Posology : מינונים

4.2    Posology and method of administration
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).

Posology

Adult patients with newly-diagnosed glioblastoma multiforme

Temodal is administered in combination with focal radiotherapy (concomitant phase) followed by up to 6 cycles of temozolomide (TMZ) monotherapy (monotherapy phase).

Concomitant 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:
-      absolute neutrophil count (ANC) ≥ 1.5 x 109/l
-      thrombocyte count ≥ 100 x 109/l
-      common toxicity criteria (CTC) non-haematological toxicity ≤ Grade 1 (except for alopecia, nausea and vomiting).
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 x 109/l        < 0.5 x 109/l Thrombocyte count                          ≥ 10 and < 100 x 109/l         < 10 x 109/l CTC non-haematological toxicity
CTC Grade 2                           CTC Grade 3 or 4
(except for alopecia, nausea, vomiting) a:   Treatment with concomitant TMZ can be continued when all of the following conditions are met: absolute neutrophil count ≥ 1.5 x 109/l; thrombocyte count ≥ 100 x 109/l; CTC non-haematological toxicity ≤ Grade 1 (except for alopecia, nausea, vomiting).

Monotherapy phase

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 x 109/l, and the thrombocyte count is ≥ 100 x 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                                            Remarks (mg/m2/day)
–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 x 109/l                              See footnote b Thrombocyte count                                        < 50 x 109/l                               See footnote b 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:
•    dose level -1 (100 mg/m2) still results in unacceptable toxicity
•    the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction.


Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma (Recurrent glioblastoma multiforme or anaplastic astrocytoma):
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, providing the absolute neutrophil count (ANC) is ≥ 1.5 x 109/L and the platelet count is ≥ 100 x 109/L on Day 1 of the next cycle.

Dose modification for TEMODAL should be based on toxicities according to nadir ANC or platelet counts.

Adults: Metastatic malignant melanoma

For patients with metastatic malignant melanoma, the recommended dose is 200 mg/m2 once daily for 5 days per 28-day cycle.


Paediatric patients: Recurrent glioblastoma multiforme or anaplastic astrocytoma 
In patients 3 years of age or older, TEMODAL is administered orally at a dose of 200 mg/m2 once daily for 5 days per 28-day cycle. Paediatric patients previously treated with chemotherapy or craniospinal irradiation should receive an initial dose of 150 mg/m2 once daily for 5 days, with escalation to 200 mg/m2 once daily at the next cycle if there is no haematological toxicity.

In patients with recurrent glioblastoma multiforme/anaplastic astrocytoma or metastatic melanoma, TEMODAL can be continued until disease progression or for a maximum of 2 years.

Special populations
Paediatric population

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.

Patients with hepatic or renal impairment
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.


Elderly 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).

Method of administration

Temodal 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.