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Temozolomide capsules are indicated for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment.
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.
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 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 /L, platelet count ≥100 x 10 /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
*Treatment with concomitant TMZ could be continued when all of the following conditions were met: absolute neutrophil count ≥1.5 x 10 /L; platelet count ≥100 x 10 /L; CTC nonhematological toxicity ≤Grade 1 (except for alopecia, nausea, vomiting). TMZ=temozolomide; CTC=Common Toxicity Criteria.
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 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 , 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 /L, and the platelet count is ≥100 x 10 /L. The dose remains at 200 mg/m 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 /L (1500/μL) and the platelet count exceeds 100 x 10 /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
TABLE 3: Temozolomide Dose Reduction or Discontinuation During Maintenance Treatment
*TMZ dose levels are listed in Table 2.
TMZ is to be discontinued if dose reduction to <100 mg/m 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 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 /L (1500/μL) and both the nadir and Day 29, Day 1 of next cycle platelet counts are ≥100 x 10 /L (100,000/μL), the temozolomide capsules dose may be increased to 200 mg/m /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 /L (1500/μL) and the platelet count exceeds 100 x 10 /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 /L (1000/μL) or the platelet count is <50 x 10 /L (50,000/μL) during any cycle, the next cycle should be reduced by 50 mg/m , but not below 100 mg/m , 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)
TABLE 6: Suggested Capsule Combinations Based on Daily Dose in Adults
|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|
|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|
|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 †|
(m 2 )
|Number of Daily Capsules by Strength (mg)|
|Total Daily Dose (mg)||250 mg||180 mg||140 mg||100 mg||20 mg||5 mg|
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) ].
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).
Patients treated with temozolomide may experience myelosuppression, including prolonged pancytopenia, which may result in aplastic anemia, which in some cases has resulted in a fatal outcome. In some cases, exposure to concomitant medications associated with aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to dosing, patients must have an absolute neutrophil count (ANC) ≥1.5 x 10 /L and a platelet count ≥100 x 10 /L. 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 /L and platelet count exceeds 100 x 10 /L. Geriatric patients and women have been shown in clinical trials to have a higher risk of developing myelosuppression.
Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed.
For treatment of newly diagnosed glioblastoma multiforme: Prophylaxis against Pneumocystis pneumonia (PCP) is required for all patients receiving concomitant temozolomide and radiotherapy for the 42-day regimen.
There may be a higher occurrence of PCP when temozolomide is administered during a longer dosing regimen. However, all patients receiving temozolomide, particularly patients receiving steroids, should be observed closely for the development of PCP regardless of the regimen.
For the concomitant treatment phase with RT, a complete blood count should be obtained prior to initiation of treatment and weekly during treatment.
For the 28-day treatment cycles, a complete blood count should be obtained prior to treatment on Day 1 and on Day 22 (21 days after the first dose) of each cycle. Blood counts should be performed weekly until recovery if the ANC falls below 1.5 x 10 /L and the platelet count falls below 100 x 10 /L [see Recommended Dosing and Dose Modification Guidelines (2.1) ].
Fatal and severe hepatotoxicity have been reported in patients receiving temozolomide. Perform liver function 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.
Temozolomide can cause fetal harm when administered to a pregnant woman. Administration of temozolomide to rats and rabbits during organogenesis at 0.38 and 0.75 times the maximum recommended human dose (75 and 150 mg/m ), respectively, caused numerous fetal malformations of the external organs, soft tissues, and skeleton in both species [see Use in Specific Populations (8.1) ].
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)
*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% )
*Blurred vision; visual deficit; vision changes; vision troubles
TABLE 9: Adverse Hematologic Effects (Grade 3 to 4) in the Anaplastic Astrocytoma
Trial in Adults
*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.
|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|
|Central and Peripheral Nervous System Disorders|
|Disorders of the Eye|
|Disorders of the Immune System|
|Gastrointestinal System Disorders|
|Injury and Poisoning|
|Radiation Injury NOS||11||(4)||1||(<1)||20||(7)||0||5||(2)||0|
|Musculoskeletal System Disorders|
|Platelet, Bleeding and Clotting Disorders|
|Respiratory System Disorders|
|Skin and Subcutaneous Tissue Disorders|
|Special Senses Other, Disorders|
No. (%) of Temozolomide
|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)|
|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)|
|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)|
|Adrenal hypercorticism||13 (8)||0|
|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)|
|Weight increase||8 (5)||0|
|Anxiety||11 (7)||1 (1)|
|Breast pain, female||4 (6)|
|Resistance Mechanism Disorders|
|Infection viral||17 (11)||0|
|Upper respiratory tract infection||13 (8)||0|
|Skin and Appendages|
|Pruritus||12 (8)||2 (1)|
|Urinary tract infection||12 (8)||0|
|Micturition increased frequency||9 (6)||0|
|Vision abnormal*||8 (5)|
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.
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) ].
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 ) 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 ) 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.
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.
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 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%)
*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.
No. (%) of Temozolomide
|Body System/Organ Class||All Reactions||Grade 3/4|
|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)|
|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)|
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).
Caution should be exercised when temozolomide is administered to patients with severe renal impairment [see Clinical Pharmacology (12.3) ].
Caution should be exercised when temozolomide is administered to patients with severe hepatic impairment [see Clinical Pharmacology (12.3) ].
Doses of 500, 750, 1000, and 1250 mg/m (total dose per cycle over 5 days) have been evaluated clinically in patients. Dose-limiting toxicity was hematologic 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 bone marrow suppression, which in some cases was severe and prolonged, and infections and resulted in death. In the event of an overdose, hematologic evaluation is needed. Supportive measures should be provided as necessary.
Temozolomide capsules contain temozolomide, an imidazotetrazine derivative. The chemical name of temozolomide is 3,4-dihydro-3-methyl-4-oxoimidazo[5,1d]-as-tetrazine-8-carboxamide. The structural formula is:
The material is a white to light tan/light pink powder with a molecular formula of C H N O and a molecular weight of 194.15. The molecule is stable at acidic pH (<5) and labile at pH >7; hence temozolomide can be administered orally and intravenously. The prodrug, temozolomide, is rapidly hydrolyzed to the active 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) at neutral and alkaline pH values, with hydrolysis taking place even faster at alkaline pH.
Each capsule for oral use contains either 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 mg of temozolomide.
The inactive ingredients for temozolomide capsules are as follows: colloidal silicon dioxide, ethyl alcohol, lactose anhydrous, sodium starch glycolate, stearic acid and tartaric acid.
The body of the capsules are made of gelatin and titanium dioxide, and are white opaque color. The cap is also made of gelatin, and the colors vary based on the dosage strength. The capsule body and cap are imprinted with pharmaceutical branding ink, which contains alcohol, D&C Yellow #10, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, iron oxide black, n-butyl alcohol, propylene glycol and shellac.
Temozolomide Capsules 5 mg : The green cap contains FD&C Blue #2, gelatin, titanium dioxide and yellow iron oxide.
Temozolomide Capsules 20 mg : The yellow cap contains D&C Yellow #10, FD&C Yellow #6, gelatin and titanium dioxide.
Temozolomide Capsules 100 mg : The pink cap contains FD&C Blue #1, FD&C Red #3, FD&C Red #40, gelatin and titanium dioxide.
Temozolomide Capsules 140 mg : The blue cap contains FD&C Blue #1, gelatin and titanium dioxide.
Temozolomide Capsules 180 mg : The red cap contains FD&C Blue #1, FD&C Red #40, gelatin and titanium dioxide.
Temozolomide Capsules 250 mg : The white cap contains gelatin and titanium dioxide.
Temozolomide is not directly active but undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound 5-(3-methyltriazen1-yl)-imidazole-4-carboxamide (MTIC). The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA. Alkylation (methylation) occurs mainly at the O and N positions of guanine.
Absorption: Temozolomide is rapidly and completely absorbed after oral administration with a peak plasma concentration (C ) achieved in a median T of 1 hour. Food reduces the rate and extent of temozolomide absorption. Mean peak plasma concentration and AUC decreased by 32% and 9%, respectively, and median T increased by 2-fold (from 1 to 2.25 hours) when temozolomide was administered after a modified high-fat breakfast.
Following a single oral dose of 150 mg/m , the geometric mean C values for temozolomide and MTIC were 7.5 mcg/mL and 282 ng/mL, respectively. Following a single oral dose of 150 mg/m , the geometric mean AUC values for temozolomide and MTIC were 23.4 mcg·hr/mL and 864 ng·hr/mL, respectively.
Distribution: Temozolomide has a mean apparent volume of distribution of 0.4 L/kg (%CV=13%). It is weakly bound to human plasma proteins; the mean percent bound of drug-related total radioactivity is 15%.
Metabolism and Elimination: Temozolomide is spontaneously hydrolyzed at physiologic pH to the active species, MTIC and to temozolomide acid metabolite. MTIC is further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC), which is known to be an intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. Cytochrome P450 enzymes play only a minor role in the metabolism of temozolomide and MTIC. Relative to the AUC of temozolomide, the exposure to MTIC and AIC is 2.4% and 23%, respectively.
Excretion: About 38% of the administered temozolomide total radioactive dose is recovered over 7 days: 37.7% in urine and 0.8% in feces. The majority of the recovery of radioactivity in urine is unchanged temozolomide (5.6%), AIC (12%), temozolomide acid metabolite (2.3%), and unidentified polar metabolite(s) (17%). Overall clearance of temozolomide is about 5.5 L/hr/m . Temozolomide is rapidly eliminated, with a mean elimination half-life of 1.8 hours, and exhibits linear kinetics over the therapeutic dosing range of 75 to 250 mg/m /day.
Effect of Age: A population pharmacokinetic analysis indicated that age (range: 19 to 78 years) has no influence on the pharmacokinetics of temozolomide.
Effect of Gender: A population pharmacokinetic analysis indicated that women have an approximately 5% lower clearance (adjusted for body surface area) for temozolomide than men.
Effect of Race: The effect of race on the pharmacokinetics of temozolomide has not been studied.
Tobacco Use: A population pharmacokinetic analysis indicated that the oral clearance of temozolomide is similar in smokers and nonsmokers.
Effect of Renal Impairment: A population pharmacokinetic analysis indicated that creatinine clearance over the range of 36 to 130 mL/min/m has no effect on the clearance of temozolomide after oral administration. The pharmacokinetics of temozolomide have not been studied in patients with severely impaired renal function (CLcr <36 mL/min/m ). Caution should be exercised when temozolomide is administered to patients with severe renal impairment [see Use in Special Populations (8.6) ]. Temozolomide has not been studied in patients on dialysis.
Effect of Hepatic Impairment: A study showed that the pharmacokinetics of temozolomide in patients with mild-to-moderate hepatic impairment (Child-Pugh Class I - II) were similar to those observed in patients with normal hepatic function. Caution should be exercised when temozolomide is administered to patients with severe hepatic impairment [see Use in Specific Populations (8.7) ].
Effect of Other Drugs on Temozolomide Pharmacokinetics: In a multiple-dose study, administration of temozolomide capsules with ranitidine did not change the C or AUC values for temozolomide or MTIC.
A population analysis indicated that administration of valproic acid decreases the clearance of temozolomide by about 5% [see Drug Interactions (7.1) ].
A population analysis did not demonstrate any influence of coadministered dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H -receptor antagonists, or phenobarbital on the clearance of orally administered temozolomide.
Temozolomide is carcinogenic in rats at doses less than the maximum recommended human dose. Temozolomide induced mammary carcinomas in both males and females at doses 0.13 to 0.63 times the maximum human dose (25 to 125 mg/m ) when administered orally on 5 consecutive days every 28 days for 6 cycles. Temozolomide also induced fibrosarcomas of the heart, eye, seminal vesicles, salivary glands, abdominal cavity, uterus, and prostate, carcinomas of the seminal vesicles, schwannomas of the heart, optic nerve, and harderian gland, and adenomas of the skin, lung, pituitary, and thyroid at doses 0.5 times the maximum daily dose. Mammary tumors were also induced following 3 cycles of temozolomide at the maximum recommended daily dose.
Temozolomide is a mutagen and a clastogen. In a reverse bacterial mutagenesis assay (Ames assay), temozolomide increased revertant frequency in the absence and presence of metabolic activation. Temozolomide was clastogenic in human lymphocytes in the presence and absence of metabolic activation.
Temozolomide impairs male fertility. Temozolomide caused syncytial cells/immature sperm formation at 0.25 and 0.63 times the maximum recommended human dose (50 and 125 mg/m ) in rats and dogs, respectively, and testicular atrophy in dogs at 0.63 times the maximum recommended human dose (125 mg/m ).
Toxicology studies in rats and dogs identified a low incidence of hemorrhage, degeneration, and necrosis of the retina at temozolomide doses equal to or greater than 0.63 times the maximum recommended human dose (125 mg/m ). These changes were most commonly seen at doses where mortality was observed.
Five hundred and seventy-three patients were randomized to receive either temozolomide (TMZ)+Radiotherapy (RT) (n=287) or RT alone (n=286). Patients in the temozolomide+RT arm received concomitant temozolomide (75 mg/m ) once daily, starting the first day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 6 cycles of temozolomide alone (150 or 200 mg/m ) on Days 1 to 5 of every 28-day cycle, starting 4 weeks after the end of RT. Patients in the control arm received RT only. In both arms, focal radiation therapy was delivered as 60 Gy/30 fractions. Focal RT includes the tumor bed or resection site with a 2- to 3- cm margin. Pneumocystis pneumonia (PCP) prophylaxis was required during the TMZ + RT, regardless of lymphocyte count, and was to continue until recovery of lymphocyte count to less than or equal to Grade 1.
At the time of disease progression, temozolomide was administered as salvage therapy in 161 patients of the 282 (57%) in the RT alone arm, and 62 patients of the 277 (22%) in the temozolomide+RT arm.
The addition of concomitant and maintenance temozolomide to radiotherapy in the treatment of patients with newly diagnosed GBM showed a statistically significant improvement in overall survival compared to radiotherapy alone ( Figure 1). The hazard ratio (HR) for overall survival was 0.63 (95% CI for HR=0.52 to 0.75) with a log-rank P<0.0001 in favor of the temozolomide arm. The median survival was increased by 2.5 months in the temozolomide arm.
FIGURE 1: Kaplan-Meier Curves for Overall Survival (ITT Population)
A single-arm, multicenter study was conducted in 162 patients who had anaplastic astrocytoma at first relapse and who had a baseline Karnofsky performance status of 70 or greater. Patients had previously received radiation therapy and may also have previously received a nitrosourea with or without other chemotherapy. Fifty-four patients had disease progression on prior therapy with both a nitrosourea and procarbazine, and their malignancy was considered refractory to chemotherapy (refractory anaplastic astrocytoma population). Median age of this subgroup of 54 patients was 42 years (19 to 76). Sixty-five percent were male. Seventy-two percent of patients had a KPS of >80. Sixty-three percent of patients had surgery other than a biopsy at the time of initial diagnosis. Of those patients undergoing resection, 73% underwent a subtotal resection and 27% underwent a gross total resection. Eighteen percent of patients had surgery at the time of first relapse. The median time from initial diagnosis to first relapse was 13.8 months (4.2 to 75.4).
Temozolomide capsules were given for the first 5 consecutive days of a 28-day cycle at a starting dose of 150 mg/m /day. If the nadir and day of dosing (Day 29, Day 1 of next cycle) absolute neutrophil count was ≥1.5 x 10 /L (1500/μL) and the nadir and Day 29, Day 1 of next cycle platelet count was ≥100 x 10 /L (100,000/μL), the temozolomide dose was increased to 200 mg/m /day for the first 5 consecutive days of a 28-day cycle.
In the refractory anaplastic astrocytoma population, the overall tumor response rate (CR + PR) was 22% (12/54 patients) and the complete response rate was 9% (5/54 patients). The median duration of all responses was 50 weeks (range: 16 to 114 weeks) and the median duration of complete responses was 64 weeks (range: 52 to 114 weeks). In this population, progression-free survival at 6 months was 45% (95% CI: 31% to 58%) and progression-free survival at 12 months was 29% (95% CI: 16% to 42%). Median progression-free survival was 4.4 months. Overall survival at 6 months was 74% (95% CI: 62% to 86%) and 12-month overall survival was 65% (95% CI: 52% to 78%). Median overall survival was 15.9 months.
Care should be exercised in the handling and preparation of temozolomide. Capsules should not be opened. If capsules are accidentally opened or damaged, rigorous precautions should be taken with the contents to avoid inhalation or contact with the skin or mucous membranes. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the capsules. Procedures for proper handling and disposal of anticancer drugs should be considered . Several guidelines on this subject have been published.
Temozolomide capsules 5 mg are supplied as size “3” hard gelatin capsules with green opaque color caps imprinted “AMNEAL” and white opaque color bodies imprinted “801” with black ink.
Temozolomide capsules 20 mg are supplied as size “2” hard gelatin capsules with yellow opaque color caps imprinted “AMNEAL” and white opaque color bodies imprinted “802” with black ink. They are available as follows:
NDC 50268-761-12 (5 capsules per card, 4 cards per carton).
Temozolomide capsules 100 mg are supplied as size “1” hard gelatin capsules with pink opaque color caps imprinted “AMNEAL” and white opaque color bodies imprinted “803” with black ink.They are available as follows:
NDC 50268-762-12 (5 capsules per card, 4 cards per carton).
Temozolomide capsules 140 mg are supplised as size “0” hard gelatin capsules with blue opaque color caps imprinted “AMNEAL” and white opaque color bodies imprinted “804” with black ink.
They are available as follows:
NDC 50268-763-12 (5 capsules per card, 4 cards per carton).
Temozolomide capsules 180 mg are supplied as size “0” hard gelatin capsules with red opaque color caps imprinted “AMNEAL” and white opaque color bodies imprinted “805” with black ink.
Temozolomide capsules 250 mg are supplied as size “0” hard gelatin capsules with white opaque color caps imprinted “AMNEAL” and white opaque color bodies imprinted “806” with black ink.
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].
See FDA-Approved Patient Labeling (Patient Information).
Physicians should discuss the following with their patients:
Temozolomide (TEM-oh-ZOE-loe-mide) Capsules
What is the most important information I should know about temozolomide?
What should I tell my doctor before taking temozolomide?
Tell your doctor about all your medical conditions, including if you:
Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take a medicine that contains valproic acid (Stavzor , Depakene ).
Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.
How should I take temozolomide?
Temozolomide may be taken by mouth as a capsule at home.
There are two common dosing schedules for taking temozolomide.
What should I avoid while taking temozolomide?
Your doctor will check your blood regularly while you are taking temozolomide to see if these side effects are happening. Your doctor may need to change the dose of temozolomide or when you get it depending on your blood cell counts. People who are age 70 or older and women may be more likely to have their blood cells affected.
Tell your doctor about any side effect that bothers you or that does not go away.
These are not all the possible side effects with temozolomide. For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store temozolomide capsules?
General information about temozolomide.
Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use temozolomide for a condition for which it was not prescribed. Do not give temozolomide to other people, even if they have the same symptoms that you have. It may harm them.
This leaflet summarizes the most important information about temozolomide. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about temozolomide that is written for health professionals.
For more information, go to www.avkare.com or call 1-855-361-3993.
How are temozolomide capsules supplied?
Temozolomide capsules contain a white capsule body with a color cap and the colors vary based on the dosage strength. The capsules are available in six different strengths.
Temozolomide Capsule Strength Color
5 mg Green Cap
20 mg Yellow Cap
100 mg Pink Cap
140 mg Blue Cap
180 mg Red Cap
250 mg White Cap
What are the ingredients in temozolomide capsules?
Active ingredient: temozolomide.
Inactive ingredients: colloidal silicon dioxide, ethyl alcohol, lactose anhydrous, sodium starch glycolate, stearic acid and tartaric acid.
The body of the capsules are made of gelatin and titanium dioxide and are opaque white. The cap is also made of gelatin, and the colors vary based on the dosage strength. The capsule body and cap are imprinted with pharmaceutical branding ink, which contains alcohol, D&C Yellow #10, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, iron oxide black, n-butyl alcohol, propylene glycol and shellac.
Temozolomide Capsules 5 mg: The green cap contains FD&C Blue #2, gelatin, titanium dioxide and yellow iron oxide.
Temozolomide Capsules 20 mg: The yellow cap contains D&C Yellow #10, FD&C Yellow #6, gelatin and titanium dioxide.
Temozolomide Capsules 100 mg: The pink cap contains FD&C Blue #1, FD&C Red #3, FD&C Red #40, gelatin and titanium dioxide.
Temozolomide Capsules 140 mg: The blue cap contains FD&C Blue #1, gelatin and titanium dioxide.
Temozolomide Capsules 180 mg: The red cap contains FD&C Blue #!, FD&C Red #40, gelatin and titanium dioxide.
Temozolomide Capsules 250 mg: The white cap contains gelatin and titanium dioxide.
*The trademarks depicted in this piece are owned by their respective companies.
Manufactured for: AvKARE, Inc. Pulaski, TN 38478Mfg. Rev. 10-2015-01 AV 09/16 (P) AvPAK
NDC 50268-761-12 Temozolomide Capsules 20 mg For Oral Administration Cytotoxic - Read accompanying directions carefully Rx Only 20 Capsules (4 x 5) Unit Dose 5026876112 NDC 50268-761-12 Temozolomide Capsules 20 mg For Oral Administration Cytotoxic - Read accompanying directions carefully Rx Only 20 Capsules (4 x 5) Unit Dose 5026876112 Each capsule contains: 20 mg temozolomide. Usual Dose: See package insert for recommendations regarding the use of varying capsule strengths in establishing a daily regimen. Store 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]. Dispense in tight, light-resistant containers as defined in the USP. Manufactured for: AvKARE, Inc. Pulaski, TN 38478 AvPAK A Product of AvKARE MFg. Rev. 10-2015-01 AV 09/16 (P)
NDC 50268-762-12 Temozolomide Capsules 100 mg For Oral Administration Cytotoxic - Read accompanying directions carefully Rx Only 20 Capsules (4 x 5) Unit Dose 5026876212 NDC 50268-762-12 Temozolomide Capsules 100 mg For Oral Administration Cytotoxic - Read accompanying directions carefully Rx Only 20 Capsules (4 x 5) Unit Dose 5026876212 Each capsule contains: 100 mg temozolomide. Usual Dose: See package insert for recommendations regarding the use of varying capsule strengths in establishing a daily regimen. Store 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]. Dispense in tight, light-resistant containers as defined in the USP. Manufactured for: AvKARE, Inc. Pulaski, TN 38478 AvPAK A Product of AvKARE Mfg. Rev. 10-2015-01 AV 09/16 (P)
NDC 50268-763-12 Temozolomide Capsules 140 mg For Oral Administration Cytotoxic - Read accompanying directions carefully Rx Only 20 Capsules (4 x 5) Unit Dose 5026876312 NDC 50268-763-12 Temozolomide Capsules 140 mg For Oral Administration Cytotoxic - Read accompanying directions carefully Rx Only 20 Capsules (4 x 5) Unit Dose 5026876312 Each capsule contains: 140 mg temozolomide. Usual Dose: See package insert for recommendations regarding the use of varying capsule strengths in establishing a daily regimen. Store 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]. Dispense in tight, light-resistant containers as defined in the USP. Manufactured for: AvKARE, Inc. Pulaski, TN 38478 AvPAK A Product of AvKARE Mfg Rev. 10-2015-01 AV 09/16 (P)
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