Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
Temodal is indicated for the treatment of:
Temodal should only be prescribed by physicians experienced in the oncological treatment of brain tumours.
Anti-emetic therapy may be administered (see section 4.4).
Temodal is administered in combination with focal radiotherapy (concomitant phase) followed by up to 6 cycles of temozolomide (TMZ) monotherapy (monotherapy phase).
TMZ is administered orally at a dose of 75 mg/m² daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions). No dose reductions are recommended, but delay or discontinuation of TMZ administration should be decided weekly according to haematological and non-haematological toxicity criteria. TMZ administration can be continued throughout the 42 day concomitant period (up to 49 days) if all of the following conditions are met:
During treatment a complete blood count should be obtained weekly. TMZ administration should be temporarily interrupted or permanently discontinued during the concomitant phase according to the haematological and non-haematological toxicity criteria as noted in Table 1.
Table 1. TMZ dosing interruption or discontinuation during concomitant radiotherapy and TMZ:
| Toxicity | TMZ interruptiona | TMZ discontinuation |
|---|---|---|
| Absolute neutrophil count | ≥0.5 and <1.5 × 109/l | <0.5 × 109/l |
| Thrombocyte count | ≥10 and <100 × 109/l | <10 × 109/l |
| CTC non-haematological toxicity (except for alopecia, nausea, vomiting) | CTC Grade 2 | CTC Grade 3 or 4 |
a Treatment with concomitant TMZ can be continued when all of the following conditions are met: absolute neutrophil count ≥1.5 × 109/l; thrombocyte count ≥100 × 109/l; CTC non-haematological toxicity ≤Grade 1 (except for alopecia,
nausea, vomiting).
Four weeks after completing the TMZ + RT concomitant phase, TMZ is administered for up to 6 cycles of monotherapy treatment. Dose in Cycle 1 (monotherapy) is 150 mg/m² once daily for 5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 200 mg/m² if the CTC non-haematological toxicity for Cycle 1 is Grade ≤2 (except for alopecia, nausea and vomiting), absolute neutrophil count (ANC) is ≥1.5 × 109/l, and the thrombocyte count is ≥100 × 109/l. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles. Once escalated, the dose remains at 200 mg/m² per day for the first 5 days of each subsequent cycle except if toxicity occurs. Dose reductions and discontinuations during the monotherapy phase should be applied according to Tables 2 and 3.
During treatment a complete blood count should be obtained on Day 22 (21 days after the first dose of TMZ). The dose should be reduced or administration discontinued according to Table 3.
Table 2. TMZ dose levels for monotherapy treatment:
| Dose level | TMZ dose (mg/m²/day) | Remarks |
|---|---|---|
| –1 | 100 | Reduction for prior toxicity |
| 0 | 150 | Dose during Cycle 1 |
| 1 | 200 | Dose during Cycles 2-6 in absence of toxicity |
Table 3. TMZ dose reduction or discontinuation during monotherapy treatment:
| Toxicity | Reduce TMZ by 1 dose levela | Discontinue TMZ |
|---|---|---|
| Absolute neutrophil count | <1.0 × 109/l | See footnoteb |
| Thrombocyte count | <50 × 109/l | See footnoteb |
| CTC non-haematological Toxicity (except for alopecia, nausea, vomiting) | CTC Grade 3 | CTC Grade 4b |
a TMZ dose levels are listed in Table 2.
b TMZ is to be discontinued if:
Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma:
A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is administered orally at a dose of 200 mg/m² once daily for the first 5 days followed by a 23 day treatment interruption (total of 28 days). In patients previously treated with chemotherapy, the initial dose is 150 mg/m² once daily, to be increased in the second cycle to 200 mg/m² once daily, for 5 days if there is no haematological toxicity (see section 4.4).
In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant glioma. Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy of TMZ in children under the age of 3 years have not been established. No data are available.
The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those with mild or moderate hepatic impairment. No data are available on the administration of TMZ in patients with severe hepatic impairment (Child’s Class C) or with renal impairment. Based on the pharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients with severe hepatic impairment or any degree of renal impairment. However, caution should be exercised when TMZ is administered in these patients.
Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ is not affected by age. However, elderly patients (>70 years of age) appear to be at increased risk of neutropenia and thrombocytopenia (see section 4.4).
Temodal hard capsules should be administered in the fasting state.
The capsules must be swallowed whole with a glass of water and must not be opened or chewed.
If vomiting occurs after the dose is administered, a second dose should not be administered that day.
Doses of 500, 750, 1,000, and 1,250 mg/m² (total dose per cycle over 5 days) have been evaluated clinically in patients. Dose-limiting toxicity was haematological and was reported with any dose but is expected to be more severe at higher doses. An overdose of 10,000 mg (total dose in a single cycle, over 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 the recommended dose for more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow suppression, with or without infection, in some cases severe and prolonged and resulting in death. In the event of an overdose, haematological evaluation is needed. Supportive measures should be provided as necessary.
3 years.
Bottle presentation: Do not store above 30°C. Store in the original bottle in order to protect from moisture. Keep the bottle tightly closed.
Sachet presentation: Do not store above 30°C.
Bottle presentation: Type I amber glass bottles with polypropylene child-resistant closures containing 5 or 20 hard capsules. The carton contains one bottle.
Sachet presentation: Sachets are composed of linear low density polyethylene (innermost layer), aluminium and polyethylene terephthalate. Each sachet contains 1 hard capsule and is dispensed in a cardboard carton. The carton contains 5 or 20 hard capsules, individually sealed in sachets.
Not all pack sizes may be marketed.
Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with skin or mucous membrane must be avoided. If Temodal comes into contact with skin or mucosa, it should be washed immediately and thoroughly with soap and water.
Patients should be advised to keep capsules out of the sight and reach of children, preferably in a locked cupboard. Accidental ingestion can be lethal for children.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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