Temozolomide (Page 3 of 8)
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)] .
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%).
The most common adverse reactions (≥20%) across the cumulative temozolomide experience were alopecia, fatigue, nausea, and vomiting. Table 3 summarizes the adverse reactions in Newly Diagnosed Glioblastoma Trial. Overall, the pattern of reactions during the maintenance phase was consistent with the known safety profile of temozolomide.
Adverse Reactions | Concomitant Phase | Maintenance 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 | 63 | 55 | |||
Rash | 19 | 1 | 15 | 13 | 1 | |
Dry Skin | 2 | 2 | 5 | <1 | ||
Pruritus | 4 | 1 | 5 | |||
Erythema | 5 | 5 | 1 | |||
General | ||||||
Fatigue | 54 | 7 | 49 | 5 | 61 | 9 |
Anorexia | 19 | 1 | 9 | <1 | 27 | 1 |
Headache | 19 | 2 | 17 | 4 | 23 | 4 |
Weakness | 3 | 2 | 3 | 1 | 7 | 2 |
Dizziness | 4 | 1 | 4 | 5 | ||
Gastrointestinal System | ||||||
Nausea | 36 | 1 | 16 | <1 | 49 | 1 |
Vomiting | 20 | <1 | 6 | <1 | 29 | 2 |
Constipation | 18 | 1 | 6 | 22 | ||
Diarrhea | 6 | 3 | 10 | 1 | ||
Stomatitis | 7 | 5 | <1 | 9 | 1 | |
Abdominal Pain | 2 | <1 | 1 | 5 | <1 | |
Eye | ||||||
Vision Blurred | 9 | 1 | 9 | 1 | 8 | |
Injury | ||||||
Radiation Injury NOS | 7 | 4 | <1 | 2 | ||
Central and Peripheral Nervous System | ||||||
Convulsions | 6 | 3 | 7 | 3 | 11 | 3 |
Memory Impairment | 3 | <1 | 4 | <1 | 7 | 1 |
Confusion | 4 | 1 | 4 | 2 | 5 | 2 |
Special Senses Other | ||||||
Taste Perversion | 6 | 2 | 5 | |||
Respiratory System | ||||||
Coughing | 5 | 1 | 1 | 8 | <1 | |
Dyspnea | 4 | 2 | 3 | 1 | 5 | <1 |
Psychiatric | ||||||
Insomnia | 5 | 3 | <1 | 4 | ||
Immune System | ||||||
Allergic Reaction | 5 | 2 | <1 | 3 | ||
Platelet, Bleeding and Clotting | ||||||
Thrombocytopenia | 4 | 3 | 1 | 8 | 4 | |
Musculoskeletal System | ||||||
Arthralgia | 2 | <1 | 1 | 6 |
*One patient who was randomized to radiation therapy only arm received radiation therapy and Temozolomide.
NOS=not otherwise specified.
Note: Grade 5 (fatal) adverse reactions are included in the Grade ≥3 column.
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 patients.
Refractory Anaplastic Astrocytoma:
The safety of temozolomide was evaluated in Study MK-7365-006 [see Clinical Studies (14.2)] .
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.
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 Refractory Anaplastic Astrocytoma Trial.
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 |
Abdominal Pain | 9 | 1 |
Anorexia | 9 | 1 |
General | ||
Headache | 41 | 6 |
Fatigue | 34 | 4 |
Asthenia | 13 | 6 |
Fever | 13 | 2 |
Back Pain | 8 | 3 |
Central and Peripheral Nervous System | ||
Convulsions | 23 | 5 |
Hemiparesis | 18 | 6 |
Dizziness | 12 | 1 |
Coordination abnormal | 11 | 1 |
Amnesia | 10 | 4 |
Insomnia | 10 | |
Paresthesia | 9 | 1 |
Somnolence | 9 | 3 |
Paresis | 8 | 3 |
Urinary incontinence | 8 | 2 |
Ataxia | 8 | 2 |
Dysphasia | 7 | 1 |
Convulsions local | 6 | |
Gait abnormal | 6 | 1 |
Confusion | 5 | |
Cardiovascular | ||
Edema peripheral | 11 | 1 |
Resistance Mechanism | ||
Infection viral | 11 | |
Endocrine | ||
Adrenal hypercorticism | 8 | |
Respiratory System | ||
Upper respiratory tract infection | 8 | |
Pharyngitis | 8 | |
Sinusitis | 6 | |
Coughing | 5 | |
Skin and Appendages | ||
Rash | 8 | |
Pruritus | 8 | 1 |
U rinary System | ||
Urinary tract infection | 8 | |
Micturition increased frequency | 6 | |
Psychiatric Disorders | ||
Anxiety | 7 | 1 |
Depression | 6 | |
Reproductive Disorders | ||
Breast pain, female | 6 | |
Metabolic | ||
Weight increase | 5 | |
Musculoskeletal System | ||
Myalgia | 5 | |
Vision | ||
Diplopia | 5 | |
Vision abnormal* | 5 |
*This item includes blurred vision; visual deficit; vision changes; and vision troubles.
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.
† Dominator 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 9.5% (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 5.5% (48/879) experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. Pancytopenia, leukopenia, and anemia also occurred.
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