Temozolomide

TEMOZOLOMIDE- temozolomide capsule
Roxane Laboratories, Inc.

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

The recommended dose for temozolomide as an intravenous infusion over 90 minutes is the same as the dose for the oral capsule formulation. Bioequivalence has been established only when temozolomide for injection was given over 90 minutes [see Clinical Pharmacology (12.3) ]. 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 × 109 /L, platelet count greater than or equal to 100 × 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
TMZ=temozolomide; CTC=Common Toxicity Criteria.
*
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 109 /L; platelet count greater than or equal to 100 x 109 /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 <1.5 × 109 /L

less than 0.5 × 109 /L

Platelet Count

greater than or equal to

10 and <100 × 109 /L

less than 10 × 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 2–6:

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 × 109 /L, and the platelet count is greater than or equal to 100 × 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 2 and 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 × 109 /L (1500/mcL) and the platelet count exceeds 100 × 109 /L (100,000/mcL). 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 2–6 in absence of toxicity

Table 3: Temozolomide Dose Reduction of Discontinuation During Maintenance Treatment
TMZ=temozolomide; CTC=Common Toxicity Criteria
*
TMZ dose levels are listed in Table 2.
TMZ is to be discontinued if dose reduction to less than 100 mg/m2 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 × 109 /L

See footnote

Platelet Count

less than 50 × 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 × 109 /L (1500/mcL) and both the nadir and Day 29, Day 1 of next cycle platelet counts are greater than or equal to 100 × 109 /L (100,000/mcL), 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 × 109 /L (1500/mcL) and the platelet count exceeds 100 × 109 /L (100,000/mcL). 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 × 109 /L (1000/mcL) or the platelet count is less than 50 × 109 /L (50,000/mcL) 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

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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

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