Temodar Information
Temodar (Temozolomide) Warnings And Precautions
For treatment of newly diagnosed glioblastoma multiforme: Prophylaxis against pneumonia is required for all patients receiving concomitant Temodar (Temozolomide) and radiotherapy for the 42-day regimen.
There may be a higher occurrence of PCP when temozolomide is administered during a longer dosing regimen. However, all patients receiving temozolomide, particularly patients receiving steroids, should be observed closely for the development of PCP regardless of the regimen.
For the concomitant treatment phase with RT, a complete blood count should be obtained prior to initiation of treatment and weekly during treatment.
For the 28-day treatment cycles, a complete blood count should be obtained prior to treatment on Day 1 and on Day 22 (21 days after the first dose) of each cycle. Blood counts should be performed weekly until recovery if the ANC falls below 1.5 × 10/L and the platelet count falls below 100 × 10/L
Temodar (Temozolomide) Adverse Reactions
The following adverse reactions have been identified during postapproval use of Temodar (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.
Temodar (Temozolomide) Capsules: allergic reactions, including anaphylaxis, have been reported. Erythema multiforme has been reported, which resolved after discontinuation of Temodar (Temozolomide) and, in some cases, recurred upon rechallenge. Cases of toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported.
There have been reported cases of hepatotoxicity, including elevations of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis.
Opportunistic infections including pneumonia (PCP) have also been reported. Cases of interstitial pneumonitis/pneumonitis, alveolitis, and pulmonary fibrosis have been reported. Prolonged pancytopenia, which may result in aplastic anemia, has been reported, and in some cases has resulted in a fatal outcome.
Temodar (Temozolomide) Use In Specific Populations
Clinical studies of temozolomide did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
In the anaplastic astrocytoma study population, patients 70 years of age or older had a higher incidence of Grade 4 neutropenia and Grade 4 thrombocytopenia (2/8; 25%, =0.31 and 2/10; 20%, =0.09, respectively) in the first cycle of therapy than patients under 70 years of age
In newly diagnosed patients with glioblastoma multiforme, the adverse reaction profile was similar in younger patients (
Temodar (Temozolomide) Overdosage
Doses of 500, 750, 1000, and 1250 mg/m(total dose per cycle over 5 days) have been evaluated clinically in patients. Dose-limiting toxicity was hematologic 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 bone marrow suppression, which in some cases was severe and prolonged, and infections and resulted in death. In the event of an overdose, hematologic evaluation is needed. Supportive measures should be provided as necessary.
Temodar (Temozolomide) Description
Temodar (Temozolomide) contains temozolomide, an imidazotetrazine derivative. The chemical name of temozolomide is 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-s-tetrazine-8-carboxamide. The structural formula is:
The material is a white to light tan/light pink powder with a molecular formula of CHNO and a molecular weight of 194.15. The molecule is stable at acidic pH (7; hence Temodar (Temozolomide) can be administered orally and intravenously. The prodrug, temozolomide, is rapidly hydrolyzed to the active 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) at neutral and alkaline pH values, with hydrolysis taking place even faster at alkaline pH.
Temodar (Temozolomide) Nonclinical Toxicology
Temozolomide is carcinogenic in rats at doses less than the maximum recommended human dose. Temozolomide induced mammary carcinomas in both males and females at doses 0.13 to 0.63 times the maximum human dose (25–125 mg/m) when administered orally on 5 consecutive days every 28 days for 6 cycles. Temozolomide also induced fibrosarcomas of the heart, eye, seminal vesicles, salivary glands, abdominal cavity, uterus, and prostate, carcinomas of the seminal vesicles, schwannomas of the heart, optic nerve, and harderian gland, and adenomas of the skin, lung, pituitary, and thyroid at doses 0.5 times the maximum daily dose. Mammary tumors were also induced following 3 cycles of temozolomide at the maximum recommended daily dose.
Temozolomide is a mutagen and a clastogen. In a reverse bacterial mutagenesis assay (Ames assay), temozolomide increased revertant frequency in the absence and presence of metabolic activation. Temozolomide was clastogenic in human lymphocytes in the presence and absence of metabolic activation.
Temozolomide impairs male fertility. Temozolomide caused syncytial cells/immature sperm formation at 0.25 and 0.63 times the maximum recommended human dose (50 and 125 mg/m) in rats and dogs, respectively, and testicular atrophy in dogs at 0.63 times the maximum recommended human dose (125 mg/m).
Temodar (Temozolomide) Clinical Studies
Five hundred and seventy-three patients were randomized to receive either Temodar (Temozolomide) (TMZ)+Radiotherapy (RT) (n=287) or RT alone (n=286). Patients in the Temodar (Temozolomide) +RT arm received concomitant Temodar (Temozolomide) (75 mg/m ) once daily, starting the first day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by 6 cycles of Temodar (Temozolomide) alone (150 or 200 mg/m) on Days 1 to 5 of every 28-day cycle, starting 4 weeks after the end of RT. Patients in the control arm received RT only. In both arms, focal radiation therapy was delivered as 60 Gy/30 fractions. Focal RT includes the tumor bed or resection site with a 2- to 3-cm margin. pneumonia (PCP) prophylaxis was required during the TMZ + RT, regardless of lymphocyte count, and was to continue until recovery of lymphocyte count to less than or equal to Grade 1.
At the time of disease progression, Temodar (Temozolomide) was administered as salvage therapy in 161 patients of the 282 (57%) in the RT alone arm, and 62 patients of the 277 (22%) in the Temodar (Temozolomide) +RT arm.
The addition of concomitant and maintenance Temodar (Temozolomide) to radiotherapy in the treatment of patients with newly diagnosed GBM showed a statistically significant improvement in overall survival compared to radiotherapy alone (). The hazard ratio (HR) for overall survival was 0.63 (95% CI for HR=0.52-0.75) with a log-rank
FIGURE 1: Kaplan-Meier Curves for Overall Survival (ITT Population)
A single-arm, multicenter study was conducted in 162 patients who had anaplastic astrocytoma at first relapse and who had a baseline Karnofsky performance status 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). Median age of this subgroup of 54 patients was 42 years (19–76). Sixty-five percent were male. Seventy-two percent of patients 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 (4.2–75.4).
Temodar (Temozolomide) Capsules were given for the first 5 consecutive days of a 28-day cycle at a starting dose of 150 mg/m/day. If the nadir and day of dosing (Day 29, Day 1 of next cycle) absolute neutrophil count was ≥1.5 × 10/L (1500/µL) and the nadir and Day 29, Day 1 of next cycle platelet count was ≥100 × 10/L (100,000/µL), the Temodar (Temozolomide) dose was increased to 200 mg/m/day for the first 5 consecutive days of a 28-day cycle.
In the refractory anaplastic astrocytoma population, the overall tumor response rate (CR + PR) was 22% (12/54 patients) and the complete response rate was 9% (5/54 patients). The median duration of all responses was 50 weeks (range: 16–114 weeks) and the median duration of complete responses was 64 weeks (range:52–114 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.
Temodar (Temozolomide) How Supplied/storage And Handling
Store Temodar (Temozolomide) Capsules at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F)
[see USP Controlled Room Temperature].
Store Temodar (Temozolomide) for Injection refrigerated at 2°–8°C (36°–46°F). After reconstitution, store reconstituted product at room temperature (25°C [77°F]). Reconstituted product must be used within 14 hours, including infusion time.
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