2.1 Recommended Dosing and Dose Modification Guidelines
Dosage of temozolomide must be adjusted according to nadir neutrophil and platelet counts in the previous cycle and the neutrophil and platelet counts at the time of initiating the next cycle. For temozolomide dosage calculations based on body surface area (BSA) see Table 5. For suggested capsule combinations on a daily dose see Table 6.
Patients with Newly Diagnosed High Grade Glioma
Concomitant Phase
Temozolomide is administered at 75 mg/m2 daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions) followed by maintenance temozolomide for 6 cycles. Focal RT includes the tumor bed or resection site with a 2- to 3- cm margin. No dose reductions are recommended during the concomitant phase; however, dose interruptions or discontinuation may occur based on toxicity. The temozolomide dose should be continued throughout the 42-day concomitant period up to 49 days if all of the following conditions are met: absolute neutrophil count greater than or equal to 1.5 x 109/L, platelet count greater than or equal to 100 x 109/L, common toxicity criteria (CTC) nonhematological toxicity less than or equal to Grade 1 (except for alopecia, nausea, and vomiting). During treatment a complete blood count should be obtained weekly. Temozolomide dosing should be interrupted or discontinued during concomitant phase according to the hematological and nonhematological toxicity criteria as noted in Table 1. Pneumocystis pneumonia (PCP) prophylaxis is required during the concomitant administration of temozolomide and radiotherapy, and should be continued in patients who develop lymphocytopenia until recovery from lymphocytopenia (CTC Grade less than or equal to 1).
TABLE 1: Temozolomide Dosing Interruption or Discontinuation During Concomitant Radiotherapy and Temozolomide
*
Treatment with concomitant TMZ could be continued when all of the following conditions were met: absolute neutrophil count greater than or equal to 1.5 x 10
9/L; platelet count greater than or equal to 100 x 10
9/L; CTC nonhematological toxicity less than or equal to Grade 1 (except for alopecia, nausea, vomiting).
Toxicity
TMZ Interruption*
TMZ Discontinuation
Absolute Neutrophil Count
greater than or equal to 0.5
and less than 1.5 x 109/L
less than 0.5 x 109/L
Platelet Count
greater than or equal to 10
and less than 100 x 109/L
less than 10 x 109/L
CTC Nonhematological Toxicity
(except for alopecia, nausea, vomiting)
CTC Grade 2
CTC Grade 3 or 4
Maintenance Phase
Cycle 1
Four weeks after completing the temozolomide + RT phase, temozolomide is administered for an additional 6 cycles of maintenance treatment. Dosage in Cycle 1 (maintenance) is 150 mg/m2 once daily for 5 days followed by 23 days without treatment.
Cycles 2 to 6
At the start of Cycle 2, the dose can be escalated to 200 mg/m2, if the CTC nonhematologic toxicity for Cycle 1 is Grade less than or equal to 2 (except for alopecia, nausea, and vomiting), absolute neutrophil count (ANC) is greater than or equal to 1.5 x 109/L, and the platelet count is greater than or equal to 100 x 109/L. The dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles.
Dose Reduction or Discontinuation During Maintenance
Dose reductions during the maintenance phase should be applied according to Tables 2and 3.
During treatment, a complete blood count should be obtained on Day 22 (21 days after the first dose of temozolomide) or within 48 hours of that day, and weekly until the ANC is above 1.5 x 109/L (1500/microL) and the platelet count exceeds 100 x 109/L (100,000/microL). The next cycle of temozolomide should not be started until the ANC and platelet count exceed these levels. Dose reductions during the next cycle should be based on the lowest blood counts and worst nonhematologic toxicity during the previous cycle. Dose reductions or discontinuations during the maintenance phase should be applied according to Tables 2 and 3.
TABLE 2: Temozolomide Dose Levels for Maintenance Treatment
Dose Level
Dose (mg/m2/day)
Remarks
-1
100
Reduction for prior toxicity
0
150
Dose during Cycle 1
1
200
Dose during Cycles 2 to 6 in absence of toxicity
TABLE 3: Temozolomide Dose Reduction or Discontinuation During Maintenance Treatment
*
TMZ dose levels are listed in
Table 2.
†
TMZ is to be discontinued if dose reduction to less than 100 mg/m
2 is required or if the same Grade 3 nonhematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction.
Toxicity
Reduce TMZ by 1 Dose Level*
Discontinue TMZ
Absolute Neutrophil Count
less than 1 x 109/L
See footnote†
Platelet Count
less than 50 x 109/L
See footnote†
CTC Nonhematological Toxicity
(except for alopecia, nausea, vomiting)
CTC Grade 3
CTC Grade 4†
Patients with Refractory Anaplastic Astrocytoma
For adults the initial dose is 150 mg/m2 once daily for 5 consecutive days per 28-day treatment cycle. For adult patients, if both the nadir and day of dosing (Day 29, Day 1 of next cycle) ANC are greater than or equal to 1.5 x 109/L (1500/microL) and both the nadir and Day 29, Day 1 of next cycle platelet counts are greater than or equal to 100 x 109/L (100,000/microL), the temozolomide dose may be increased to 200 mg/m2/day for 5 consecutive days per 28-day treatment cycle. During treatment, a complete blood count should be obtained on Day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until the ANC is above 1.5 x 109/L (1500/microL) and the platelet count exceeds 100 x 109/L (100,000/microL). The next cycle of temozolomide should not be started until the ANC and platelet count exceed these levels. If the ANC falls to less than 1 x 109/L (1000/microL) or the platelet count is less than 50 x 109/L (50,000/microL) during any cycle, the next cycle should be reduced by 50 mg/m2, but not below 100 mg/m2, the lowest recommended dose (see Table 4). Temozolomide therapy can be continued until disease progression. In the clinical trial, treatment could be continued for a maximum of 2 years, but the optimum duration of therapy is not known.
TABLE 4: Dosing Modification Table
TABLE 5: Daily Dose Calculations by Body Surface Area (BSA)
TABLE 5: Daily Dose Calculations by Body Surface Area (BSA)
Total BSA
(m2)
75 mg/m2
(mg daily)
150 mg/m2
(mg daily)
200 mg/m2
(mg daily)
1
75
150
200
1.1
82.5
165
220
1.2
90
180
240
1.3
97.5
195
260
1.4
105
210
280
1.5
112.5
225
300
1.6
120
240
320
1.7
127.5
255
340
1.8
135
270
360
1.9
142.5
285
380
2
150
300
400
2.1
157.5
315
420
2.2
165
330
440
2.3
172.5
345
460
2.4
180
360
480
2.5
187.5
375
500
TABLE 6: Suggested Capsule Combinations Based on Daily Dose in Adults
Number of Daily Capsules by Strength (mg)
Total Daily Dose (mg)
250 mg
180 mg
140 mg
100 mg
20 mg
5 mg
75
0
0
0
0
3
3
82.5
0
0
0
0
4
0
90
0
0
0
0
4
2
97.5
0
0
0
1
0
0
105
0
0
0
1
0
1
112.5
0
0
0
1
0
2
120
0
0
0
1
1
0
127.5
0
0
0
1
1
1
135
0
0
0
1
1
3
142.5
0
0
1
0
0
0
150
0
0
1
0
0
2
157.5
0
0
1
0
1
0
165
0
0
1
0
1
1
172.5
0
0
1
0
1
2
180
0
1
0
0
0
0
187.5
0
1
0
0
0
1
195
0
1
0
0
0
3
200
0
1
0
0
1
0
210
0
0
0
2
0
2
220
0
0
0
2
1
0
225
0
0
0
2
1
1
240
0
0
1
1
0
0
255
1
0
0
0
0
1
260
1
0
0
0
0
2
270
1
0
0
0
1
0
280
0
0
2
0
0
0
285
0
0
2
0
0
1
300
0
0
0
3
0
0
315
0
0
0
3
0
3
320
0
1
1
0
0
0
330
0
1
1
0
0
2
340
0
1
1
0
1
0
345
0
1
1
0
1
1
360
0
2
0
0
0
0
375
0
2
0
0
0
3
380
0
1
0
2
0
0
400
0
0
0
4
0
0
420
0
0
3
0
0
0
440
0
0
3
0
1
0
460
0
2
0
1
0
0
480
0
1
0
3
0
0
500
2
0
0
0
0
0
2.2 Preparation and Administration
Temozolomide Capsules
In clinical trials, temozolomide was administered under both fasting and nonfasting conditions; however, absorption is affected by food [see Clinical Pharmacology (12.3)], and consistency of administration with respect to food is recommended. There are no dietary restrictions with temozolomide. To reduce nausea and vomiting, temozolomide should be taken on an empty stomach. Bedtime administration may be advised. Antiemetic therapy may be administered prior to and/or following administration of temozolomide.
Temozolomide Capsules should not be opened or chewed. They should be swallowed whole with a glass of water. If capsules are accidentally opened or damaged, precautions should be taken to avoid inhalation or contact with the skin or mucous membranes [see How Supplied/Storage and Handling (16.1)].
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