TEMOZOLOMIDE

TEMOZOLOMIDE- temozolomide capsule
Rising 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 capsules 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 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 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).
ToxicityTMZ Interruption *TMZ Discontinuation
Absolute Neutrophil Count greater than or equal to 0.5 and less than 1.5 x 109 /Lless than 0.5 x 109 /L
Platelet Countgreater than or equal to 10 and less than 100 x 109 /Lless than 10 x 109 /L
CTC Nonhematological Toxicity(except for alopecia, nausea, vomiting)CTC Grade 2CTC Grade 3 or 4

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/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 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 capsules) 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 LevelDose (mg/m2 /day)Remarks
-1100Reduction for prior toxicity
0150Dose during Cycle 1
1200Dose during Cycles 2-6 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.
ToxicityReduce TMZ by 1 Dose Level *Discontinue TMZ
Absolute Neutrophil Countless than 1.0 x 109 /LSee footnote
Platelet Countless 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/µL) 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/µL), the Temozolomide capsules 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/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. If the ANC falls to less than 1.0 x 109 /L (1000/µL) or the platelet count is less than 50 x 109 /L (50,000/µL) 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 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
(click image for full-size original)
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)
1.0 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 mg180 mg140 mg100 mg20 mg5 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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