Temozolomide: Package Insert and Label Information

TEMOZOLOMIDE- temozolomide capsule
Accord Healthcare Inc.

1 INDICATIONS AND USAGE

1.1 Newly Diagnosed Glioblastoma

Temozolomide capsule is indicated for the treatment of adult patients with newly diagnosed glioblastoma concomitantly with radiotherapy and then as maintenance treatment.

1.2 Refractory Anaplastic Astrocytoma

Temozolomide capsule is indicated for the treatment of adult patients with refractory anaplastic astrocytoma who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage and Dosage Modifications for Newly Diagnosed Glioblastoma

Administer temozolomide capsules either orally or intravenously once daily for 42 consecutive days during the concomitant phase with focal radiotherapy and then once daily on Days 1 to 5 of each 28-day cycle for 6 cycles during the maintenance phase.

Provide Pneumocystis pneumonia (PCP) prophylaxis during the concomitant phase and continue in patients who develop lymphocytopenia until resolution to grade 1 or less [see Warnings and Precautions (5.3)] .

Concomitant Phase

The recommended dosage of temozolomide capsules is 75 mg/m 2 orally once daily for 42 days (up to 49 days) concomitant with focal radiotherapy (60 Gy administered in 30 fractions). Focal radiotherapy includes the tumor bed or resection site with a 2-to 3-cm margin.

Obtain a complete blood count weekly. No dose reductions are recommended during the concomitant phase. The recommended dosage modifications during the concomitant phase are provided in Table 1.

TABLE 1: Temozolomide Dosage Modifications During Concomitant Phase
Adverse Reaction Interruption Discontinuation
Absolute Neutrophil Count

Withhold temozolomide if ANC is greater than or equal to 0.5 x 10 9 /L and less than 1.5 x 10 9 /L.

Resume temozolomide when ANC is greater than or equal to 1.5 x 10 9 /L.

Discontinue temozolomide if platelet count is less than 0.5 x 10 9 /L.
Platelet Count

Withhold temozolomide if platelet count is greater than or equal to 10 x 10 9 /L and less than 100 x 10 9 /L.

Resume temozolomide when platelet count is greater than or equal to 100 x 10 9 /L.

Discontinue temozolomide if platelet count is less than 10 x 10 9 /L.
Non-hematological Adverse Reaction (except for alopecia, nausea, vomiting)

Withhold temozolomide if Grade 2 adverse reaction occurs.

Resume temozolomide when resolution to Grade 1 or less.

Discontinue temozolomide if Grade 3 or 4 adverse reaction occurs.

Maintenance Phase

Beginning 4 weeks after Concomitant Phase completion, administer temozolomide either orally or intravenously once daily on Days 1 to 5 of each 28-day cycle for 6 cycles. The recommended dosage of temozolomide is as follows:

  • Cycle 1: 150 mg/m 2 per day
  • Cycles 2 to 6: May increase to 200 mg/m 2 per day if the following conditions are met before starting cycle 2. If the dose was not escalated at the onset of Cycle 2, do not increase the dose for Cycles 3 to 6.
    • Non-hematologic toxicity is Grade 2 or less (except for alopecia, nausea, vomiting)
    • 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.

Obtain a complete blood count on Day 22 and then weekly until the ANC is above 1.5 x 10 9 /L and the platelet count is above 100 x 10 9 /L. Do not start the next cycle until the ANC and platelet count exceed these levels.

The recommended dosage modifications during the maintenance phase are provided in Table 2. If Temozolomide is withheld, reduce the dose for the next cycle by 50 mg/m 2 per day. Permanently discontinue Temozolomide in patients who are unable to tolerate a dose of 100 mg/m 2 per day.

TABLE 2: Temozolomide Dosage Modifications During Maintenance Treatment
Toxicity Interruption and Dose Reduction Discontinuation

Absolute Neutrophil Count

Withhold temozolomide if ANC less than 1 x 10 9 /L. When ANC is above 1.5 x 10 9 /L, resume temozolomide at reduced dose for the next cycle.

Unable to tolerate a dose of 100 mg/m 2 per day.

Platelet Count

Withhold temozolomide if platelet less than 50 x 10 9 /L.

When platelet count is above 100 x 10 9 /L, resume temozolomide at reduced dose for the next cycle.

Unable to tolerate a dose of 100 mg/m 2 per day.

Non-hematological Adverse Reaction (except for alopecia, nausea, vomiting)

Withhold temozolomide if Grade 3 adverse reaction. When resolved to grade 1 or less, resume temozolomide at reduced dose for the next cycle.

Recurrent Grade 3 after dose reduction.

Grade 4

Unable to tolerate a dose of 100 mg/m 2 per day.

2.2 Recommended Dosage and Dosage Modifications for Refractory Anaplastic Astrocytoma

The recommended initial dosage of temozolomide is 150 mg/m 2 once daily on Days 1 to 5 of each 28-day cycle. Increase the temozolomide dose to 200 mg/m 2 per day if the following conditions are met at the nadir and on Day 1 of the next cycle:

  • ANC is greater than or equal 1.5 x 10 9 /L an
  • Platelet count is greater than or equal to 100 x 10 9 /L.

Continue temozolomide until disease progression or unacceptable toxicity. In the clinical trial, treatment could be continued for a maximum of 2 years, but the optimum duration of therapy is not known.

Obtain a complete blood count on Day 22 and then weekly until the ANC is above 1.5 x 10 9 /L and the platelet count is above 100 x 10 9 /L. Do not start the next cycle until the ANC and platelet count exceed these levels.

If the ANC is less than 1 x 10 9 /L or the platelet count is less than 50 x 10 9 /L during any cycle, reduce the temozolomide dose for the next cycle by 50 mg/m 2 per day. Permanently discontinue temozolomide in patients who are unable to tolerate a dose of 100 mg/m 2 per day.

2.3 Preparation and Administration

Temozolomide is a cytotoxic drug. Follow applicable special handling and disposal procedures.

Temozolomide capsules

Administer Temozolomide consistently with respect to food (fasting vs. nonfasting) [see Clinical Pharmacology (12.3)]. To reduce nausea and vomiting, take temozolomide on an empty stomach or at bedtime and consider antiemetic therapy prior to and/or following temozolomide administration.

Swallow temozolomide capsules whole. Do not open or chew capsules.

If capsules are accidentally opened or damaged, take precautions to avoid inhalation or contact with the skin or mucous membranes. In case of powder contact, the hands should be washed.

3 DOSAGE FORMS AND STRENGTHS

  • Temozolomide capsules, USP for oral administration
    • 5-mg capsules have white bodies with green caps. The capsule body is imprinted with ‘5’. The cap is imprinted with ‘TMZ’.
    • 20-mg capsules have white bodies with yellow caps. The capsule body is imprinted with ’20’. The cap is imprinted with ‘TMZ’.
    • 100-mg capsules have white bodies with pink caps. The capsule body is imprinted with ‘100’. The cap is imprinted with ‘TMZ’.
    • 140-mg capsules have white bodies with transparent blue caps. The capsule body is imprinted with ‘140’. The cap is imprinted with ‘TMZ’.
    • 180-mg capsules have white bodies with maroon caps. The capsule body is imprinted with ‘180’. The cap is imprinted with ‘TMZ’.
    • 250-mg capsules have white bodies with white caps. The capsule body is imprinted with ‘250’. The cap is imprinted with ‘TMZ’.

4 CONTRAINDICATIONS

Temozolomide is contraindicated in patients with a history of hypersensitivity reactions to:

  • temozolomide or any other ingredients in temozolomide; and
  • dacarbazine, since both temozolomide and dacarbazine are metabolized to the same active metabolite 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide.

Reactions to Temozolomide have included anaphylaxis [see Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

Myelosuppression, including pancytopenia, leukopenia and anemia, some with fatal outcomes, have occurred with temozolomide [see Adverse Reactions (6.1, 6.2)]. Geriatric patients and women have been shown in clinical trials to have a higher risk of developing myelosuppression.

Prior to dosing, patients must have an ANC of 1.5 x 10 9 /L or greater and a platelet count of 100 x 10 9 /L or greater.

For the concomitant phase with radiotherapy, obtain a complete blood count prior to initiation of treatment and weekly during treatment [see Dosage and Administration (2.1)].

For the 28-day treatment cycles, obtain a complete blood count prior to treatment on Day 1 and on Day 22 of each cycle. Perform complete blood counts weekly until recovery if the ANC falls below 1.5 x 10 9 /L and the platelet count falls below 100 x 10 9 /L [see Dosage and Administration (2.1, 2.2)].

5.2 Myelodysplastic Syndrome and Secondary Malignancies

Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed following temozolomide administration.

5.3 Pneumocystis Pneumonia

Pneumocystis pneumonia (PCP) can occur in patients receiving temozolomide. The risk of PCP is increased in patients receiving steroids or with longer treatment regimens.

For patients with newly diagnosed glioblastoma, provide PCP prophylaxis for all patients during the concomitant phase. Continue in patients who experience lymphopenia until resolution to grade 1 or less [see Dosage and Administration (2.1)].

Monitor all patients receiving temozolomide for the development of lymphopenia and PCP.

5.4 Hepatotoxicity

Fatal and severe hepatotoxicity have been reported in patients receiving temozolomide. Perform liver tests at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately two to four weeks after the last dose of temozolomide.

5.5 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, temozolomide can cause fetal harm when administered to a pregnant woman. Adverse developmental outcomes have been reported in both pregnant patients and pregnant partners of male patients. Oral administration of temozolomide to rats and rabbits during the period of organogenesis resulted in embryolethality and polymalformations at doses less than the maximum human dose based on body surface area.

Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with temozolomide and for at least 6 months after the final dose. Because of potential risk of genotoxic effects on sperm, advise male patients with female partners of reproductive potential to use condoms during treatment with temozolomide and for at least 3 months after the final dose. Advise male patients not to donate semen during treatment with temozolomide and for at least 3 months after the final dose [see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

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