Temozolomide

TEMOZOLOMIDE- temozolomide capsule
AvPAK

1 INDICATIONS AND USAGE

1.1 Newly Diagnosed Glioblastoma Multiforme

Temozolomide capsules are indicated for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment.

1.2 Refractory Anaplastic Astrocytoma

Temozolomide capsules are indicated for the treatment of adult patients with refractory anaplastic astrocytoma, i.e., patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing and Dose Modification Guidelines

Dosage of temozolomide capsules 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 capsules 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 capsules are administered at 75 mg/m 2 daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions) followed by maintenance temozolomide capsules 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 capsules 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 ≥1.5 x 10 9 /L, platelet count ≥100 x 10 9 /L, common toxicity criteria (CTC) nonhematological toxicity ≤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 capsules and radiotherapy, and should be continued in patients who develop lymphocytopenia until recovery from lymphocytopenia (CTC Grade ≤1).

TABLE 1: Temozolomide Dosing Interruption or Discontinuation

During Concomitant Radiotherapy and Temozolomide

Toxicity TMZ Interruption* TMZ Discontinuation
Absolute Neutrophil Count ≥0.5 and <1.5 x 10 9 /L <0.5 x 10 9 /L
Platelet Count ≥10 and <100 x 10 9 /L <10 x 10 9 /L
CTC Nonhematological Toxicity (except for alopecia, nausea, vomiting) CTC Grade 2 CTC Grade 3 or 4

*Treatment with concomitant TMZ could be continued when all of the following conditions were met: absolute neutrophil count ≥1.5 x 10 9 /L; platelet count ≥100 x 10 9 /L; CTC nonhematological toxicity ≤Grade 1 (except for alopecia, nausea, vomiting). TMZ=temozolomide; CTC=Common Toxicity Criteria.

Maintenance Phase:

Cycle 1: Four weeks after completing the temozolomide capsules+RT phase, temozolomide capsules are administered for an additional 6 cycles of maintenance treatment. Dosage in Cycle 1 (maintenance) is 150 mg/m 2 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/m 2 , if the CTC nonhematologic toxicity for Cycle 1 is Grade ≤2 (except for alopecia, nausea, and vomiting), absolute neutrophil count (ANC) is ≥1.5 x 10 9 /L, and the platelet count is ≥100 x 10 9 /L. The dose remains at 200 mg/m 2 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 2 and 3.

During treatment, a complete blood count should be obtained on Day 22 (21 days after the first dose of temozolomide capsules) or within 48 hours of that day, and weekly until the ANC is above 1.5 x 10 9 /L (1500/μL) and the platelet count exceeds 100 x 10 9 /L (100,000/μL). The next cycle of temozolomide capsules 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/m 2 /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

Toxicity Reduce TMZ by 1 Dose Level* Discontinue TMZ
Absolute Neutrophil Count <1.0 x 10 9 /L See footnote
Platelet Count <50 x 10 9 /L See footnote
CTC Nonhematological Toxicity (except for alopecia, nausea, vomiting) CTC Grade 3 CTC Grade 4

*TMZ dose levels are listed in Table 2.

TMZ is to be discontinued if dose reduction to <100 mg/m 2 is required or if the same Grade 3 nonhematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction. TMZ=temozolomide; CTC=Common Toxicity Criteria.

Patients with Refractory Anaplastic Astrocytoma: For adults the initial dose is 150 mg/m 2 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 ≥1.5 x 10 9 /L (1500/μL) and both the nadir and Day 29, Day 1 of next cycle platelet counts are ≥100 x 10 9 /L (100,000/μL), the temozolomide capsules dose may be increased to 200 mg/m 2 /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 10 9 /L (1500/μL) and the platelet count exceeds 100 x 10 9 /L (100,000/μL). The next cycle of temozolomide capsules should not be started until the ANC and platelet count exceed these levels. If the ANC falls to <1.0 x 10 9 /L (1000/μL) or the platelet count is <50 x 10 9 /L (50,000/μL) during any cycle, the next cycle should be reduced by 50 mg/m 2 , but not below 100 mg/m 2 , the lowest recommended dose (see Table 4). Temozolomide capsules 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 4: Dosing Modification Table
(click image for full-size original)

TABLE 5: Daily Dose Calculations by Body Surface Area (BSA)

Total BSA (m 2 ) 75 mg/m 2 (mg daily) 150 mg/m 2 (mg daily) 200 mg/m 2 (mg daily)
1.0 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
2.0 150 300 400
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

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