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Temodar

Brand Name:	Temodar	Trade Name:	temozolomide
FDA Approved For:	TEMODAR (temozolomide) Capsules are indicated for the treatment of adult patients with refractory anaplastic astrocytoma, i.e., patients at first relapse who have experienced disease progression on a drug regimen containing a nitrosourea and procarbazine. This indication is based on the response rate in the indicated population. No results are available from randomized controlled trials in recurrent anaplastic astrocytoma that demonstrate a clinical benefit resulting from treatment, such as improvement in disease- related symptoms, delayed disease progression, or improved survival.	Pediatric Use:	Safety and effectiveness in pediatric patients have not been established.
Carcinogen:	Standard carcinogenicity studies were not conducted with temozolomide. In rats treated with 200 mg/m2 temozolomide (equivalent to the maximum recommended daily human dose) on 5 consecutive days every 28 days for 3 cycles, mammary carcinomas were found in both males and females. With 6 cycles of treatment at 25, 50 and 125 mg/m2 (about 1/ 8-1/2 the maximum recommended daily human dose), mammary carcinomas were observed at all doses and fibrosarcomas of the heart, eye, seminal vesicles, salivary glands, abdominal cavity, uterus and prostate; carcinoma of the seminal vesicles, schwannoma of the heart, optic nerve and harderian gland; and adenomas of the skin, lung, pituitary and thyroid were observed at at the high dose.	Mutagen:	Temozolomide was mutagenic in vitro in bacteria (Ames assay) and clastogenic in mammalian cells (human peripheral blood lymphocyte assays).
Manufacturer and/or Distributor:	Schering

Adverse Reactions:

Tables 1 and 2 show the incidence of adverse events 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 events 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 side effects were nausea, vomiting, headache and fatigue. The adverse events 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 event. 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 21-40 days] and 28 days for neutrophils [range 1-44 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. (See WARNINGS). Less than 10% of patients required hospitalization, blood transfusion or discontinuation of therapy due to myelosuppression. In clinical trial experience with 110-111 women and 169-174 men (depending on measurements), there were higher rates of Grade 4 neutropenia (ANC < 500 cells/µL) thrombocytopenia (< 20,000 cells/µL) in women than men in the first cycle of therapy: (12% versus 5% and 9% versus 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.)

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