Temozolomide
Capsule · Oral
Uses
Temozolomide is 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.
Dosage and administration
• Administer orally (2.4)
• Newly Diagnosed Glioblastoma: o 75 mg/m2 once daily for 42 to 49 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m2 once daily for Days 1 to 5 of each 28-day cycle for 6 cycles. May increase maintenance dose to 200 mg/ m2 for Cycles 2 to 6 based on toxicity. (2.1) o 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 orally in a single dose on days 1-5 of a 28-day cycle for 12 cycles. The recommended dosage for cycle 1 is 150 mg/ m2 per day and for Cycles 2 to 12 is 200 mg/ m2 if patient experienced no or minimal toxicity in Cycle 1. (2.2)
• Refractory Anaplastic Astrocytoma: Initial dose 150 mg/ m2 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 until patients have an absolute neutrophil count (ANC) of 1.5 x 109/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 109/L and the platelet count falls below 100 x 109/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 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 is 75 mg/ m2 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 if ANC is greater than or equal to 0.5 x 10 9 /L and less than 1.5 x 10 9 /L. Resume Temozolomide at the same dose when ANC is greater than or equal to 1.5 x 10 9 /L. Discontinue Temozolomide if ANC count is less than 0.5 x 10 9 /L. Platelet Count Withhold Temozolomide if platelet count is greater than or equal to 10 x 10 9 /L and less than 100 x 10 9 /L. Resume Temozolomide at the same dose when platelet count is greater than or equal to 100 x 10 9 /L. Discontinue Temozolomide if platelet count is less than 10 x 10 9 /L. Non-hematological Adverse Reaction (except for alopecia, nausea, vomiting) Withhold Temozolomide if Grade 2 adverse reaction occurs. Resume Temozolomide at the same dose when resolution to Grade 1 or less. Discontinue Temozolomide if Grade 3 or 4 adverse reaction occurs. Single Agent Maintenance Use Phase: Beginning 4 weeks after concomitant use phase completion, administer Temozolomide 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/ m2 per day on days 1 to 5.
• Cycles 2 to 6: May increase to 200 mg/m2 per day on days 1 to 5 before starting Cycle 2 if no dosage interruptions or discontinuation 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 x 109/L and the platelet count is above 100 x 109/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 the maintenance use phase are provided in Table 2. If Temozolomide is withheld, reduce the dose for the next cycle by 50 mg/m2 per day. Permanently discontinue Temozolomide in patients who are unable to tolerate a dose of 100 mg/m2 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 if ANC less than 1 x 10 9 /L. When ANC is above 1.5 x 10 9 /L, resume Temozolomide at reduced dose for the next cycle. Discontinue Temozolomide if unable to tolerate a dose of 100 mg/m 2 per day. Platelet Count Withhold Temozolomide if platelet less than 50 x 10 9 /L. When platelet count is above 100 x 10 9 /L, resume Temozolomide at reduced dose for the next cycle. Discontinue Temozolomide if unable to tolerate a dose of 100 mg/m 2 per day. Nonhematological Adverse Reaction (except for alopecia, nausea, vomiting) Withhold Temozolomide if Grade 3 adverse reaction occurs. When resolved to Grade 1 or less, resume Temozolomide at reduced dose for the next cycle. Discontinue Temozolomide if recurrent Grade 3 adverse reaction occurs after dose reduction, if Grade 4 adverse reaction occurs, or if unable to tolerate a dose of 100mg/m 2 per day.
Dosage forms and strengths
• Temozolomide Capsules, USP for oral administration – 5 mg: have opaque white bodies with opaque green caps. The cap is – imprinted with “NSP” and the capsule body is imprinted with “5 mg” in black ink. – 20 mg: have opaque white bodies with opaque yellow caps. The cap is – imprinted with “NSP” and the capsule body is imprinted with “20 mg” in black ink. – 100 mg: have opaque white bodies with opaque purple caps. The cap is imprinted with “NSP” and the capsule body is imprinted with “100 mg” in black ink. – 140 mg: have opaque white bodies with opaque blue caps. The cap is imprinted with “NSP” and the capsule body is imprinted with “140 mg” in black ink. – 180 mg: have opaque white bodies with opaque orange caps. The cap is imprinted with “NSP” and the capsule body is imprinted with “180 mg” in black ink. – 250 mg: have opaque white bodies with opaque white caps. The cap is imprinted with “NSP” and the capsule body is imprinted with “250 mg” in black ink.
• 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg capsules. (3)
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)
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)
• 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)
• 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)
• 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.
Side effects
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 OPKO Pharmaceuticals, LLC., at 1-844-729-2539 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 (%) Grade ≥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 NOS=not otherwise specified. Note: Grade 5 (fatal) adverse reactions are included in the Grade ≥3 column. *One patient who was randomized to radiation therapy-only arm received radiation therapy and TEMOZOLOMIDE. 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 Refactory Anaplastic Astrocytoma Adverse Reactions Temozolomide N=158 All Reactions (%) Grade 3 to 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 1 1 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.
Use in specific populations
Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summar 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/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 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/m2 [see Clinical Pharmacology (12.3)]. The recommended dose of Temozolomide 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. 8.7 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).
Pregnancy
8.1 Pregnancy Risk Summar 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/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.
Pediatric use
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.
Geriatric use
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.
Overdosage
Dose-limiting toxicity was myelosuppression and was reported with any dose but is expected to be more severe at higher doses. An overdose of 2000 mg per day for 5 days was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia, multi-organ failure, and death. There are reports of patients who have taken more than 5 days of treatment (up to 64 days), with adverse reactions reported including myelosuppression, which in some cases was severe and prolonged, and infections and resulted in death. In the event of an overdose, monitor complete blood count and provide supportive measures as necessary.
Description
Temozolomide Capsules, USP are an alkylating drug. The chemical name of temozolomide, USP is 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide. The structural formula of temozolomide, USP is: The material is a white to light tan/light pink powder with a molecular formula of C 6 H 6 N 6 O 2 and a molecular weight of 194.15. The molecule is stable at acidic pH (<5) and labile at pH >7; hence temozolomide, USP can be administered orally. The prodrug, temozolomide, is rapidly hydrolyzed to the active 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) at neutral and alkaline pH values, with hydrolysis taking place even faster at alkaline pH. Chemical Structure Temozolomide Capsules, USP: Temozolomide capsules, USP for oral use contain either 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 mg of temozolomide. The inactive ingredients are as follows: Temozolomide Capsules 5 mg: lactose anhydrous (62.17 mg), colloidal silicon dioxide (0.33 mg), sodium starch glycolate (3.75 mg), tartaric acid (1.5 mg) and stearic acid (2.25 mg). Temozolomide Capsules 20 mg: lactose anhydrous (248.67 mg), colloidal silicon dioxide (1.33 mg), sodium starch glycolate (15.00 mg), tartaric acid (6.00 mg) and stearic acid (9.00 mg). Temozolomide Capsules 100 mg: lactose anhydrous (61.20 mg), colloidal silicon dioxide (0.80 mg), sodium starch glycolate (9.00 mg), tartaric acid (3.60 mg), and stearic acid (5.40 mg). Temozolomide Capsules 140 mg: lactose anhydrous (85.68 mg), colloidal silicon dioxide (1.12 mg), sodium starch glycolate (12.60 mg), tartaric acid (5.04 mg), and stearic acid (7.56 mg). Temozolomide Capsules 180 mg: lactose anhydrous (110.16 mg), colloidal silicon dioxide (1.44 mg), sodium starch glycolate (16.20 mg), tartaric acid (6.48 mg), and stearic acid (9.72 mg). Temozolomide Capsules 250 mg: lactose anhydrous (153.00 mg), colloidal silicon dioxide (2.00 mg), sodium starch glycolate (22.50 mg), tartaric acid (9.00 mg), and stearic acid (13.50 mg). The body of the capsules is made of gelatin and is opaque white with the dosage strength imprinted on them. The cap is also made of gelatin, imprinted with “NSP”, 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, strong ammonia solution, black iron oxide, and purified water. Temozolomide Capsules 5 mg: The green opaque cap contains Indigotine FD&C Blue #2, iron oxide yellow, gelatin and titanium dioxide. Temozolomide Capsules 20 mg: The yellow opaque cap contains yellow iron oxide, gelatin and titanium dioxide. Temozolomide Capsules 100 mg: The purple cap contains FD&C Blue #2, gelatin, iron oxide red, and titanium dioxide. Temozolomide Capsules 140 mg: The blue cap contains FD&C Blue #2, gelatin, and titanium dioxide. Temozolomide Capsules 180 mg: The orange cap contains gelatin, iron oxide red, iron oxide yellow, and titanium dioxide. Temozolomide Capsules 250 mg: The white cap contains gelatin and titanium dioxide.
Mechanism of action
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 DNA alkylation, mainly at the O6 and N7 positions of guanine, which causes DNA double strand breaks and results in programmed cell death. 12.2 Pharmacodynamics Temozolomide exposure-response relationships and the time course of pharmacodynamic response are unknown.
How supplied
Temozolomide is a hazardous drug. Follow applicable special handling and disposal procedures.1 Temozolomide Capsules, USP Temozolomide Capsules, USP are supplied in sachets containing the following capsule strengths: Temozolomide Capsules 5 mg: have opaque white bodies with opaque green caps. The cap is imprinted with “NSP” and the capsule body is imprinted with “5 mg” in black ink. They are supplied as follows: 5-count - NDC 70301-2001-1 14-count - NDC 70301-2001-2 Temozolomide Capsules 20 mg: have opaque white bodies with opaque yellow caps. The cap is imprinted with “NSP” and the capsule body is imprinted with “20 mg” in black ink. They are supplied as follows: 5-count - NDC 70301-2003-1 14-count - NDC 70301-2003-2 Temozolomide Capsules 100 mg: have opaque white bodies with opaque purple caps. The cap is imprinted with “NSP” and the capsule body is imprinted with “100 mg” in black ink. They are supplied as follows: 5-count - NDC 70301-2005-1 14-count - NDC 70301-2005-2 Temozolomide Capsules 140 mg: have opaque white bodies with opaque blue caps. The cap is imprinted with “NSP” and the capsule body is imprinted with “140 mg” in black ink. They are supplied as follows: 5-count - NDC 70301-2007-1 14-count - NDC 70301-2007-2 Temozolomide Capsules 180 mg: have opaque white bodies with opaque orange caps. The cap is imprinted with “NSP” and the capsule body is imprinted with “180 mg” in black ink. They are supplied as follows: 5-count - NDC 70301-2009-1 14-count - NDC 70301-2009-2 Temozolomide Capsules 250 mg: have opaque white bodies with opaque white caps. The cap is imprinted with “NSP” and the capsule body is imprinted with “250 mg” in black ink. They are supplied as follows: 5-count - NDC 70301-2011-1 Store Temozolomide Capsules at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].
Patient information
Advise the patient to read the FDA-approved patient labeling (Patient Information). Myelosuppression Inform patients that Temozolomide can cause low blood cell counts and the need for frequent monitoring of blood cell counts. Advise patients to contact their healthcare provider immediately for bleeding, fever, or other signs of infection [see Warnings and Precautions (5.1)]. Hepatotoxicity Advise patients of the increased risk of hepatotoxicity and to contact their healthcare provider immediately for signs or symptoms of hepatotoxicity. Inform patients that they will have periodic liver enzyme tests during treatment and following the last dose of Temozolomide [see Warnings and Precautions (5.2)]. Pneumocystis Pneumonia Advise 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)]. Secondary Malignancies Advise patients of the increased risk of myelodysplastic syndrome and secondary malignancies [see Warnings and Precautions (5.4)]. Exposure to Opened Capsules Advise patient to not open, chew, or dissolve the 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 [see Warnings and Precautions (5.6)]. In case of powder contact, wash the affected area with water immediately [see Dosage and Administration (2.4)]. Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.5), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Temozolomide and for 6 months after the last dose [see Use in Specific Populations (8.3)]. Advise male patients with pregnant partners or female partners of reproductive potential to use condoms during treatment with Temozolomide and for 3 months after the last dose [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)]. Advise male patients not to donate semen during treatment with Temozolomide and for 3 months after the last dose [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)]. Lactation Advise women not to breastfeed during treatment with Temozolomide and for 1 week after the last dose [see Use in Specific Populations (8.2)]. Infertility Advise males of reproductive potential that Temozolomide may impair fertility [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)]. Manufactured by: Eirgen Pharma Ltd. Waterford, Ireland Distributed by: OPKO Pharmaceuticals, LLC, 4400 Biscayne Blvd., Miami, FL 33137 Made in Ireland PC PC2748 Rev. 02/2026
Label text from the FDA structured product label by OPKO Pharmaceuticals, LLC (revised Aug 27, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Temozolomide in 64 products
Temozolomide NDC products (64)
Temozolomide recalls
- D-0384-2026 Mar 11, 2026 · Class II · Ongoing
Failed Impurities/Degradation Specifications: An out-of-specification result observed during 9th-month long term stability testing - D-1508-2019 Jul 31, 2019 · Class II · Terminated
CGMP Deviations: product was manufactured that did not prevent possible cross contamination with beta lactam products. - D-1509-2019 Jul 31, 2019 · Class II · Terminated
CGMP Deviations: product was manufactured that did not prevent possible cross contamination with beta lactam products. - D-1510-2019 Jul 31, 2019 · Class II · Terminated
CGMP Deviations: product was manufactured that did not prevent possible cross contamination with beta lactam products. - D-1511-2019 Jul 31, 2019 · Class II · Terminated
CGMP Deviations: product was manufactured that did not prevent possible cross contamination with beta lactam products. - D-1512-2019 Jul 31, 2019 · Class II · Terminated
CGMP Deviations: product was manufactured that did not prevent possible cross contamination with beta lactam products. - D-1513-2019 Jul 31, 2019 · Class II · Terminated
CGMP Deviations: product was manufactured that did not prevent possible cross contamination with beta lactam products.
Frequently asked questions
What is Temozolomide used for?
Temozolomide is 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…
What are the side effects of Temozolomide?
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,… See the full label for the complete list.
Who makes Temozolomide?
Temozolomide is listed by 11 labelers in the FDA NDC directory, including Accord Healthcare Inc., Amneal Pharmaceuticals LLC, Ascend Laboratories, LLC, Bryant Ranch Prepack.
Has Temozolomide been recalled?
The FDA enforcement database lists 7 recalls for Temozolomide, most recently D-0384-2026 (class ii): Failed Impurities/Degradation Specifications: An out-of-specification result observed during 9th-month long term stability testing