Temozolomide

1 INDICATIONS AND USAGE Temozolomide capsules are an alkylating drug indicated for the treatment of adults with: Newly diagnosed glioblastoma concomitantly with radiotherapy and then as maintenance treatment. ( 1.1 ) Anaplastic astrocytoma. ( 1.2 ) Adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma. ( 1.2 ) Treatment of adults with refractory anaplastic astrocytoma. ( 1.2 ) 1.1 Newly Diagnosed Glioblastoma Temozolomide capsules are indicated for the treatment of adults with newly diagnosed glioblastoma, concomitantly with radiotherapy and then as maintenance treatment. 1.2 Anaplastic Astrocytoma Temozolomide capsules are indicated for the: adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma; treatment of adults with refractory anaplastic astrocytoma.

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

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

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 a higher risk of developing myelosuppression. ( 5.1 , 8.5 ) Pneumocystis Pneumonia (PCP): Closely monitor all patients, particularly those receiving steroids, for the development of lymphopenia and PCP. ( 5.3 ) Secondary Malignancies : Myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed. ( 5.4 ) 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 2 to 4 weeks after the last dose of temozolomide. ( 5.2 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a 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 ) Exposure to Opened Capsules: Temozolomide capsules should not be opened, chewed, or dissolved but should be swallowed whole with a glass of water. ( 5.6 ) 5.1 Myelosuppression Myelosuppression, including pancytopenia, leukopenia and anemia, some with fatal outcomes, have occurred with temozolomide [see Adverse Reactions (6.1 , 6.2) ] . In MK-7365-006, myelosuppression usually occurred during the first few cycles of therapy and was generally not cumulative. The median nadirs occurred at 26 days for platelets (range: 21 to 40 days) and 28 days for neutrophils (range: 1 to 44 days). Approximately 10% of patients required hospitalization, blood transfusion, or discontinuation of therapy due to myelosuppression. Geriatric patients and women have been shown in clinical trials to have a higher risk of developing myelosuppression. Obtain a complete blood count and monitor ANC and platelet counts before initiation of treatment and as clinically indicated during treatment. When temozolomide is used in combination with radiotherapy, obtain a complete blood count prior to initiation of treatment, weekly during treatment, and as clinically indicated [see Dosage and Administration (2.1 , 2.2 , 2.3) ] . For severe myelosuppression, withhold temozolomide and then resume at same or reduced dose, or permanently discontinue, based on occurrence [see Dosage and Administration (2.1 , 2.2 , 2.3) ] . 5.2 Hepatotoxicity Fatal and severe hepatotoxicity have been reported in patients receiving temozolomide. Perform liver tests at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately two to four weeks after the last dose of temozolomide. 5.3 Pneumocystis Pneumonia Pneumocystis pneumonia (PCP) has been reported in patients receiving temozolomide. The risk of PCP is increased in patients receiving steroids or with longer treatment regimens of temozolomide. For patients with newly diagnosed glioblastoma, provide PCP prophylaxis for all patients during the concomitant phase. Continue PCP prophylaxis in patients who experience lymphopenia, until resolution to Grade 1 or less [see Dosage and Administration (2.1) ] . Monitor all patients receiving temozolomide for the development of lymphopenia and PCP. 5.4 Secondary Malignancies The incidence of secondary malignancies is increased in patients treated with temozolomide-containing regimens. Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed following temozolomide administration. 5.5 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, temozolomide can cause fetal harm when administered to a 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 and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with temozolomide and for 6 months after the last dose. Because of potential risk of genotoxic effects on sperm, advise male patients with female partners of reproductive potential to use condoms during treatment with temozolomide and for 3 months after the last dose. Advise male patients not to donate semen during treatment with temozolomide and for 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ]. 5.6 Exposure to Opened Capsules Advise patients not to open, chew or dissolve the contents of the temozolomide capsules. Swallow capsules whole with a glass of water. If a capsule becomes damaged, avoid contact of the powder contents with skin or mucous membranes. In case of powder contact, wash affected area with water immediately [see Dosage and Administration (2.4) ] . If temozolomide capsules must be opened or the contents must be dissolved, this should be done by a professional trained in safe handling of hazardous drugs using appropriate equipment and safety procedures.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions (5.1) ]. Hepatotoxicity [see Warnings and Precautions (5.2) ]. Pneumocystis Pneumonia [see Warnings and Precautions (5.3) ]. Secondary Malignancies [see Warnings and Precautions (5.4) ]. The most common adverse reactions (≥ 20%) are: alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, and convulsions. ( 6.1 ) The most common Grade 3 to 4 hematologic laboratory abnormalities (≥ 10%) in patients with anaplastic astrocytoma are: decreased lymphocytes, decreased platelets, decreased neutrophils, and decreased leukocytes. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly Diagnosed Glioblastoma The safety of temozolomide was evaluated in study MK-7365-051 [see Clinical Studies (14.1) ]. Severe or life-threatening adverse reactions occurred in 49% of patients treated with temozolomide; the most common were fatigue (13%), convulsions (6%), headache (5%), and thrombocytopenia (5%). The most common adverse reactions (≥ 20%) in patients treated with temozolomide were alopecia, fatigue, nausea, anorexia, headache, constipation and vomiting. Table 3 summarizes the adverse reactions in MK-7365-051. TABLE 3: Adverse Reactions (≥ 10%) in Patients with Newly Diagnosed Glioblastoma Adverse Reactions Concomitant Use Phase Maintenance Use Phase Radiation Therapy and Temozolomide N = 288* Radiation Therapy Alone N = 285 Temozolomide N=224 All Grades (%) Grade ≥ 3 (%) All Grades (%) Grades ≥ 3 (%) All Grades (%) Grade ≥ 3 (%) Skin and Subcutaneous Tissue Alopecia 69 0 63 0 55 0 Rash 19 1 15 0 13 1 General Fatigue 54 7 49 5 61 9 Anorexia 19 1 9 < 1 27 1 Headache 19 2 17 4 23 4 Gastrointestinal System Nausea 36 1 16 < 1 49 1 Vomiting 20 < 1 6 <1 29 2 Constipation 18 1 6 0 22 0 Diarrhea 6 0 3 0 10 1 Central and Peripheral Nervous System Convulsions 6 3 7 3 11 3 *One patient who was randomized to radiation therapy-only arm received radiation therapy and temozolomide. NOS = not otherwise specified. Note: Grade 5 (fatal) adverse reactions are included in the Grade ≥ 3 column. Clinically relevant adverse reactions in < 10% of patients are presented below: Central & Peripheral Nervous System: memory impairment, confusion Eye: vision blurred Gastrointestinal System: stomatitis, abdominal pain General: weakness, dizziness Immune System: allergic reaction Injury: radiation injury not otherwise specified Musculoskeletal System: arthralgia Platelet, Bleeding, & Clotting: thrombocytopenia Psychiatric: insomnia Respiratory System: coughing, dyspnea Special Senses Other: taste perversion Skin & Subcutaneous Tissue: dry skin, pruritus, erythema When laboratory abnormalities and adverse reactions were combined, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic reactions were observed in 8% of patients, and Grade 3 or Grade 4 platelet abnormalities including thrombocytopenic reactions were observed in 14% of patients. Newly Diagnosed Anaplastic Astrocytoma The safety of temozolomide for the adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma was derived from published literature [see Clinical Studies (14.2) ] . The safety of temozolomide for the adjuvant treatment of patients with newly diagnosed anaplastic astrocytoma was consistent with the known safety profile of temozolomide. Refractory Anaplastic Astrocytoma The safety of temozolomide was evaluated in study MK-7365-006 [see Clinical Studies (14.2) ]. The most common adverse reactions (≥ 20%) were nausea, vomiting, headache, fatigue, constipation, and convulsions. Tables 4 and 5 summarize the adverse reactions and hematological laboratory abnormalities in MK-7365-006. TABLE 4: Adverse Reactions (≥ 10%) in Patients with Refractory Anaplastic Astrocytoma Adverse Reactions Temozolomide N=158 All Reactions (%) Grades 3-4 (%) Gastrointestinal System Nausea 53 10 Vomiting 42 6 Constipation 33 1 Diarrhea 16 2 General Headache 41 6 Fatigue 34 4 Asthenia 13 6 Fever 13 2 Central and Peripheral Nervous System Convulsions 23 5 Hemiparesis 18 6 Dizziness 12 1 Coordination abnormal 11 1 Amnesia 10 4 Insomnia 10 0 Cardiovascular Edema peripheral 11 1 Resistance Mechanism Infection viral 11 0 Clinically relevant adverse reactions in < 10% of patients are presented below: Central and Peripheral Nervous System: paresthesia, somnolence, paresis, urinary incontinence, ataxia, dysphasia, convulsions local, gait abnormal, confusion Endocrine: adrenal hypercorticism Gastrointestinal System: abdominal pain, anorexia General: back pain Metabolic: weight increase Musculoskeletal System: myalgia Psychiatric: anxiety, depression Reproductive Disorders: breast pain female Respiratory System: upper respiratory tract infection, pharyngitis, sinusitis, coughing Skin & Appendages: rash, pruritus Urinary System: urinary tract infection, micturition increased frequency Vision: diplopia, vision abnormal * * This term includes blurred vision; visual deficit; vision changes; and vision troubles. TABLE 5: Grade 3 to 4 Hematologic Laboratory Abnormalities That Worsened from Baseline in Patients with Refractory Anaplastic Astrocytoma Temozolomide*,† (%) Decreased lymphocytes 55 Decreased platelets 19 Decreased neutrophils 14 Decreased leukocytes 11 Decreased hemoglobin 4 * Change from Grade 0 to 2 at baseline to Grade 3 or 4 during treatment. † Denominator range= 142, 158 Hematological Toxicities for Advanced Gliomas In clinical trial experience with 110 to 111 females and 169 to 174 males (depending on measurements), females experienced higher rates of Grade 4 neutropenia (ANC < 0.5 × 10 9 /L) and thrombocytopenia (< 20 × 10 9 /L) than males in the first cycle of therapy (12% vs. 5% and 9% vs. 3%, respectively). In the entire safety database for which hematologic data exist (N=932), 7% (4/61) and 10% (6/63) of patients > 70 years experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. For patients ≤ 70 years, 7% (62/871) and 6% (48/879) experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. Pancytopenia, leukopenia, and anemia also occurred. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of temozolomide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug exposure. Dermatologic: Toxic epidermal necrolysis and Stevens-Johnson syndrome. Immune System: Hypersensitivity reactions, including anaphylaxis. Erythema multiforme, which resolved after discontinuation of temozolomide and, in some cases, recurred upon rechallenge. Hematopoietic: Prolonged pancytopenia, which may result in aplastic anemia and fatal outcomes. Hepatobiliary: Fatal and severe hepatotoxicity, elevation of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis. Infections: Serious opportunistic infections, including some cases with fatal outcomes, with bacterial, viral (primary and reactivated), fungal, and protozoan organisms. Pulmonary: Interstitial pneumonitis, pneumonitis, alveolitis, and pulmonary fibrosis. Endocrine: Diabetes insipidus.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , temozolomide can cause fetal harm when administered to a pregnant woman. Available postmarketing reports describe cases of spontaneous abortions and congenital malformations, including polymalformations with central nervous system, facial, cardiac, skeletal, and genitourinary system anomalies with exposure to temozolomide during pregnancy. These cases report similar adverse developmental outcomes to those observed in animal studies. Administration of temozolomide to rats and rabbits during the period of organogenesis caused numerous external, internal, and skeletal malformations at doses less than the maximum human dose based on body surface area (see Data) . Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Five consecutive days of oral administration of temozolomide at doses of 75 and 150 mg/m 2 (0.38 and 0.75 times the human dose of 200 mg/m 2 ) in rats and rabbits, respectively, during the period of organogenesis (Gestation Days 8 to 12) caused numerous malformations of the external and internal organs and skeleton in both species. In rabbits, temozolomide at the 150 mg/m 2 dose (0.75 times the human dose of 200 mg/m 2 ) caused embryolethality as indicated by increased resorptions. 8.2 Lactation There are no data on the presence of temozolomide or its metabolites in human milk, the effects on a breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions, including myelosuppression from temozolomide in the breastfed children, advise women not to breastfeed during treatment with temozolomide and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Temozolomide can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating temozolomide [see Use in Specific Populations (8.1) ] . Contraception Females Advise females of reproductive potential to use effective contraception during treatment with temozolomide and for 6 months after the last dose. Males Because of the potential for embryofetal toxicity and genotoxic effects on sperm cells, advise male patients with pregnant partners or female partners of reproductive potential to use condoms during treatment with temozolomide and for 3 months after the last dose [see Use in Specific Populations (8.1) , Nonclinical Toxicology (13.1) ] . Advise male patients not to donate semen during treatment with temozolomide and for 3 months after the last dose. Infertility Temozolomide may impair male fertility [see Nonclinical Toxicology (13.1) ] . Limited data from male patients show changes in sperm parameters during treatment with temozolomide; however, no information is available on the duration or reversibility of these changes. 8.4 Pediatric Use Safety and effectiveness of temozolomide have not been established in pediatric patients. Safety and effectiveness of temozolomide capsules were assessed, but not established, in 2 open-label studies in pediatric patients aged 3 to 18 years. In one study, 29 patients with recurrent brain stem glioma and 34 patients with recurrent high-grade astrocytoma were enrolled. In a second study conducted by the Children's Oncology Group (COG), 122 patients were enrolled, including patients with medulloblastoma/PNET (29), high grade astrocytoma (23), low grade astrocytoma (22), brain stem glioma (16), ependymoma (14), other CNS tumors (9), and non-CNS tumors (9). The adverse reaction profile in pediatric patients was similar to adults. 8.5 Geriatric Use In MK-7365-051, 15% of patients with newly diagnosed glioblastoma 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. The CATNON trial did not include sufficient numbers of patients aged 65 years and older to determine differences in safety or effectiveness when compared to younger patients. In MK-7365-006, 4% of patients with refractory anaplastic astrocytoma were 70 years and older. This study did not include sufficient numbers of patients aged 70 years and older to determine differences in effectiveness from younger patients. Patients 70 years and older had a higher incidence of Grade 4 neutropenia (25%) and Grade 4 thrombocytopenia (20%) in the first cycle of therapy than patients less than 70 years of age [see Warnings and Precautions (5.1) , Adverse Reactions (6.1) ] . In the entire safety database for which hematologic data exist (N=932), 7% (4/61) and 10% (6/63) of patients > 70 years experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. For patients ≤ 70 years, 7% (62/871) and 6% (48/879) experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. Pancytopenia, leukopenia, and anemia also occurred. 8.6 Renal Impairment No dosage adjustment is recommended for patients with creatinine clearance (CLcr) of 36 to 130 mL/min/m 2 [see Clinical Pharmacology (12.3) ] . The recommended dose of temozolomide has not been established for patients with severe renal impairment (CLcr < 36 mL/min/m 2 ) or for patients with end-stage renal disease on dialysis. 8.7 Hepatic Impairment No dosage adjustment is recommended for patients with mild to moderate hepatic impairment (Child Pugh class A and B) [see Clinical Pharmacology (12.3) ] . The recommended dose of temozolomide has not been established for patients with severe hepatic impairment (Child-Pugh class C).