Temozolomide Drug Information
Generic name: TEMOZOLOMIDE
Alkylating Drug [EPC]
Uses of Temozolomide
Newly Diagnosed Glioblastoma
TEMOZOLOMIDE Capsules is indicated for the treatment of adults with newly diagnosed glioblastoma, concomitantly with radiotherapy and then as maintenance treatment.
Anaplastic Astrocytoma
TEMOZOLOMIDE Capsules is indicated for the: adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma; treatment of adults with refractory anaplastic astrocytoma.
Dosage & Administration of Temozolomide
| Withhold TEMOZOLOMIDE if ANC is greater than or equal to 0.5 x 109/L and less than 1.5 x 109/L.Resume TEMOZOLOMIDE when ANC is greater than or equal to 1.5 x 109/L. | |
| Withhold TEMOZOLOMIDE if platelet count is greater than or equal to 10 x 109/L and less than 100 x 109/L.Resume TEMOZOLOMIDE when platelet count is greater than or equal to 100 x 109/L. | |
| Withhold TEMOZOLOMIDE if Grade 2 adverse reaction occurs.Resume TEMOZOLOMIDE when resolution to Grade 1 or less. |
Side Effects of Temozolomide
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. Severe or life-threatening adverse reactions occurred in 49% of patients treated with TEMOZOLOMIDE; the most common were fatigue (13%), convulsions (6%), headache (5%), and thrombocytopenia (5%). The most common adverse reactions (≥20%) in patients treated with TEMOZOLOMIDE were alopecia, fatigue, nausea, anorexia, headache, constipation, and vomiting. Table 3 summarizes the adverse reactions in MK-7365-051 TABLE 3: Adverse Reactions (≥10%) in Patients with Newly Diagnosed Glioblastoma Adverse Reactions Concomitant Use Phase Maintenance Use Phase Radiation Therapy and TEMOZOLOMIDE N=288* Radiation Therapy Alone N=285 TEMOZOLOMIDE N=224 All Grades (%) Grade ≥3 (%) All Grades (%) Grades ≥3 (%) All Grades (%) Grade ≥3 (%) Skin and Subcutaneous Tissue Alopecia 69 0 63 0 55 0 Rash 19 1 15 0 13 1 General Fatigue 54 7 49 5 61 9 Anorexia 19 1 9 <1 27 1 Headache 19 2 17 4 23 4 Gastrointestinal System Nausea 36 1 16 <1 49 1 Vomiting 20 <1 6 <1 29 2 Constipation 18 1 6 0 22 0 Diarrhea 6 0 3 0 10 1 Central and Peripheral Nervous System Convulsions 6 3 7 3 11 3 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. 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. The most common adverse reactions (≥20%) were nausea, vomiting, headache, fatigue, constipation, and convulsions.
Tables 4 and 5 summarize the adverse reactions and hematological laboratory abnormalities in MK-7365-006. TABLE 4: Adverse Reactions (≥10%) in Patients with Refractory Anaplastic Astrocytoma Trial Adverse Reactions TEMOZOLOMIDE N=158 All Reactions (%) Grades 3-4 (%) Gastrointestinal System Nausea 53 10 Vomiting 42 6 Constipation 33 1 Diarrhea 16 2 General Headache 41 6 Fatigue 34 4 Asthenia 13 6 Fever 13 2 Central and Peripheral Nervous System Convulsions 23 5 Hemiparesis 18 6 Dizziness 12 1 Coordination abnormal 11 1 Amnesia 10 4 Insomnia 10 0 Cardiovascular Edema peripheral 11 1 Resistance Mechanism Infection viral 11 0 Clinically relevant adverse reactions in <10% of patients are presented below: Central and Peripheral Nervous System: paresthesia, somnolence, paresis, urinary incontinence, ataxia, dysphasia, convulsions local, gait abnormal, confusion Endocrine: adrenal hypercorticism Gastrointestinal System: abdominal pain, anorexia General: back pain Metabolic: weight increase Musculoskeletal System: myalgia Psychiatric : anxiety, depression Reproductive Disorders: breast pain female Respiratory System: upper respiratory tract infection, pharyngitis, sinusitis, coughing Skin & Appendages: rash, pruritus Urinary System: urinary tract infection, micturition increased frequency Vision: diplopia, vision abnormal 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. †Denominator range= 142, 158 Hematological Toxicities for Advanced Gliomas: In clinical trial experience with 110 to 111 females and 169 to 174 males (depending on measurements), females experienced higher rates of Grade 4 neutropenia (ANC < 0.5 x 10 9 /L) and thrombocytopenia (< 20 x 10 9 /L) than males in the first cycle of therapy (12% vs. 5% and 9% vs. 3%, respectively). In the entire safety database for which hematologic data exist (N=932), 7% (4/61) and 10% (6/63) of patients > 70 years experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. For patients ≤ 70 years, 7% (62/871) and 6% (48/879) experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively.
Pancytopenia, leukopenia, and anemia also occurred.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of TEMOZOLOMIDE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug exposure. Dermatologic: Toxic epidermal necrolysis and Stevens-Johnson syndrome Immune System: Hypersensitivity reactions, including anaphylaxis. Erythema multiforme, which resolved after discontinuation of TEMOZOLOMIDE and, in some cases, recurred upon rechallenge.
Hematopoietic: Prolonged pancytopenia, which may result in aplastic anemia and fatal outcomes. Hepatobiliary : Fatal and severe hepatotoxicity, elevation of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis Infections: Serious opportunistic infections, including some cases with fatal outcomes, with bacterial, viral (primary and reactivated), fungal, and protozoan organisms. Pulmonary: Interstitial pneumonitis, pneumonitis, alveolitis, and pulmonary fibrosis.
Endocrine : Diabetes insipidus
Warnings & Cautions for Temozolomide
Myelosuppression Myelosuppression, including pancytopenia, leukopenia and anemia, some with fatal outcomes, have
occurred with TEMOZOLOMIDE . 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 . For severe myelosuppression, withhold TEMOZOLOMIDE and then resume at same or reduced dose, or permanently discontinue, based on occurrence.
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.
Pneumocystis Pneumonia Pneumocystis pneumonia (PCP) can occur 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 in patients who experience lymphopenia until resolution to Grade 1 or less. Monitor all patients receiving TEMOZOLOMIDE for the development of lymphopenia and PCP.
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.
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.
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 . 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.
Pregnancy Safety for Temozolomide
Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action TEMOZOLOMIDE can cause fetal harm when administered to a pregnant woman. Available postmarketing reports describe cases of spontaneous abortions and congenital malformations, including polymalformations with central nervous system, facial, cardiac, skeletal, and genitourinary system anomalies with exposure to TEMOZOLOMIDE during pregnancy. These cases report similar adverse developmental outcomes to those observed in animal studies.
Administration of TEMOZOLOMIDE to rats and rabbits during the period of organogenesis caused numerous external, internal, and skeletal malformations at doses less than the maximum human dose based on body surface area (see Data). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Five consecutive days of oral administration of temozolomide at doses of 75 and 150 mg/m 2 (0.38 and 0.75 times the human dose of 200 mg/m 2 ) in rats and rabbits, respectively, during the period of organogenesis (Gestation Days 8-12) caused numerous malformations of the external and internal organs and skeleton in both species.
In rabbits, temozolomide at the 150 mg/m 2 dose (0.75 times the human dose of 200 mg/m 2 ) caused embryolethality as indicated by increased resorptions.
Pediatric Use of Temozolomide
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, high grade astrocytoma, low grade astrocytoma, brain stem glioma, ependymoma, other CNS tumors, and non-CNS tumors. The adverse reaction profile in pediatric patients was similar to adults.
Contraindications for Temozolomide
- 4. CONTRAINDICATIONS TEMOZOLOMIDE is contraindicated in patients with a history of hypersensitivity reactions to:
- temozolomide or any other ingredients in TEMOZOLOMIDE; 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 hypersensitivity to temozolomide or any other ingredients in TEMOZOLOMIDE capsules and dacarbazine. ( 4 )
Overdosage Information for Temozolomide
10. OVERDOSAGE Dose-limiting toxicity was myelosuppression and was reported with any dose but is expected to be more severe at higher doses. An overdose of 2000 mg per day for 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.
Clinical Studies of Temozolomide
Newly Diagnosed Glioblastoma
The efficacy of TEMOZOLOMIDE was evaluated in MK-7365-051 (NCT00006353), a randomized (1:1), multicenter, open-label trial. Eligible patients were required to have newly diagnosed glioblastoma. Patients were randomized to receive either radiation therapy alone or concomitant TEMOZOLOMIDE 75 mg/m 2 once daily starting the first day of radiation therapy and continuing until the last day of radiation therapy for 42 days (with a maximum of 49 days), followed by TEMOZOLOMIDE 150 mg/m 2 or 200 mg/m 2 once daily on Days 1 to 5 of each 28-day cycle, starting 4 weeks after the end of radiation therapy and continuing for 6 cycles.
In both arms, focal radiation therapy was delivered as 60 Gy/30 fractions and included radiation to the tumor bed or resection site with a 2- to 3-cm margin. PCP prophylaxis was required during the concomitant phase, regardless of lymphocyte count and continued until recovery of lymphocyte count to Grade 1 or less. The major efficacy outcome measure was overall survival.
A total of 573 patients were randomized, 287 to TEMOZOLOMIDE and radiation therapy and 286 to radiation therapy alone. At the time of disease progression, TEMOZOLOMIDE was administered as salvage therapy in 161 patients of the 282 (57%) in the radiation therapy alone arm and 62 patients of the 277 (22%) in the TEMOZOLOMIDE and radiation therapy arm. The addition of concomitant and maintenance TEMOZOLOMIDE to radiation therapy for the treatment of patients with newly diagnosed glioblastoma 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: 0.52, 0.75) with a log-rank P <0.0001 in favor of the TEMOZOLOMIDE arm.
The median overall survival was 14.6 months in the TEMOZOLOMIDE arm and 12.1 months for radiation therapy alone arm. FIGURE 1: Kaplan-Meier Curves for Overall Survival (ITT Population) in Newly Diagnosed Glioblastoma Trial in MK-7365-051
Refractory Anaplastic Astrocytoma Newly Diagnosed Anaplastic Astrocytoma
The efficacy of TEMOZOLOMIDE for the adjuvant treatment of newly diagnosed anaplastic astrocytoma was derived from studies of TEMOZOLOMIDE in the published literature. TEMOZOLOMIDE was evaluated in CATNON (NCT00626990), a randomized, open-label, multicenter trial, where the major efficacy outcome measure was overall survival. Refractory Anaplastic Astrocytoma The efficacy of TEMOZOLOMIDE was evaluated in Study MK-7365-006, a single-arm, multicenter trial.
Eligible patients had anaplastic astrocytoma at first relapse and a baseline Karnofsky performance status (KPS) 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). TEMOZOLOMIDE capsules were given on Days 1 to 5 of each 28-day cycle at a starting dose of 150 mg/m 2 /day.
If ANC was ≥1.5 x 10 9 /L and platelet count was ≥100 x 10 9 /L at the nadir and on Day 1 of the next cycle, the TEMOZOLOMIDE dose was increased to 200 mg/m 2 /day. The major efficacy outcome measure was progression-free survival at 6 months and the additional efficacy outcome measures were overall survival and overall response rate. In the refractory anaplastic astrocytoma population (n=54), the median age was 42 years (range: 19 to 76); 65% were male; and 72% had 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 (range: 4.2 months to 6.3 years). In the refractory anaplastic astrocytoma population, the overall response rate (CR + PR) was 22% (12 of 54 patients) and the complete response rate was 9% (5 of 54 patients). The median duration of all responses was 50 weeks (range: 16 to114 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%, 58%) and progression-free survival at 12 months was 29% (95% CI: 16%, 42%). Median progression-free survival was 4.4 months.
Overall survival at 6 months was 74% (95% CI: 62%, 86%) and 12-month overall survival was 65% (95% CI: 52%, 78%). Median overall survival was 15.9 months.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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