ONS Connect - August 2008 - (Page 33)

Table 20 - Adverse Hematologic Experiences in Patients Previously Untreated for Advanced Colorectal Cancer ( 5% of patients) ELOXATIN irinotecan ELOXATIN + 5-FU/LV + 5-FU/LV + irinotecan N=259 N=256 N=258 Hematology All Grade All Grade All Grade Parameter Grades 3/4 Grades 3/4 Grades 3/4 (%) (%) (%) (%) (%) (%) Anemia 27 3 28 4 25 3 Leukopenia 85 20 84 23 76 24 Neutropenia 81 53 77 44 71 36 Thrombocytopenia 71 5 26 2 44 4 Table 21 - Adverse Hematologic Experiences in Previously Treated Patients ( 5% of patients) 5-FU/LV ELOXATIN ELOXATIN + 5-FU/LV (N=142) (N=153) (N=150) Hematology All Grade All Grade All Grade Parameter Grades 3/4 Grades 3/4 Grades 3/4 (%) (%) (%) (%) (%) (%) Anemia 68 2 64 1 81 2 Leukopenia 34 1 13 0 76 19 Neutropenia 25 5 7 0 73 44 Thrombocytopenia 20 0 30 3 64 4 Thrombocytopenia Thrombocytopenia was frequently reported with the combination of ELOXATIN and infusional 5-FU/LV. The incidence of all hemorrhagic events in the adjuvant and previously treated patients was higher on the ELOXATIN combination arm compared to the infusional 5-FU/LV arm. These events included gastrointestinal bleeding, hematuria, and epistaxis. In the adjuvant trial, two patients died from intracerebral hemorrhages. The incidence of Grade 3/4 thrombocytopenia was 2% in adjuvant patients with colon cancer. In patients treated for advanced colorectal cancer the incidence of Grade 3/4 thrombocytopenia was 3-5%, and the incidence of these events was greater for the combination of ELOXATIN and 5-FU/LV over the irinotecan plus 5-FU/LV or 5-FU/LV control groups. Grade 3/4 gastrointestinal bleeding was reported in 0.2% of adjuvant patients receiving ELOXATIN and 5-FU/LV. In the previously untreated patients, the incidence of epistaxis was 10% in the ELOXATIN and 5-FU/LV arm, and 2% and 1%, respectively, in the irinotecan plus 5-FU/LV or irinotecan plus ELOXATIN arms. Neutropenia Neutropenia was frequently observed with the combination of ELOXATIN and 5-FU/LV, with Grade 3 and 4 events reported in 29% and 12% of adjuvant patients with colon cancer, respectively. In the adjuvant trial, 3 patients died from sepsis/neutropenic sepsis. Grade 3 and 4 events were reported in 35% and 18% of the patients previously untreated for advanced colorectal cancer, respectively. Grade 3 and 4 events were reported in 27% and 17% of previously treated patients, respectively. In adjuvant patients the incidence of either febrile neutropenia (0.7%) or documented infection with concomitant grade 3/4 neutropenia (1.1%) was 1.8% in the ELOXATIN and 5-FU/LV arm. The incidence of febrile neutropenia in the patients previously untreated for advanced colorectal cancer was 15% (3% of cycles) in the irinotecan plus 5-FU/LV arm and 4% (less than 1% of cycles) in the ELOXATIN and 5-FU/LV combination arm. Additionally, in this same population, infection with grade 3 or 4 neutropenia was 12% in the irinotecan plus 5-FU/LV, and 8% in the ELOXATIN and 5-FU/LV combination. The incidence of febrile neutropenia in the previously treated patients was 1% in the 5-FU/LV arm and 6% (less than 1% of cycles) in the ELOXATIN and 5-FU/LV combination arm. Gastrointestinal In patients receiving the combination of ELOXATIN plus infusional 5-FU/LV for adjuvant treatment for colon cancer the incidence of Grade 3/4 nausea and vomiting was greater than those receiving infusional 5-FU/LV alone (see table). In patients previously untreated for advanced colorectal cancer receiving the combination of ELOXATIN and 5-FU/LV, the incidence of Grade 3 and 4 vomiting and diarrhea was less compared to irinotecan plus 5-FU/LV controls (see table). In previously treated patients receiving the combination of ELOXATIN and 5-FU/LV, the incidence of Grade 3 and 4 nausea, vomiting, diarrhea, and mucositis/stomatitis increased compared to 5-FU/LV controls (see table). The incidence of gastrointestinal adverse events in the previously untreated and previously treated patients appears to be similar across cycles. Premedication with antiemetics, including 5-HT3 blockers, is recommended. Diarrhea and mucositis may be exacerbated by the addition of ELOXATIN to 5-FU/LV, and should be managed with appropriate supportive care. Since cold temperature can exacerbate acute neurological symptoms, ice (mucositis prophylaxis) should be avoided during the infusion of ELOXATIN. Dermatologic ELOXATIN did not increase the incidence of alopecia compared to 5-FU/LV alone. No complete alopecia was reported. The incidence of Grade 3/4 skin disorders was 2% in both the ELOXATIN plus infusional 5-FU/LV and the infusional 5-FU/LV alone arms in the adjuvant colon cancer patients. The incidence of hand-foot syndrome in patients previously untreated for advanced colorectal cancer was 2% in the irinotecan plus 5-FU/LV arm and 7% in the ELOXATIN and 5-FU/LV combination arm. The incidence of hand-foot syndrome in previously treated patients was 13% in the 5-FU/LV arm and 11% in the ELOXATIN and 5-FU/LV combination arm. Care of Intravenous Site: Extravasation may result in local pain and inflammation that may be severe and lead to complications, including necrosis. Injection site reaction, including redness, swelling, and pain, has been reported. Neurologic Peripheral sensory neuropathy was reported in adjuvant patients treated with the ELOXATIN combination with a frequency of 92% (all grades) and 13% (grade 3), and by 18 months of follow up, 21% patients had persistent peripheral sensory neuropathy (all grades). In these patients the median cycle of onset for grade 3 peripheral sensory neuropathy was 9. In patients previously untreated for advanced colorectal cancer neuropathy was reported in 82% (all grades) and 19% (grade 3/4), and in the previously treated patients in 74% (all grades) and 7% (grade 3/4) events. ELOXATIN is consistently associated with two types of peripheral neuropathy (see PRECAUTIONS, Neuropathy). In the previously treated patients, the incidence of overall and Grade 3/4 persistent peripheral neuropathy was 48% and 6%, respectively. The majority of the patients (80%) that developed grade 3 persistent neuropathy progressed from prior Grade 1 or 2 events. The median number of cycles administered on the ELOXATIN with 5-FU/LV combination arm in the previously treated patients was 6. Pulmonary ELOXATIN has been associated with pulmonary fibrosis (see PRECAUTIONS, Pulmonary Toxicity). One patient treated with the ELOXATIN combination regimen in the adjuvant trial died from eosinophilic pneumonia. Allergic Reactions Grade 3/4 hypersensitivity to ELOXATIN has been observed in 2-3% of colon cancer patients. These allergic reactions which can be fatal, can occur at any cycle, and were similar in nature and severity to those reported with other platinum-containing compounds, such as rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension. The symptoms associated with hypersensitivity reactions reported in the previously untreated patients were urticaria, pruritus, flushing of the face, diarrhea associated with oxaliplatin infusion, shortness of breath, bronchospasm, diaphoresis, chest pains, hypotension, disorientation and syncope. These reactions are usually managed with standard epinephrine, corticosteroid, antihistamine therapy, and may require discontinuation of therapy (see WARNINGS for anaphylactic/ anaphylactoid reactions). Anticoagulation and Hemorrhage There have been reports while on study and from post-marketing surveillance of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received ELOXATIN plus 5-FU/LV while on anticoagulants. Patients receiving ELOXATIN plus 5-FU/LV and requiring oral anticoagulants may require closer monitoring. Renal About 5-10% of patients in all groups had some degree of elevation of serum creatinine. The incidence of Grade 3/4 elevations in serum creatinine in the ELOXATIN and 5-FU/LV combination arm was 1% in the previously treated patients. Serum creatinine measurements were not reported in the adjuvant trial. Hepatic Hepatotoxicity (defined as elevation of liver enzymes) appears to be related to ELOXATIN combination therapy (see PRECAUTIONS). The following tables list the clinical chemistry changes associated with hepatic toxicity occurring in 5% of patients, based on adverse events reported and NCI CTC grade for adjuvant patients and patients previously untreated for advanced colorectal cancer, laboratory values and NCI CTC grade for previously treated patients. Table 22 - Adverse Hepatic Experiences in Patients with Stage II or III Colon Cancer Receiving Adjuvant Therapy ( 5% of patients) ELOXATIN + 5-FU/LV 5-FU/LV (N=1108) (N=1111) Hepatic Parameter All Grades Grade 3/4 All Grades Grade 3/4 (%) (%) (%) (%) Increase in Transaminases 57 2 34 1 ALP Increased 42 <1 20 <1 Bilirubinaemia 20 4 20 5 Table 23 - Adverse Hepatic – Clinical Chemistry Experience in Patients Previously Untreated for Advanced Colorectal Cancer ( 5% of patients) ELOXATIN irinotecan ELOXATIN + 5-FU/LV + 5-FU/LV + irinotecan N=259 N=256 N=258 Clinical Chemistry All Grade All Grade All Grade Grades 3/4 Grades 3/4 Grades 3/4 (%) (%) (%) (%) (%) (%) ALT (SGPT-ALAT) 6 1 2 0 5 2 AST (SGOT-ASAT) 17 1 2 1 11 1 Alkaline Phosphatase 16 0 8 0 14 2 Total Bilirubin 6 1 3 1 3 2 Table 24 - Adverse Hepatic – Clinical Chemistry Experience in Previously Treated Patients ( 5% of patients) 5-FU/LV ELOXATIN ELOXATIN + 5-FU/LV (N=142) (N=153) (N=150) Clinical Chemistry All Grade All Grade All Grade Grades 3/4 Grades 3/4 Grades 3/4 (%) (%) (%) (%) (%) (%) ALT (SGPT-ALAT) 28 3 36 1 31 0 AST (SGOT-ASAT) 39 2 54 4 47 0 Total Bilirubin 22 6 13 5 13 1 Thromboembolism The incidence of thromboembolic events in adjuvant patients with colon cancer was 6% (1.8% grade 3/4) in the infusional 5-FU/LV arm and 6% (1.2% grade 3/4) in the ELOXATIN and infusional 5-FU/LV combined arm, respectively. The incidence was 6 and 9% of the patients previously untreated for advanced colo

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ONS Connect - August 2008

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