Temozolomide: Package Insert and Label Information

TEMOZOLOMIDE- temozolomide capsule
Amneal Pharmaceuticals LLC

1 INDICATIONS AND USAGE

1.1 Newly Diagnosed Glioblastoma

Temozolomide capsules are 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 capsules are 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 orally 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/m2 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 Capsules Dosage Modifications During Concomitant Phase

Adverse Reaction

Interruption

Discontinuation

Absolute Neutrophil Count

Withhold temozolomide capsules if ANC is greater than or equal to 0.5 × 109 /L and less than 1.5 × 109 /L.

Resume temozolomide capsules when ANC is greater than or equal to 1.5 × 109 /L.

Discontinue temozolomide capsules if platelet count is less than 0.5 × 109 /L.

Platelet Count

Withhold temozolomide capsules if platelet count is greater than or equal to 10 × 109 /L and less than 100 × 109 /L.

Resume temozolomide capsules when platelet count is greater than or equal to 100 × 109 /L.

Discontinue temozolomide capsules if platelet count is less than 10 × 109 /L.

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

Withhold temozolomide capsules if Grade 2 adverse reaction occurs.

Resume temozolomide capsules when resolution to Grade 1 or less.

Discontinue temozolomide capsules if Grade 3 or 4 adverse reaction occurs.

Maintenance Phase:

Beginning 4 weeks after Concomitant Phase completion, administer temozolomide capsules orally 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/m2 per day
  • Cycles 2 to 6: May increase to 200 mg/m2 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.
  • Nonhematologic toxicity is Grade 2 or less (except for alopecia, nausea, and vomiting)
  • ANC is greater than or equal to 1.5 × 109 /L, and
  • Platelet count is greater than or equal to 100 × 109 /L.

Obtain a complete blood count on Day 22 and then weekly until the ANC is above 1.5 × 109 /L and the platelet count is above 100 × 109 /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 capsules are withheld, reduce the dose for the next cycle by 50 mg/m2 per day. Permanently discontinue temozolomide capsules in patients who are unable to tolerate a dose of 100 mg/m2 per day.

TABLE 2: Temozolomide Capsules Dosage Modifications During Maintenance Treatment

Toxicity

Interruption and Dose Reduction

Discontinuation

Absolute Neutrophil Count

Withhold temozolomide capsules if ANC less than 1 × 109 /L.

When ANC is above 1.5 × 109 /L, resume temozolomide capsules at reduced dose for the next cycle.

Unable to tolerate a dose of 100 mg/m2 per day.

Platelet Count

Withhold temozolomide capsules if platelet less than 50 × 109 /L.

When platelet count is above 100 × 109 /L, resume temozolomide capsules at reduced dose for the next cycle.

Unable to tolerate a dose of 100 mg/m2 per day.

Nonhematological Adverse

Reaction (except for alopecia,

nausea, vomiting)

Withhold temozolomide capsules if Grade 3 adverse reaction.

When resolved to Grade 1 or less, resume temozolomide capsules at reduced dose for the next cycle.

Recurrent Grade 3 after dose reduction.

Grade 4 Unable to tolerate a dose of 100 mg/m2 per day.

2.2 Recommended Dosage and Dosage Modifications for Refractory Anaplastic Astrocytoma

The recommended initial dosage of temozolomide capsules is 150 mg/m2 once daily on Days 1 to 5 of each 28-day cycle. Increase the temozolomide capsules dose to 200 mg/m2 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 to 1.5 × 109 /L, and
  • Platelet count is greater than or equal to 100 × 109 /L.

Continue temozolomide capsules 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 × 109 /L and the platelet count is above 100 × 109 /L. Do not start the next cycle until the ANC and platelet count exceed these levels.

If the ANC is less than 1 × 109 /L or the platelet count is less than 50 × 109 /L during any cycle, reduce the temozolomide capsules dose for the next cycle by 50 mg/m2 per day. Permanently discontinue temozolomide capsules in patients who are unable to tolerate a dose of 100 mg/m2 per day.

2.3 Preparation and Administration

Temozolomide is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

Temozolomide capsules

Administer temozolomide capsules consistently with respect to food (fasting vs. nonfasting) [see Clinical Pharmacology (12.3)]. To reduce nausea and vomiting, take temozolomide capsules on an empty stomach or at bedtime and consider antiemetic therapy prior to and/or following temozolomide capsules 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:
  • 5 mg capsules have green opaque color caps imprinted “AMNEAL” and white opaque color bodies imprinted “801” with black ink.
  • 20 mg capsules have yellow opaque color caps imprinted “AMNEAL” and white opaque color bodies imprinted “802” with black ink.
  • 100 mg capsules have pink opaque color caps imprinted “AMNEAL” and white opaque color bodies imprinted “803” with black ink.
  • 140 mg capsules have blue opaque color caps imprinted “AMNEAL” and white opaque color bodies imprinted “804” with black ink.
  • 180 mg capsules have red opaque color caps imprinted “AMNEAL” and white opaque color bodies imprinted “805” with black ink.
  • 250 mg capsules have white opaque color caps imprinted “AMNEAL” and white opaque color bodies imprinted “806” with black ink.

4 CONTRAINDICATIONS

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

  • temozolomide or any other ingredients in temozolomide capsules; 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 × 109 /L or greater and a platelet count of 100 × 109 /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 × 109 /L and the platelet count falls below 100 × 109 /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:

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Newly Diagnosed Glioblastoma

The safety of temozolomide was evaluated in Study MK-7365-051 [see Clinical Studies (14.1)].

Forty-nine percent (49%) of patients treated with temozolomide reported one or more severe or life-threatening reactions, most commonly fatigue (13%), convulsions (6%), headache (5%), and thrombocytopenia (5%).

The most common adverse reactions (≥ 20%) across the cumulative temozolomide experience were alopecia, fatigue, nausea, and vomiting. Table 3 summarizes the adverse reactions in Newly Diagnosed Glioblastoma Trial. Overall, the pattern of reactions during the maintenance phase was consistent with the known safety profile of temozolomide.

TABLE 3: Adverse Reactions (≥ 5%) in Patients Receiving Temozolomide in Newly Diagnosed Glioblastoma Trial

Adverse

Reactions

Concomitant Phase

Maintenance

Phase

Radiation Therapy

and Temozolomide

N = 288*

Radiation Therapy

Alone

N = 285

Temozolomide

N=224

All

Grades

(%)

Grade ≥ 3

(%)

All

Grades

(%)

Grades

≥ 3

(%)

All

Grades

(%)

Grade

≥ 3

(%)

Skin and Subcutaneous Tissue

Alopecia

69

63

55

Rash

19

1

15

13

1

Dry Skin

2

2

5

<1

Pruritus

4

1

5

Erythema

5

5

1

General

Fatigue

54

7

49

5

61

9

Anorexia

19

1

9

< 1

27

1

Headache

19

2

17

4

23

4

Weakness

3

2

3

1

7

2

Dizziness

4

1

4

5

Gastrointestinal System

Nausea

36

1

16

< 1

49

1

Vomiting

20

< 1

6

<1

29

2

Constipation

18

1

6

22

Diarrhea

6

3

10

1

Stomatitis

7

5

< 1

9

1

Abdominal Pain

2

< 1

1

5

< 1

Eye

Vision Blurred

9

1

9

1

8

Injury

Radiation Injury

NOS

7

4

< 1

2

Central and Peripheral Nervous System

Convulsions

6

3

7

3

11

3

Memory

Impairment

3

< 1

4

< 1

7

1

Confusion

4

1

4

2

5

2

Special Senses Other

Taste Perversion

6

2

5

Respiratory System

Coughing

5

1

1

8

< 1

Dyspnea

4

2

3

1

5

< 1

Psychiatric

Insomnia

5

3

< 1

4

Immune System

Allergic Reaction

5

2

< 1

3

Platelet, Bleeding and Clotting

Thrombocytopenia

4

3

1

8

4

Musculoskeletal System

Arthralgia

2

< 1

1

6

NOS = not otherwise specified.

Note: Grade 5 (fatal) adverse reactions are included in the Grade ≥ 3 column.

*One patient who was randomized to radiation therapy-only arm received radiation therapy and temozolomide.

When laboratory abnormalities and adverse reactions were combined, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic reactions were observed in 8% of patients, and Grade 3 or Grade 4 platelet abnormalities including thrombocytopenic reactions were observed in 14% of patients.

Refractory Anaplastic Astrocytoma

The safety of temozolomide was evaluated in Study MK-7365-006 [see Clinical Studies (14.2)].

Myelosuppression (thrombocytopenia and neutropenia) was the dose-limiting adverse reaction. It usually occurred within the first few cycles of therapy and was not cumulative. Myelosuppression occurred late in the treatment cycle and returned to normal, on average, within 14 days of nadir counts. The median nadirs occurred at 26 days for platelets (range: 21 to 40 days) and 28 days for neutrophils (range: 1 to 44 days). Only 14% (22/158) of patients had a neutrophil nadir and 20% (32/158) of patients had a platelet nadir, which may have delayed the start of the next cycle. Less than 10% of patients required hospitalization, blood transfusion, or discontinuation of therapy due to myelosuppression.

The most common adverse reactions (≥ 20%) were nausea, vomiting, headache, fatigue, constipation, and convulsions.

Tables 4 and 5 summarize the adverse reactions and hematological laboratory abnormalities in

Refractory Anaplastic Astrocytoma Trial.

TABLE 4: Adverse Reactions (≥ 5%) in Patients Receiving Temozolomide in Refractory Anaplastic Astrocytoma Trial

Adverse Reactions

Temozolomide

N=158

All Reactions

(%)

Grades 3-4

(%)

Gastrointestinal System

Nausea

53

10

Vomiting

42

6

Constipation

33

1

Diarrhea

16

2

Abdominal pain

9

1

Anorexia

9

1

General

Headache

41

6

Fatigue

34

4

Asthenia

13

6

Fever

13

2

Back pain

8

3

Central and Peripheral Nervous System

Convulsions

23

5

Hemiparesis

18

6

Dizziness

12

1

Coordination abnormal

11

1

Amnesia

10

4

Insomnia

10

Paresthesia

9

1

Somnolence

9

3

Paresis

8

3

Urinary incontinence

8

2

Ataxia

8

2

Dysphasia

7

1

Convulsions local

6

Gait abnormal

6

1

Confusion

5

Cardiovascular

Edema peripheral

11

1

Resistance Mechanism

Infection viral

11

Endocrine

Adrenal hypercorticism

8

Respiratory System

Upper respiratory tract infection

8

Pharyngitis

8

Sinusitis

6

Coughing

5

Skin and Appendages

Rash

8

Pruritus

8

1

Urinary System

Urinary tract infection

8

Micturition increased frequency

6

Psychiatric

Anxiety

7

1

Depression

6

Reproductive Disorders

Breast pain, female

6

Metabolic

Weight increase

5

Musculoskeletal System

Myalgia

5

Vision

Diplopia

5

Vision abnormal*

5

* This term includes blurred vision; visual deficit; vision changes; and vision troubles.

TABLE 5: Grade 3 to 4 Adverse Hematologic Laboratory Abnormalities in Refractory Anaplastic Astrocytoma Trial

Temozolomide*,†

Decreased lymphocytes

55%

Decreased platelets

19%

Decreased neutrophils

14%

Decreased leukocytes

11%

Decreased hemoglobin

4%

* Change from Grade 0 to 2 at baseline to Grade 3 or 4 during treatment.

Denominator range= 142, 158

Hematological Toxicities for Advanced Gliomas:

In clinical trial experience with 110 to 111 females and 169 to 174 males (depending on measurements), females experienced higher rates of Grade 4 neutropenia (ANC < 0.5 × 109 /L) and thrombocytopenia (< 20 × 109 /L) than males in the first cycle of therapy (12% vs. 5% and 9% vs. 3%, respectively).

In the entire safety database for which hematologic data exist (N=932), 7% (4/61) and 9.5% (6/63) of patients > 70 years experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. For patients ≤ 70 years, 7% (62/871) and 5.5% (48/879) experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. Pancytopenia, leukopenia, and anemia also occurred.

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