Temozolomide

TEMOZOLOMIDE- temozolomide capsule
Mylan Pharmaceuticals 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 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/m2 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 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 capsules 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 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 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 x 109 /L (1500/μL) and the platelet count exceeds 100 x 109 /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/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 = 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 1.0 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

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