Temozolomide (Page 3 of 8)

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

(%)

Grade ≥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

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

NOS=not otherwise specified.

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

When laboratory abnormalities and adverse reactions were combined, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic reactions were observed in 8% of the 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

(%)

Grade 3 to 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

U rinary System

Urinary tract infection

8

Micturition increased frequency

6

Psychiatric Disorders

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 item 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.

† Dominator 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 x 10 9 /L) and thrombocytopenia (< 20 x 10 9 /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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