TEMODAR SIDE EFFECTS
- Generic Name: temozolomide
- Brand Name: Temodar
- Drug Class: Antineoplastics, Alkylating
SIDE EFFECTS
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Myelosuppression
- Myelodysplastic Syndrome and Secondary Malignancies
- Pneumocystis Pneumonia
- Hepatotoxicity
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 TEMODAR was evaluated in Study MK-7365-051.
Forty-nine percent (49%) of patients treated with TEMODAR 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 TEMODAR 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 TEMODAR.
TABLE 1: Adverse Reactions (≥5%) in Patients Receiving TEMODAR in Newly Diagnosed Glioblastoma Trial
| Adverse Reactions | Concomitant Phase | Maintenance Phase | ||||
| Radiation Therapy and TEMODAR N=288* |
Radiation Therapy Alone N=285 |
TEMODAR N=224 |
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| All Grades (%) | Grade ≥3 (%) | All Grades (%) | Grades ≥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 |
| Fleadache | 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 | ||
| 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 TEMODAR. |
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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.
Refractory Anaplastic Astrocytoma
The safety of TEMODAR was evaluated in Study MK-7365-006.
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 2 and 3 summarize the adverse reactions and hematological laboratory abnormalities in Refractory Anaplastic Astrocytoma Trial.
TABLE 2: Adverse Reactions (≥5%) in Patients Receiving TEMODAR in Refractory Anaplastic Astrocytoma Trial
| Adverse Reactions | TEMODAR N=158 |
|
| All Reactions (%) | Grades 3-4 (%) | |
| 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 |
| Urinary System | ||
| Urinary tract infection | 8 | |
| Micturition increased frequency | 6 | |
| Psychiatric | ||
| 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 term includes blurred vision; visual deficit; vision changes; and vision troubles. | ||
TABLE 3: Grade 3 to 4 Adverse Hematologic Laboratory Abnormalities in Refractory Anaplastic Astrocytoma Trial
| TEMODAR* † | |
| 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 109/L) and thrombocytopenia (<20 x 109/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.
Adverse Reactions With TEMODAR For Injection
Adverse reactions that were reported in 35 patients who received TEMODAR for injection that were not reported in patients who received TEMODAR capsules were pain, irritation, pruritus, warmth, swelling, and erythema at infusion site; petechiae; and hematoma.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of TEMODAR. 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 TEMODAR 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
SRC: NLM .