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adverse reactions
6 ADVERSE REACTIONS The most common adverse reactions (≥10% incidence) are: alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, convulsions, rash, hemiparesis, diarrhea, asthenia, fever, dizziness, coordination abnormal, viral infection, amnesia, and insomnia. ( 6.1 ) The most common Grade 3 to 4 hematologic laboratory abnormalities (≥10% incidence) that have developed during treatment with temozolomide are: lymphopenia, thrombocytopenia, neutropenia, and leukopenia. ( 6.1 ) Allergic reactions have also been reported. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Schering Corporation, a subsidiary of Merck & Co., Inc. at 1-800-526-4099 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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 Multiforme: During the concomitant phase (TEMODAR+radiotherapy), adverse reactions including thrombocytopenia, nausea, vomiting, anorexia, and constipation were more frequent in the TEMODAR+RT arm. The incidence of other adverse reactions was comparable in the two arms. The most common adverse reactions across the cumulative TEMODAR experience were alopecia, nausea, vomiting, anorexia, headache, and constipation (see Table 7 ). Forty-nine percent (49%) of patients treated with TEMODAR reported one or more severe or life-threatening reactions, most commonly fatigue (13%), convulsions (6%), headache (5%), and thrombocytopenia (5%). Overall, the pattern of reactions during the maintenance phase was consistent with the known safety profile of TEMODAR. TABLE 7: Number (%) of Patients with Adverse Reactions: All and Severe/Life Threatening (Incidence of 5% or Greater) Concomitant Phase RT Alone (n=285) Concomitant Phase RT+TMZ (n=288) One patient who was randomized to RT only arm received RT+temozolomide. Maintenance Phase TMZ (n=224) All Grade ≥3 All Grade ≥3 All Grade ≥3 RT+TMZ=radiotherapy plus temozolomide; NOS=not otherwise specified. Note : Grade 5 (fatal) adverse reactions are included in the Grade ≥3 column. Subjects Reporting any Adverse Reaction 258 (91) 74 (26) 266 (92) 80 (28) 206 (92) 82 (37) Body as a Whole - General Disorders Anorexia 25 (9) 1 (<1) 56 (19) 2 (1) 61 (27) 3 (1) Dizziness 10 (4) 0 12 (4) 2 (1) 12 (5) 0 Fatigue 139 (49) 15 (5) 156 (54) 19 (7) 137 (61) 20 (9) Headache 49 (17) 11 (4) 56 (19) 5 (2) 51 (23) 9 (4) Weakness 9 (3) 3 (1) 10 (3) 5 (2) 16 (7) 4 (2) Central and Peripheral Nervous System Disorders Confusion 12 (4) 6 (2) 11 (4) 4 (1) 12 (5) 4 (2) Convulsions 20 (7) 9 (3) 17 (6) 10 (3) 25 (11) 7 (3) Memory Impairment 12 (4) 1 (<1) 8 (3) 1 (<1) 16 (7) 2 (1) Disorders of the Eye Vision Blurred 25 (9) 4 (1) 26 (9) 2 (1) 17 (8) 0 Disorders of the Immune System Allergic Reaction 7 (2) 1 (<1) 13 (5) 0 6 (3) 0 Gastrointestinal System Disorders Abdominal Pain 2 (1) 0 7 (2) 1 (<1) 11 (5) 1 (<1) Constipation 18 (6) 0 53 (18) 3 (1) 49 (22) 0 Diarrhea 9 (3) 0 18 (6) 0 23 (10) 2 (1) Nausea 45 (16) 1 (<1) 105 (36) 2 (1) 110 (49) 3 (1) Stomatitis 14 (5) 1 (<1) 19 (7) 0 20 (9) 3 (1) Vomiting 16 (6) 1 (<1) 57 (20) 1 (<1) 66 (29) 4 (2) Injury and Poisoning Radiation Injury NOS 11 (4) 1 (<1) 20 (7) 0 5 (2) 0 Musculoskeletal System Disorders Arthralgia 2 (1) 0 7 (2) 1 (<1) 14 (6) 0 Platelet, Bleeding and Clotting Disorders Thrombocytopenia 3 (1) 0 11 (4) 8 (3) 19 (8) 8 (4) Psychiatric Disorders Insomnia 9 (3) 1 (<1) 14 (5) 0 9 (4) 0 Respiratory System Disorders Coughing 3 (1) 0 15 (5) 2 (1) 19 (8) 1 (<1) Dyspnea 9 (3) 4 (1) 11 (4) 5 (2) 12 (5) 1 (<1) Skin and Subcutaneous Tissue Disorders Alopecia 179 (63) 0 199 (69) 0 124 (55) 0 Dry Skin 6 (2) 0 7 (2) 0 11 (5) 1 (<1) Erythema 15 (5) 0 14 (5) 0 2 (1) 0 Pruritus 4 (1) 0 11 (4) 0 11 (5) 0 Rash 42 (15) 0 56 (19) 3 (1) 29 (13) 3 (1) Special Senses Other, Disorders Taste Perversion 6 (2) 0 18 (6) 0 11 (5) 0 Myelosuppression (neutropenia and thrombocytopenia), which is a known dose-limiting toxicity for most cytotoxic agents, including TEMODAR, was observed. 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 the patients treated with TEMODAR. Refractory Anaplastic Astrocytoma: Tables 8 and 9 show the incidence of adverse reactions in the 158 patients in the anaplastic astrocytoma study for whom data are available. In the absence of a control group, it is not clear in many cases whether these reactions should be attributed to temozolomide or the patients' underlying conditions, but nausea, vomiting, fatigue, and hematologic effects appear to be clearly drug-related. The most frequently occurring adverse reactions were nausea, vomiting, headache, and fatigue. The adverse reactions were usually NCI Common Toxicity Criteria (CTC) Grade 1 or 2 (mild to moderate in severity) and were self-limiting, with nausea and vomiting readily controlled with antiemetics. The incidence of severe nausea and vomiting (CTC Grade 3 or 4) was 10% and 6%, respectively. 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: 21–40 days) and 28 days for neutrophils (range: 1–44 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. In clinical trial experience with 110 to 111 women and 169 to 174 men (depending on measurements), there were higher rates of Grade 4 neutropenia (ANC<500 cells/µL) and thrombocytopenia (<20,000 cells/µL) in women than men 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 over age 70 experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. For patients less than or equal to age 70, 7% (62/871) and 5.5% (48/879) experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively. Pancytopenia, leukopenia, and anemia have also been reported. TABLE 8: Adverse Reactions in the Anaplastic Astrocytoma Trial in Adults (≥5%) No. (%) of TEMODAR Patients (N=158) All Reactions Grade 3/4 Any Adverse Reaction 153 (97) 79 (50) Body as a Whole Headache 65 (41) 10 (6) Fatigue 54 (34) 7 (4) Asthenia 20 (13) 9 (6) Fever 21 (13) 3 (2) Back pain 12 (8) 4 (3) Cardiovascular Edema peripheral 17 (11) 1 (1) Central and Peripheral Nervous System Convulsions 36 (23) 8 (5) Hemiparesis 29 (18) 10 (6) Dizziness 19 (12) 1 (1) Coordination abnormal 17 (11) 2 (1) Amnesia 16 (10) 6 (4) Insomnia 16 (10) 0 Paresthesia 15 (9) 1 (1) Somnolence 15 (9) 5 (3) Paresis 13 (8) 4 (3) Urinary incontinence 13 (8) 3 (2) Ataxia 12 (8) 3 (2) Dysphasia 11 (7) 1 (1) Convulsions local 9 (6) 0 Gait abnormal 9 (6) 1 (1) Confusion 8 (5) 0 Endocrine Adrenal hypercorticism 13 (8) 0 Gastrointestinal System Nausea 84 (53) 16 (10) Vomiting 66 (42) 10 (6) Constipation 52 (33) 1 (1) Diarrhea 25 (16) 3 (2) Abdominal pain 14 (9) 2 (1) Anorexia 14 (9) 1 (1) Metabolic Weight increase 8 (5) 0 Musculoskeletal System Myalgia 8 (5) Psychiatric Disorders Anxiety 11 (7) 1 (1) Depression 10 (6) 0 Reproductive Disorders Breast pain, female 4 (6) Resistance Mechanism Disorders Infection viral 17 (11) 0 Respiratory System Upper respiratory tract infection 13 (8) 0 Pharyngitis 12 (8) 0 Sinusitis 10 (6) 0 Coughing 8 (5) 0 Skin and Appendages Rash 13 (8) 0 Pruritus 12 (8) 2 (1) Urinary System Urinary tract infection 12 (8) 0 Micturition increased frequency 9 (6) 0 Vision Diplopia 8 (5) 0 Vision abnormal Blurred vision; visual deficit; vision changes; vision troubles 8 (5) TABLE 9: Adverse Hematologic Effects (Grade 3 to 4) in the Anaplastic Astrocytoma Trial in Adults TEMODAR Change from Grade 0 to 2 at baseline to Grade 3 or 4 during treatment. Hemoglobin 7/158 (4%) Lymphopenia 83/152 (55%) Neutrophils 20/142 (14%) Platelets 29/156 (19%) WBC 18/158 (11%) TEMODAR for injection delivers equivalent temozolomide dose and exposure to both temozolomide and 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) as the corresponding TEMODAR capsules. Adverse reactions probably related to treatment that were reported from the 2 studies with the intravenous formulation (n=35) that were not reported in studies using the TEMODAR capsules were: pain, irritation, pruritus, warmth, swelling, and erythema at infusion site as well as the following adverse reactions: petechiae and hematoma. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of TEMODAR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug exposure. TEMODAR Capsules: allergic reactions, including anaphylaxis, have been reported. Erythema multiforme has been reported, which resolved after discontinuation of TEMODAR and, in some cases, recurred upon rechallenge. Cases of toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported. There have been reported cases of hepatotoxicity, including elevations of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis. Opportunistic infections including Pneumocystis carinii pneumonia (PCP) have also been reported. Cases of interstitial pneumonitis/pneumonitis, alveolitis, and pulmonary fibrosis have been reported. Prolonged pancytopenia, which may result in aplastic anemia, has been reported, and in some cases has resulted in a fatal outcome.