Usual Adult Dose for Anaplastic Astrocytoma

Oral:
Initial Dose: 150 mg/m2 orally once a day
Maintenance Dose: 200 mg/m2 orally once a day

Duration of Therapy: 5 consecutive days per 28-day treatment cycle

IV:
Initial Dose: 150 mg/m2 IV over 90 minutes once a day
Maintenance Dose: 200 mg/m2 IV over 90 minutes once a day

Duration of Therapy: 5 consecutive days per 28-day treatment cycle

Comments:

• Dose should only be increased to 200 mg/m2 if both the nadir and day of dosing (Day 29, Day 1 of next cycle), the ANC is greater than or equal to 1.5 x 10(9)/L and platelet count is greater than or equal to 100 x 10(9)/L.
• A complete blood count should be obtained on day 22 or within 48 hours of that day of each cycle and weekly until the ANC is above 1.5 x 10(9)/L and the platelet count is above 100 x 10(9)/L.
• The next cycle should not be started until the ANC and platelet count exceed the above levels.
• In clinical trial, treatment could be continued for a maximum of 2 years. Optimum duration of therapy is not known.
• Treatment with this drug may be continued until disease progression.

Use:

• Refractory anaplastic astrocytoma with disease progression on a drug regimen containing nitrosourea and procarbazine.

Usual Adult Dose for Glioblastoma Multiforme

Concomitant phase with focal radiotherapy:

Oral:
75 mg/m2 orally once a day

Duration of therapy: 42 days

IV:
75 mg/m2 IV over 90 minutes once a day

Duration of therapy: 42 days

Comments:

• No dose reductions are recommended during the concomitant phase.
• Dose interruptions or discontinuation may occur based on toxicity.
• Therapy should continue throughout the 42-day concomitant phase up to 49 days if all of the following conditions are met: ANC greater than or equal to 1.5 x 10(9)/L, platelet count greater than 100 x 10(9)/L, common toxicity criteria (CTC) nonhematological toxicity less than or equal to Grade 1.
• A complete blood count should be obtained weekly during treatment.
• Pneumocystis pneumonia prophylaxis is required during the concomitant administration of this drug and radiotherapy, and should be continued in patients who develop lymphocytopenia until recovery.

Monotherapy Phase:
Cycle 1:

Oral:
150 mg/m2 orally once a day

Duration of therapy: 5 days followed by 23 days without treatment

IV:
150 mg/m2 IV over 90 minutes once a day

Duration of therapy: 5 days followed by 23 days without treatment

Cycles 2-6:

Oral:
200 mg/m2 by mouth once a day

Duration of therapy: First 5 days of each cycle

IV:
200 mg/m2 IV over 90 minutes once a day

Duration of therapy: First 5 days of each cycle

Comments:

• At the start of cycle 2, the dose should be escalated to 200 mg/m2 if: CTC nonhematological toxicity for Cycle 1 is grade less than or equal to 2 (except for alopecia, nausea, and vomiting), ANC is greater than or equal to 1.5 x 10(9)/L, and the platelet count is greater than or equal to 100 x 10(9)/L.
• The dose remains at 200 mg/m2 for cycles 2 through 6 unless toxicity occurs.
• If the dose was not escalated at the beginning of cycle 2, escalation should not be done in subsequent cycles.
• Obtain a complete blood count on day 22 or within 48 hours of that day of each cycle and weekly until the ANC is greater than 1.5 x 10(9)/L and the platelet count is greater than 100 x 10(9)/L. The next cycle should not be started until the ANC and platelet levels exceed these numbers.
• Dose reductions should be based on the lowest blood counts and worst nonhematologic toxicity during the previous cycle.

Use:

• Newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment.

Usual Pediatric Dose for Anaplastic Astrocytoma

Less than 3 years: Safety and efficacy have not been established

3 years or older:
Previously Untreated with Chemotherapy:

200 mg/m2 orally once a day

Duration of therapy: 5 days followed by 23 days without treatment

Previously Treated with Chemotherapy:

Initial Dose: 150 mg/m2 orally once a day

Maintenance Dose: 200 mg/m2 orally once a day

Duration of therapy: First 5 days of each treatment cycle

Comments:

• Dose in cycle 2 for patients previously treated with chemotherapy should be increased if there is no haematological toxicity.
• If the nadir on day of dosing (Day 29, Day 1 of next cycle) absolute neutrophil counts (ANC) are greater than or equal to 1.5 × 10(9)/L and platelet counts are greater than or equal to 100 × 10(9)/L, the dose may be increased to 200 mg/m2 orally once daily 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 × 10(9)/L and the platelet count exceeds 100 × 10(9)/L. The next cycle should not be started until the ANC and platelet count exceed these levels.
• If the ANC falls to less than 1.0 × 10(9)/L or the platelet count is less than 50 × 10(9)/L during any cycle, the next cycle should be reduced by 50 mg/m2 , but not below 100 mg/m2 , the lowest recommended dose.
• Treatment may be continued until disease progression or a maximum of 2 years.

Use:

• Recurrent or progressive malignant glioblastoma multiforme or anaplastic astrocytoma

Usual Pediatric Dose for Glioblastoma Multiforme

Less than 3 years: Safety and efficacy have not been established

3 years or older:
Previously Untreated with Chemotherapy:

200 mg/m2 orally once a day

Duration of therapy: 5 days followed by 23 days without treatment

Previously Treated with Chemotherapy:

Initial Dose: 150 mg/m2 orally once a day

Maintenance Dose: 200 mg/m2 orally once a day

Duration of therapy: First 5 days of each treatment cycle

Comments:

• Dose in cycle 2 for patients previously treated with chemotherapy should be increased if there is no haematological toxicity.
• If the nadir on day of dosing (Day 29, Day 1 of next cycle) absolute neutrophil counts (ANC) are greater than or equal to 1.5 × 10(9)/L and platelet counts are greater than or equal to 100 × 10(9)/L, the dose may be increased to 200 mg/m2 orally once daily 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 × 10(9)/L and the platelet count exceeds 100 × 10(9)/L. The next cycle should not be started until the ANC and platelet count exceed these levels.
• If the ANC falls to less than 1.0 × 10(9)/L or the platelet count is less than 50 × 10(9)/L during any cycle, the next cycle should be reduced by 50 mg/m2 , but not below 100 mg/m2 , the lowest recommended dose.
• Treatment may be continued until disease progression or a maximum of 2 years.

Use:

• Recurrent or progressive malignant glioblastoma multiforme or anaplastic astrocytoma

Renal Dose Adjustments

Dose adjustment(s) may be required in patients; however, no specific guidelines have been suggested. Caution is recommended.

Liver Dose Adjustments

Dose adjustment(s) may be required; however, no specific guidelines have been suggested. Caution is recommended.

Dose Adjustments

Glioblastoma Multiforme:
Concomitant Phase:
Interruption of Therapy:

• Absolute Neutrophil Count (ANC) greater than or equal to 0.5 and less than 1.5 x 10(9)/L
• Platelet count greater than or equal to 10 and less than 100 x 10(9)/L
• Common Toxicity Criteria (CTC) Nonhematological Toxicity (except for alopecia, nausea, vomiting) grade 2

Discontinuation of Therapy:

• ANC less than 0.5 x 10(9)/L
• Platelet count less than 10 x 10(9)/L
• CTC Nonhematological Toxicity grade 3 or 4

Maintenance Phase:
Reduce Dose by 1 Dose Level:

• Dose should be reduced to 100 mg/m2 for prior toxicity
• ANC less than 1.0 x 10(9)/L
• Platelet count less than 50 x 10(9)/L
• CTC Nonhematological Toxicity grade 3

Discontinuation of Therapy:

• If dose reduction to less than 100 mg/m2 is required.
• If the same Grade 3 CTC nonhematological toxicity recurs after dose reduction.
• CTC Nonhematological Toxicity grade 4

Anaplastic Astrocytoma:
Dose Reduction:

• If the ANC falls below 1.0 x 10(9)/L or the platelet count is less than 50 x 10(9)/L during any cycle, the next cycle should be reduced by 50 mg/m2 but not below 100 mg/m2.

Precautions

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:
Oral Capsules:

• Swallow capsules whole with a glass of water.
• Consistency of administration with respect to food is recommended.
• To reduce nausea and vomiting, take this drug on an empty stomach.
• If vomiting occurs after administration, a second dose should not be administered that day.
• Bedtime administration may be advised.

IV Injection:

• Withdraw volume necessary for dose and transfer into an empty 250 mL infusion bag.
• Infuse IV over 90 minute using pump.
• Flush lines before and after each infusion. Infuse only via IV.
• May be administered in the same IV line with 0.9% Sodium Chloride injection only.

Storage requirements:
IV Injection:

• Prior to reconstitution, store in refrigerator.
• After reconstitution, store product at room temperature. Reconstituted product must be used within 14 hours including infusion time.

Reconstitution/preparation techniques:
IV Injection:

• Bring vial to room temperature prior to reconstitution.
• Reconstitute with 41 mL of Sterile Water for Injection and gently swirl vial. Do not shake.
• Inspect vial for visible particular matter. If particulates are present, do not use.
• Do not further dilute reconstituted product.

Patient advice:

• Antiemetic therapy may be administered prior to and/or following administration.
• If capsules are open or damaged, precautions should be taken to avoid inhalation or contact with the skin or mucous membranes.