Data from FDA - Curated by EPG Health - Last updated 01 April 2018

Indication(s)

1 INDICATIONS AND USAGE Temozolomide capsules are an alkylating drug indicated for the treatment of adult patients with: Newly diagnosed glioblastoma multiforme (GBM) concomitantly with radiotherapy and then as maintenance treatment. (1.1) Refractory anaplastic astrocytoma patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine. (1.2) 1.1 Newly Diagnosed Glioblastoma Multiforme Temozolomide capsules are indicated for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment. 1.2 Refractory Anaplastic Astrocytoma Temozolomide capsules are indicated for the treatment of adult patients with refractory anaplastic astrocytoma, i.e., patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.

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contraindications
4 CONTRAINDICATIONS Known hypersensitivity to any temozolomide component or to dacarbazine (DTIC). (4.1) 4.1 Hypersensitivity Temozolomide is contraindicated in patients who have a history of hypersensitivity reaction (such as urticaria, allergic reaction including anaphylaxis, toxic epidermal necrolysis, and Stevens-Johnson syndrome) to any of its components. Temozolomide is also contraindicated in patients who have a history of hypersensitivity to dacarbazine (DTIC), since both drugs are metabolized to 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC).
Adverse reactions
6 ADVERSE REACTIONS The most common adverse reactions (≥10% incidence) are: alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, convulsions, rash, hemiparesis, diarrhea, asthenia, fever, dizziness, coordination abnormal, viral infection, amnesia, and insomnia. (6.1) The most common Grade 3 to 4 hematologic laboratory abnormalities (≥10% incidence) that have developed during treatment with temozolomide are: lymphopenia, thrombocytopenia, neutropenia, and leukopenia. (6.1) Allergic reactions have also been reported. (6) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE, Inc. at 1-855-361-3993 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 Multiforme: During the concomitant phase (temozolomide+radiotherapy), adverse reactions including thrombocytopenia, nausea, vomiting, anorexia, and constipation were more frequent in the temozolomide+RT arm. The incidence of other adverse reactions was comparable in the two arms. The most common adverse reactions across the cumulative temozolomide experience were alopecia, nausea, vomiting, anorexia, headache, and constipation (see Table 7). Forty-nine percent (49%) of patients treated with temozolomide reported one or more severe or life-threatening reactions, most commonly fatigue (13%), convulsions (6%), headache (5%), and thrombocytopenia (5%). Overall, the pattern of reactions during the maintenance phase was consistent with the known safety profile of temozolomide. TABLE 7: Number (%) of Patients with Adverse Reactions: All and Severe/Life Threatening (Incidence of 5% or Greater) Concomitant Phase RT Alone (n=285) Concomitant Phase RT+TMZ (n=288)* Maintenance Phase TMZ (n=224) All Grade ≥3 All Grade ≥3 All Grade ≥3 Subjects Reporting any Adverse Reaction 258 (91) 74 (26) 266 (92) 80 (28) 206 (92) 82 (37) Body as a Whole - General Disorders Anorexia 25 (9) 1 (<1) 56 (19) 2 (1) 61 (27) 3 (1) Dizziness 10 (4) 0 12 (4) 2 (1) 12 (5) 0 Fatigue 139 (49) 15 (5) 156 (54) 19 (7) 137 (61) 20 (9) Headache 49 (17) 11 (4) 56 (19) 5 (2) 51 (23) 9 (4) Weakness 9 (3) 3 (1) 10 (3) 5 (2) 16 (7) 4 (2) Central and Peripheral Nervous System Disorders Confusion 12 (4) 6 (2) 11 (4) 4 (1) 12 (5) 4 (2) Convulsions 20 (7) 9 (3) 17 (6) 10 (3) 25 (11) 7 (3) Memory Impairment 12 (4) 1 (<1) 8 (3) 1 (<1) 16 (7) 2 (1) Disorders of the Eye Vision Blurred 25 (9) 4 (1) 26 (9) 2 (1) 17 (8) 0 Disorders of the Immune System Allergic Reaction 7 (2) 1 (<1) 13 (5) 0 6 (3) 0 Gastrointestinal System Disorders Abdominal Pain 2 (1) 0 7 (2) 1 (<1) 11 (5) 1 (<1) Constipation 18 (6) 0 53 (18) 3 (1) 49 (22) 0 Diarrhea 9 (3) 0 18 (6) 0 23 (10) 2 (1) Nausea 45 (16) 1 (<1) 105 (36) 2 (1) 110 (49) 3 (1) Stomatitis 14 (5) 1 (<1) 19 (7) 0 20 (9) 3 (1) Vomiting 16 (6) 1 (<1) 57 (20) 1 (<1) 66 (29) 4 (2) Injury and Poisoning Radiation Injury NOS 11 (4) 1 (<1) 20 (7) 0 5 (2) 0 Musculoskeletal System Disorders Arthralgia 2 (1) 0 7 (2) 1 (<1) 14 (6) 0 Platelet, Bleeding and Clotting Disorders Thrombocytopenia 3 (1) 0 11 (4) 8 (3) 19 (8) 8 (4) Psychiatric Disorders Insomnia 9 (3) 1 (<1) 14 (5) 0 9 (4) 0 Respiratory System Disorders Coughing 3 (1) 0 15 (5) 2 (1) 19 (8) 1 (<1) Dyspnea 9 (3) 4 (1) 11 (4) 5 (2) 12 (5) 1 (<1) Skin and Subcutaneous Tissue Disorders Alopecia 179 (63) 0 199 (69) 0 124 (55) 0 Dry Skin 6 (2) 0 7 (2) 0 11 (5) 1 (<1) Erythema 15 (5) 0 14 (5) 0 2 (1) 0 Pruritus 4 (1) 0 11 (4) 0 11 (5) 0 Rash 42 (15) 0 56 (19) 3 (1) 29 (13) 3 (1) Special Senses Other, Disorders Taste Perversion 6 (2) 0 18 (6) 0 11 (5) 0 *One patient who was randomized to RT only arm received RT+temozolomide. RT+TMZ=radiotherapy plus temozolomide; NOS=not otherwise specified. Note: Grade 5 (fatal) adverse reactions are included in the Grade ≥3 column. Myelosuppression (neutropenia and thrombocytopenia), which is a known dose-limiting toxicity for most cytotoxic agents, including temozolomide, was observed. When laboratory abnormalities and adverse reactions were combined, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic reactions were observed in 8% of the patients, and Grade 3 or Grade 4 platelet abnormalities, including thrombocytopenic reactions, were observed in 14% of the patients treated with temozolomide. Refractory Anaplastic Astrocytoma: Tables 8 and 9 show the incidence of adverse reactions in the 158 patients in the anaplastic astrocytoma study for whom data are available. In the absence of a control group, it is not clear in many cases whether these reactions should be attributed to temozolomide or the patients’ underlying conditions, but nausea, vomiting, fatigue, and hematologic effects appear to be clearly drug-related. The most frequently occurring adverse reactions were nausea, vomiting, headache, and fatigue. The adverse reactions were usually NCI Common Toxicity Criteria (CTC) Grade 1 or 2 (mild to moderate in severity) and were self-limiting, with nausea and vomiting readily controlled with antiemetics. The incidence of severe nausea and vomiting (CTC Grade 3 or 4) was 10% and 6%, respectively. 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: 1 to 44 days). Only 14% (22/158) of patients had a neutrophil nadir and 20% (32/158) of patients had a platelet nadir, which may have delayed the start of the next cycle. Less than 10% of patients required hospitalization, blood transfusion, or discontinuation of therapy due to myelosuppression. In clinical trial experience with 110 to 111 women and 169 to 174 men (depending on measurements), there were higher rates of Grade 4 neutropenia (ANC<500 cells/μL) and thrombocytopenia (<20,000 cells/μL) in women than men 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 over age 70 experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. For patients less than or equal to age 70, 7% (62/871) and 5.5% (48/879) experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. Pancytopenia, leukopenia, and anemia have also been reported. TABLE 8: Adverse Reactions in the Anaplastic Astrocytoma Trial in Adults (≥5% ) No. (%) of Temozolomide Patients (N=158) All Reactions Grade 3/4 Any Adverse Reaction 153 (97) 79 (50) Body as a Whole Headache 65 (41) 10 (6) Fatigue 54 (34) 7 (4) Asthenia 20 (13) 9 (6) Fever 21 (13) 3 (2) Back pain 12 (8) 4 (3) Cardiovascular Edema peripheral 17 (11) 1 (1) Central and Peripheral Nervous System Convulsions 36 (23) 8 (5) Hemiparesis 29 (18) 10 (6) Dizziness 19 (12) 1 (1) Coordination abnormal 17 (11) 2 (1) Amnesia 16 (10) 6 (4) Insomnia 16 (10) 0 Paresthesia 15 (9) 1 (1) Somnolence 15 (9) 5 (3) Paresis 13 (8) 4 (3) Urinary incontinence 13 (8) 3 (2) Ataxia 12 (8) 3 (2) Dysphasia 11 (7) 1 (1) Convulsions local 9 (6) 0 Gait abnormal 9 (6) 1 (1) Confusion 8 (5) 0 Endocrine Adrenal hypercorticism 13 (8) 0 Gastrointestinal System Nausea 84 (53) 16 (10) Vomiting 66 (42) 10 (6) Constipation 52 (33) 1 (1) Diarrhea 25 (16) 3 (2) Abdominal pain 14 (9) 2 (1) Anorexia 14 (9) 1 (1) Metabolic Weight increase 8 (5) 0 Musculoskeletal System Myalgia 8 (5) Psychiatric Disorders Anxiety 11 (7) 1 (1) Depression 10 (6) 0 Reproductive Disorders Breast pain, female 4 (6) Resistance Mechanism Disorders Infection viral 17 (11) 0 Respiratory System Upper respiratory tract infection 13 (8) 0 Pharyngitis 12 (8) 0 Sinusitis 10 (6) 0 Coughing 8 (5) 0 Skin and Appendages Rash 13 (8) 0 Pruritus 12 (8) 2 (1) Urinary System Urinary tract infection 12 (8) 0 Micturition increased frequency 9 (6) 0 Vision Diplopia 8 (5) 0 Vision abnormal* 8 (5) *Blurred vision; visual deficit; vision changes; vision troubles TABLE 9: Adverse Hematologic Effects (Grade 3 to 4) in the Anaplastic Astrocytoma Trial in Adults Temozolomide* Hemoglobin 7/158 (4%) Lymphopenia 83/152 (55%) Neutrophils 20/142 (14%) Platelets 29/156 (19%) WBC 18/158 (11%) *Change from Grade 0 to 2 at baseline to Grade 3 or 4 during treatment. Temozolomide for injection delivers equivalent temozolomide dose and exposure to both temozolomide and 5-(3-methyltriazen-1-yl)-imidazole-4carboxamide (MTIC) as the corresponding temozolomide capsules. Adverse reactions probably related to treatment that were reported from the 2 studies with the intravenous formulation (n=35) that were not reported in studies using the temozolomide capsules were: pain, irritation, pruritus, warmth, swelling, and erythema at infusion site as well as the following adverse reactions: petechiae and hematoma. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval 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 disorders: Toxic epidermal necrolysis and Stevens-Johnson syndrome. Immune system disorders: Allergic reactions, including anaphylaxis. Erythema multiforme, which resolved after discontinuation of temozolomide and, in some cases, recurred upon rechallenge. Hematopoietic disorders: Prolonged pancytopenia, which may result in aplastic anemia and fatal outcomes [see Warnings and Precautions (5.1)]. Hepatobiliary disorders: Fatal and severe hepatotoxicity, elevation of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis [see Warnings and Precautions (5.5)]. Infections and infestations: Opportunistic infections including Pneumocystis pneumonia (PCP) [ see Warnings and Precautions (5.3)], primary and reactivated cytomegalovirus (CMV), and reactivation of hepatitis B infections including some cases with fatal outcomes. Pulmonary disorders: Interstitial pneumonitis, pneumonitis, alveolitis, and pulmonary fibrosis. Endocrine disorders: Diabetes insipidus.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Newly Diagnosed GBM: 75 mg/m 2 for 42 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m 2 once daily for Days 1 to 5 of a 28-day cycle of temozolomide capsules for 6 cycles. (2.1) Refractory Anaplastic Astrocytoma: Initial dose 150 mg/m 2 once daily for 5 consecutive days per 28-day treatment cycle. (2.1) 2.1 Recommended Dosing and Dose Modification Guidelines Dosage of temozolomide capsules must be adjusted according to nadir neutrophil and platelet counts in the previous cycle and the neutrophil and platelet counts at the time of initiating the next cycle. For temozolomide capsules dosage calculations based on body surface area (BSA) see Table 5. For suggested capsule combinations on a daily dose see Table 6. Patients with Newly Diagnosed High Grade Glioma: Concomitant Phase: Temozolomide capsules are administered at 75 mg/m 2 daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions) followed by maintenance temozolomide capsules for 6 cycles. Focal RT includes the tumor bed or resection site with a 2- to 3-cm margin. No dose reductions are recommended during the concomitant phase; however, dose interruptions or discontinuation may occur based on toxicity. The temozolomide capsules dose should be continued throughout the 42-day concomitant period up to 49 days if all of the following conditions are met: absolute neutrophil count ≥1.5 x 10 9 /L, platelet count ≥100 x 10 9/L, common toxicity criteria (CTC) nonhematological toxicity ≤Grade 1 (except for alopecia, nausea, and vomiting). During treatment a complete blood count should be obtained weekly. Temozolomide dosing should be interrupted or discontinued during concomitant phase according to the hematological and nonhematological toxicity criteria as noted in Table 1. Pneumocystis pneumonia (PCP) prophylaxis is required during the concomitant administration of temozolomide capsules and radiotherapy, and should be continued in patients who develop lymphocytopenia until recovery from lymphocytopenia (CTC Grade ≤1). TABLE 1: Temozolomide Dosing Interruption or Discontinuation During Concomitant Radiotherapy and Temozolomide Toxicity TMZ Interruption* TMZ Discontinuation Absolute Neutrophil Count ≥0.5 and <1.5 x 10 9/L <0.5 x 10 9/L Platelet Count ≥10 and <100 x 10 9/L <10 x 10 9/L CTC Nonhematological Toxicity (except for alopecia, nausea, vomiting) CTC Grade 2 CTC Grade 3 or 4 *Treatment with concomitant TMZ could be continued when all of the following conditions were met: absolute neutrophil count ≥1.5 x 10 9/L; platelet count ≥100 x 10 9/L; CTC nonhematological toxicity ≤Grade 1 (except for alopecia, nausea, vomiting). TMZ=temozolomide; CTC=Common Toxicity Criteria. Maintenance Phase: Cycle 1: Four weeks after completing the temozolomide capsules+RT phase, temozolomide capsules are administered for an additional 6 cycles of maintenance treatment. Dosage in Cycle 1 (maintenance) is 150 mg/m 2 once daily for 5 days followed by 23 days without treatment. Cycles 2 to 6: At the start of Cycle 2, the dose can be escalated to 200 mg/m 2, if the CTC nonhematologic toxicity for Cycle 1 is Grade ≤2 (except for alopecia, nausea, and vomiting), absolute neutrophil count (ANC) is ≥1.5 x 10 9/L, and the platelet count is ≥100 x 10 9/L. The dose remains at 200 mg/m 2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles. Dose Reduction or Discontinuation During Maintenance: Dose reductions during the maintenance phase should be applied according to Tables 2 and 3. During treatment, a complete blood count should be obtained on Day 22 (21 days after the first dose of temozolomide capsules) or within 48 hours of that day, and weekly until the ANC is above 1.5 x 10 9/L (1500/μL) and the platelet count exceeds 100 x 10 9/L (100,000/μL). The next cycle of temozolomide capsules should not be started until the ANC and platelet count exceed these levels. Dose reductions during the next cycle should be based on the lowest blood counts and worst nonhematologic toxicity during the previous cycle. Dose reductions or discontinuations during the maintenance phase should be applied according to Tables 2 and 3. TABLE 2: Temozolomide Dose Levels for Maintenance Treatment Dose Level Dose (mg/m 2 /day) Remarks –1 100 Reduction for prior toxicity 0 150 Dose during Cycle 1 1 200 Dose during Cycles 2 to 6 in absence of toxicity TABLE 3: Temozolomide Dose Reduction or Discontinuation During Maintenance Treatment Toxicity Reduce TMZ by 1 Dose Level* Discontinue TMZ Absolute Neutrophil Count <1.0 x 10 9/L See footnote † Platelet Count <50 x 10 9/L See footnote † CTC Nonhematological Toxicity (except for alopecia, nausea, vomiting) CTC Grade 3 CTC Grade 4 † *TMZ dose levels are listed in Table 2. †TMZ is to be discontinued if dose reduction to <100 mg/m 2 is required or if the same Grade 3 nonhematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction. TMZ=temozolomide; CTC=Common Toxicity Criteria. Patients with Refractory Anaplastic Astrocytoma: For adults the initial dose is 150 mg/m 2 once daily for 5 consecutive days per 28-day treatment cycle. For adult patients, if both the nadir and day of dosing (Day 29, Day 1 of next cycle) ANC are ≥1.5 x 10 9/L (1500/μL) and both the nadir and Day 29, Day 1 of next cycle platelet counts are ≥100 x 10 9/L (100,000/μL), the temozolomide capsules dose may be increased to 200 mg/m 2/day for 5 consecutive days per 28-day treatment cycle. During treatment, a complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until the ANC is above 1.5 x 10 9/L (1500/μL) and the platelet count exceeds 100 x 10 9/L (100,000/μL). The next cycle of temozolomide capsules should not be started until the ANC and platelet count exceed these levels. If the ANC falls to <1.0 x 10 9/L (1000/μL) or the platelet count is <50 x 10 9/L (50,000/μL) during any cycle, the next cycle should be reduced by 50 mg/m 2, but not below 100 mg/m 2, the lowest recommended dose (see Table 4). Temozolomide capsules therapy can be continued until disease progression. In the clinical trial, treatment could be continued for a maximum of 2 years, but the optimum duration of therapy is not known. TABLE 4: Dosing Modification Table TABLE 5: Daily Dose Calculations by Body Surface Area (BSA) Total BSA (m 2 ) 75 mg/m 2 (mg daily) 150 mg/m 2 (mg daily) 200 mg/m 2 (mg daily) 1.0 75 150 200 1.1 82.5 165 220 1.2 90 180 240 1.3 97.5 195 260 1.4 105 210 280 1.5 112.5 225 300 1.6 120 240 320 1.7 127.5 255 340 1.8 135 270 360 1.9 142.5 285 380 2.0 150 300 400 2.1 157.5 315 420 2.2 165 330 440 2.3 172.5 345 460 2.4 180 360 480 2.5 187.5 375 500 TABLE 6: Suggested Capsule Combinations Based on Daily Dose in Adults Number of Daily Capsules by Strength (mg) Total Daily Dose (mg) 250 mg 180 mg 140 mg 100 mg 20 mg 5 mg 75 0 0 0 0 3 3 82.5 0 0 0 0 4 0 90 0 0 0 0 4 2 97.5 0 0 0 1 0 0 105 0 0 0 1 0 1 112.5 0 0 0 1 0 2 120 0 0 0 1 1 0 127.5 0 0 0 1 1 1 135 0 0 0 1 1 3 142.5 0 0 1 0 0 0 150 0 0 1 0 0 2 157.5 0 0 1 0 1 0 165 0 0 1 0 1 1 172.5 0 0 1 0 1 2 180 0 1 0 0 0 0 187.5 0 1 0 0 0 1 195 0 1 0 0 0 3 200 0 1 0 0 1 0 210 0 0 0 2 0 2 220 0 0 0 2 1 0 225 0 0 0 2 1 1 240 0 0 1 1 0 0 255 1 0 0 0 0 1 260 1 0 0 0 0 2 270 1 0 0 0 1 0 280 0 0 2 0 0 0 285 0 0 2 0 0 1 300 0 0 0 3 0 0 315 0 0 0 3 0 3 320 0 1 1 0 0 0 330 0 1 1 0 0 2 340 0 1 1 0 1 0 345 0 1 1 0 1 1 360 0 2 0 0 0 0 375 0 2 0 0 0 3 380 0 1 0 2 0 0 400 0 0 0 4 0 0 420 0 0 3 0 0 0 440 0 0 3 0 1 0 460 0 2 0 1 0 0 480 0 1 0 3 0 0 500 2 0 0 0 0 0 TABLE 4: Dosing Modification Table 2.2 Preparation and Administration Temozolomide Capsules: In clinical trials, temozolomide capsules were administered under both fasting and nonfasting conditions; however, absorption is affected by food [see Clinical Pharmacology (12.3) ], and consistency of administration with respect to food is recommended. There are no dietary restrictions with temozolomide capsules. To reduce nausea and vomiting, temozolomide capsules should be taken on an empty stomach. Bedtime administration may be advised. Antiemetic therapy may be administered prior to and/or following administration of temozolomide capsules. Temozolomide capsules should not be opened or chewed. They should be swallowed whole with a glass of water. If capsules are accidentally opened or damaged, precautions should be taken to avoid inhalation or contact with the skin or mucous membranes [see How Supplied/Storage and Handling (16.1) ].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Nursing mothers: Not recommended. (8.3) Pediatric use: No established use. (8.4) Hepatic/Renal Impairment: Caution should be exercised when temozolomide is administered to patients with severe renal or hepatic impairment. (8.6, 8.7) 8.1 Pregnancy Pregnancy Category D. See Warnings and Precautions section. Temozolomide can cause fetal harm when administered to a pregnant woman. Five consecutive days of oral temozolomide administration of 0.38 and 0.75 times the highest recommended human dose (75 and 150 mg/m 2) in rats and rabbits, respectively, during the period of organogenesis caused numerous malformations of the external and internal soft tissues and skeleton in both species. Doses equivalent to 0.75 times the highest recommended human dose (150 mg/m 2) caused embryolethality in rats and rabbits as indicated by increased resorptions. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with temozolomide. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and tumorigenicity shown for temozolomide in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of temozolomide to the mother. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Temozolomide capsules have been studied in 2 open-label studies in pediatric patients (aged 3 to 18 years) at a dose of 160 to 200 mg/m 2 daily for 5 days every 28 days. In one trial, 29 patients with recurrent brain stem glioma and 34 patients with recurrent high grade astrocytoma were enrolled. All patients had recurrence following surgery and radiation therapy, while 31% also had disease progression following chemotherapy. 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 temozolomide toxicity profile in pediatric patients is similar to adults. Table 10 shows the adverse reactions in 122 children in the COG study. TABLE 10: Adverse Reactions Reported in the Pediatric Cooperative Group Trial (≥10%) No. (%) of Temozolomide Patients (N=122)* Body System/Organ Class All Reactions Grade 3/4 Adverse Reaction Subjects Reporting an AE 107 (88) 69 (57) Body as a Whole Central and Peripheral Nervous System Central cerebral CNS cortex 22 (18) 13 (11) Gastrointestinal System Nausea 56 (46) 5 (4) Vomiting 62 (51) 4 (3) Platelet, Bleeding and Clotting Thrombocytopenia 71 (58) 31 (25) Red Blood Cell Disorders Decreased Hemoglobin 62 (51) 7 (6) White Cell and RES Disorders Decreased WBC 71 (58) 21 (17) Lymphopenia 73 (60) 48 (39) Neutropenia 62 (51) 24 (20) *These various tumors included the following: PNET-medulloblastoma, glioblastoma, low grade astrocytoma, brain stem tumor, ependymoma, mixed glioma, oligodendroglioma, neuroblastoma, Ewing's sarcoma, pineoblastoma, alveolar soft part sarcoma, neurofibrosarcoma, optic glioma, and osteosarcoma. 8.5 Geriatric Use Clinical studies of temozolomide did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In the anaplastic astrocytoma study population, patients 70 years of age or older had a higher incidence of Grade 4 neutropenia and Grade 4 thrombocytopenia (2/8; 25%, P=0.31 and 2/10; 20%, P=0.09, respectively) in the first cycle of therapy than patients under 70 years of age [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ]. In newly diagnosed patients with glioblastoma multiforme, the adverse reaction profile was similar in younger patients (<65 years) vs. older (≥65 years). 8.6 Renal Impairment Caution should be exercised when temozolomide is administered to patients with severe renal impairment [see Clinical Pharmacology (12.3) ]. 8.7 Hepatic Impairment Caution should be exercised when temozolomide is administered to patients with severe hepatic impairment [see Clinical Pharmacology (12.3) ].

Interactions

7 DRUG INTERACTIONS Valproic acid: decreases oral clearance of temozolomide. (7.1) Valproic acid: decreases oral clearance of temozolomide. (7.1) 7.1 Valproic Acid Administration of valproic acid decreases oral clearance of temozolomide by about 5%. The clinical implication of this effect is not known [see Clinical Pharmacology (12.3) ].

More information

Category Value
Authorisation number ANDA203691
Agency product number YF1K15M17Y
Orphan designation No
Product NDC 50268-762,50268-763,50268-761
Date Last Revised 29-03-2018
Type HUMAN PRESCRIPTION DRUG
Storage and handling 16.3 Storage Store temozolomide capsules at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Marketing authorisation holder AvPAK