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.