Temozolomide (Page 2 of 6)
4 CONTRAINDICATIONS
Temozolomide is contraindicated in patients with a history of 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)].
5 WARNINGS AND PRECAUTIONS
5.1 Myelosuppression
Myelosuppression, including pancytopenia, leukopenia and anemia, some with fatal outcomes, have occurred with temozolomide [see Adverse Reactions (6.1, 6.2)]. Geriatric patients and women have been shown in clinical trials to have a higher risk of developing myelosuppression.
Prior to dosing, patients must have an ANC of 1.5 x 109 /L or greater and a platelet count of 100 x 109 /L or greater.
For the concomitant phase with radiotherapy, obtain a complete blood count prior to initiation of treatment and weekly during treatment [see Dosage and Administration (2.1)].
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 [see Dosage and Administration (2.1, 2.2)].
5.2 Myelodysplastic Syndrome and Secondary Malignancies
Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed following temozolomide administration.
5.3 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.
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 [see Dosage and Administration (2.1)].Monitor all patients receiving temozolomide for the development of lymphopenia and PCP.
5.4 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.
5.5 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 of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with temozolomide and for at least 6 months after the final 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 at least 3 months after the final dose. Advise male patients not to donate semen during treatment with temozolomide and for at least 3 months after the final dose [see Use in Specific Populations (8.1, 8.3)].
6 ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Myelosuppression [see Warnings and Precautions (5.1)].
- Myelodysplastic Syndrome and Secondary Malignancies [see Warnings and Precautions (5.2)].
- Pneumocystis Pneumonia [see Warnings and Precautions (5.3)].
- Hepatotoxicity [see Warnings and Precautions (5.4)].
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.
TABLE 3: Adverse Reactions (≥5%) in Patients Receiving Temozolomide in Newly Diagnosed Glioblastoma Trial
| 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 | |||||
| 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 + 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 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.
TABLE 4: Adverse Reactions (≥5%) in Patients Receiving Temozolomide in Refractory Anaplastic Astrocytoma Trial
* This term includes blurred vision; visual deficit; vision changes; vision troubles
TABLE 5: Grade 3 to 4 Adverse Hematologic Laboratory Abnormalities in Refractory Anaplastic Astrocytoma Trial
| Temozolomidea, b | |
| Decreased lymphocytes | 55% |
| Decreased platelets | 19% |
| Decreased neutrophils | 14% |
| Decreased leukocytes | 11% |
| Decreased hemoglobin | 4% |
a Change from Grade 0 to 2 at baseline to Grade 3 or 4 during treatment.
b 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.
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