECTION.

1.1Newly Diagnosed Glioblastoma. TEMODAR(R) is indicated for the treatment of adult patients with newly diagnosed glioblastoma concomitantly with radiotherapy and then as maintenance treatment.

STORAGE AND HANDLING SECTION.

Store TEMODAR Capsules at 25C (77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].

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 TEMODAR. (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 TEMODAR. (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). 5.1Myelosuppression. Myelosuppression, including pancytopenia, leukopenia and anemia, some with fatal outcomes, have occurred with TEMODAR [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 1.5 109/L or greater and platelet count of 100 109/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 1.5 109/L and the platelet count falls below 100 109/L [see Dosage and Administration (2.1, 2.2)].. 5.2Myelodysplastic Syndrome and Secondary Malignancies. Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed following TEMODAR administration.. 5.3Pneumocystis Pneumonia. Pneumocystis pneumonia (PCP) can occur in patients receiving TEMODAR. 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 TEMODAR for the development of lymphopenia and PCP.. 5.4Hepatotoxicity. Fatal and severe hepatotoxicity have been reported in patients receiving TEMODAR. 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 TEMODAR.. 5.5Embryo-Fetal Toxicity. Based on findings from animal studies and its mechanism of action, TEMODAR 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 TEMODAR 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 TEMODAR and for at least months after the final dose. Advise male patients not to donate semen during treatment with TEMODAR and for at least months after the final dose [see Use in Specific Populations (8.1, 8.3)].