openFDA text is shown for search and cross-checking; DailyMed SPL is canonical.
Adverse reactions sections page 1 of 4 · 13 matching rows.
adverse reactions
6. ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 40%) were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis. Other adverse reactions, including serious adverse reactions, have been reported. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceutical Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Serious adverse reactions including anaphylaxis and allergic reactions, neuropathy, pulmonary toxicities and hepatotoxicities can occur [See Warnings and Precautions (5.1) ] . 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. More than 1100 patients with stage II or III colon cancer and more than 4,000 patients with advanced colorectal cancer have been treated in clinical studies with Oxaliplatin for Injection. The most common adverse reactions in patients with stage II or III colon cancer receiving adjuvant therapy were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis. The most common adverse reactions in previously untreated and treated patients were peripheral sensory neuropathies, fatigue, neutropenia, nausea, emesis, and diarrhea [see Warnings and Precautions (5) ] . Combination Adjuvant Therapy with Oxaliplatin for Injection and Infusional 5- fluorouracil/leucovorin in Patients with Colon Cancer One thousand one hundred and eight patients with stage II or III colon cancer, who had undergone complete resection of the primary tumor, have been treated in a clinical study with Oxaliplatin for Injection in combination with infusional 5- fluorouracil/leucovorin [see Clinical Studies (14) ] . The incidence of grade 3 or 4 adverse reactions was 70% on the Oxaliplatin for Injection combination arm, and 31% on the infusional 5- fluorouracil/leucovorin arm. The adverse reactions in this trial are shown in the tables below. Discontinuation of treatment due to adverse reactions occurred in 15% of the patients receiving Oxaliplatin for Injection and infusional 5-fluorouracil/leucovorin. Both 5-fluorouracil/leucovorin and Oxaliplatin for Injection are associated with gastrointestinal or hematologic adverse reactions. When Oxaliplatin for Injection is administered in combination with infusional 5- fluorouracil/leucovorin, the incidence of these events is increased. The incidence of death within 28 days of last treatment, regardless of causality, was 0.5% (n=6) in both the Oxaliplatin for Injection combination and infusional 5- fluorouracil/leucovorin arms, respectively. Deaths within 60 days from initiation of therapy were 0.3% (n=3) in both the Oxaliplatin for Injection combination and infusional 5- fluorouracil/leucovorin arms, respectively. On the Oxaliplatin for Injection combination arm, 3 deaths were due to sepsis/neutropenic sepsis, 2 from intracerebral bleeding and one from eosinophilic pneumonia. On the 5- fluorouracil/leucovorin arm, one death was due to suicide, 2 from Steven-Johnson Syndrome (1 patient also had sepsis), 1 unknown cause, 1 anoxic cerebral infarction and 1 probable abdominal aorta rupture. The following table provides adverse reactions reported in the adjuvant therapy colon cancer clinical trial [see Clinical Studies (14) ] by body system and decreasing order of frequency in the Oxaliplatin for Injection and infusional 5- fluorouracil/leucovorin arm for events with overall incidences ≥ 5% and for NCI grade 3/4 events with incidences ≥ 1%. Table 3 - Adverse Reactions Reported in Patients with Colon Cancer receiving Adjuvant Treatment (≥5% of all patients and with ≥1% NCI Grade 3/4 events) 1 Includes thrombosis related to the catheter Oxaliplatin for Injection + 5-FU/LV N=1108 5-FU/LV N=1111 Adverse reaction (WHO/Pref) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) Any Event 100 70 99 31 Allergy/Immunology Allergic Reaction 10 3 2 <1 Constitutional Symptoms/Pain Fatigue 44 4 38 1 Abdominal Pain 18 1 17 2 Dermatology/Skin Skin Disorder 32 2 36 2 Injection Site Reaction 1 11 3 10 3 Gastrointestinal Nausea 74 5 61 2 Diarrhea 56 11 48 7 Vomiting 47 6 24 1 Stomatitis 42 3 40 2 Anorexia 13 1 8 <1 Fever/Infection Fever 27 1 12 1 Infection 25 4 25 3 Neurology Overall Peripheral Sensory Neuropathy 92 12 16 <1 The following table provides adverse reactions reported in the adjuvant therapy colon cancer clinical trial [see Clinical Studies (14) ] by body system and decreasing order of frequency in the Oxaliplatin for Injection and infusional 5- fluorouracil/leucovorin arm for events with overall incidences ≥ 5% but with incidences <1% NCI grade 3/4 events. Table 4 - Adverse Reactions Reported in Patients with Colon Cancer receiving Adjuvant Treatment (≥ 5% of all patients, but with <1% NCI Grade 3/4 events) Adverse reaction Oxaliplatin for Injection + 5-FU/LV 5-FU/LV (WHO/Pref) N=1108 N=1111 All Grades (%) All Grades (%) Allergy/Immunology Rhinitis 6 8 Constitutional Symptoms/Pain/Ocular/Visual Epistaxis 16 12 Weight Increase 10 10 Conjunctivitis 9 15 Headache 7 5 Dyspnea 5 3 Pain 5 5 Lacrimation Abnormal 4 12 Dermatology/Skin Alopecia 30 28 Gastrointestinal Constipation 22 19 Taste Perversion 12 8 Dyspepsia 8 5 Metabolic Phosphate Alkaline increased 42 20 Neurology Sensory Disturbance 8 1 Although specific events can vary, the overall frequency of adverse reactions was similar in men and women and in patients <65 and ≥65 years. However, the following grade 3/4 events were more common in females: diarrhea, fatigue, granulocytopenia, nausea and vomiting. In patients ≥65 years old, the incidence of grade 3/4 diarrhea and granulocytopenia was higher than in younger patients. Insufficient subgroup sizes prevented analysis of safety by race. The following additional adverse reactions, were reported in ≥2% and <5% of the patients in the Oxaliplatin for Injection and infusional 5- fluorouracil/leucovorin combination arm (listed in decreasing order of frequency): pain, leukopenia, weight decrease, coughing. The number of patients who developed secondary malignancies was similar; 62 in the Oxaliplatin for Injection combination arm and 68 in the infusional 5-fluorouracil/leucovorin arm. An exploratory analysis showed that the number of deaths due to secondary malignancies was 1.96% in the Oxaliplatin for Injection combination arm and 0.98% in infusional 5- fluorouracil/leucovorin arm. In addition, the number of cardiovascular deaths was 1.4% in the Oxaliplatin for Injection combination arm as compared to 0.7% in the infusional 5- fluorouracil/leucovorin arm. Clinical significance of these findings is unknown. Patients Previously Untreated for Advanced Colorectal Cancer Two hundred and fifty-nine patients were treated in the Oxaliplatin for Injection and 5- fluorouracil/leucovorin combination arm of the randomized trial in patients previously untreated for advanced colorectal cancer [see Clinical Studies (14) ] . The adverse reaction profile in this study was similar to that seen in other studies and the adverse reactions in this trial are shown in the tables below. Both 5- fluorouracil and Oxaliplatin for Injection are associated with gastrointestinal and hematologic adverse reactions. When Oxaliplatin for Injection is administered in combination with 5- fluorouracil, the incidence of these events is increased. The incidence of death within 30 days of treatment in the previously untreated for advanced colorectal cancer study, regardless of causality, was 3% with the Oxaliplatin for Injection and 5- fluorouracil/leucovorin combination, 5% with irinotecan plus 5- fluorouracil/leucovorin, and 3% with Oxaliplatin for Injection plus irinotecan. Deaths within 60 days from initiation of therapy were 2.3% with the Oxaliplatin for Injection and 5- fluorouracil/leucovorin combination, 5.1% with irinotecan plus 5- fluorouracil/leucovorin, and 3.1% with Oxaliplatin for Injection plus irinotecan. The following table provides adverse reactions reported in the previously untreated for advanced colorectal cancer study [see Clinical Studies (14) ] by body system and decreasing order of frequency in the Oxaliplatin for Injection and 5- fluorouracil/leucovorin combination arm for events with overall incidences ≥5% and for grade 3/4 events with incidences ≥1%. Table 5 – Adverse Reactions Reported in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial (≥5% of all patients and with ≥1% NCI Grade 3/4 events) * Not otherwise specified ** Absolute neutrophil count Oxaliplatin for Injection + 5-FU/LV N=259 irinotecan + 5-FU/LV N=256 Oxaliplatin for Injection + irinotecan N=258 Adverse reaction (WHO/Pref) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) Any Event 99 82 98 70 99 76 Allergy/Immunology Hypersensitivity 12 2 5 0 6 1 Cardiovascular Thrombosis 6 5 6 6 3 3 Hypotension 5 3 6 3 4 3 Constitutional Symptoms/Pain/Ocular/Visual Fatigue 70 7 58 11 66 16 Abdominal Pain 29 8 31 7 39 10 Myalgia 14 2 6 0 9 2 Pain 7 1 5 1 6 1 Vision abnormal 5 0 2 1 6 1 Neuralgia 5 0 0 0 2 1 Dermatology/Skin Skin reaction – hand/foot 7 1 2 1 1 0 Injection site reaction 6 0 1 0 4 1 Gastrointestinal Nausea 71 6 67 15 83 19 Diarrhea 56 12 65 29 76 25 Vomiting 41 4 43 13 64 23 Stomatitis 38 0 25 1 19 1 Anorexia 35 2 25 4 27 5 Constipation 32 4 27 2 21 2 Diarrhea-colostomy 13 2 16 7 16 3 Gastrointestinal NOS* 5 2 4 2 3 2 Hematology/Infection Infection normal ANC** 10 4 5 1 7 2 Infection low ANC** 8 8 12 11 9 8 Lymphopenia 6 2 4 1 5 2 Febrile neutropenia 4 4 15 14 12 11 Hepatic/Metabolic/Laboratory/Renal Hyperglycemia 14 2 11 3 12 3 Hypokalemia 11 3 7 4 6 2 Dehydration 9 5 16 11 14 7 Hypoalbuminemia 8 0 5 2 9 1 Hyponatremia 8 2 7 4 4 1 Urinary frequency 5 1 2 1 3 1 Neurology Overall Neuropathy 82 19 18 2 69 7 Paresthesias 77 18 16 2 62 6 Pharyngo-laryngeal dysesthesias 38 2 1 0 28 1 Neuro-sensory 12 1 2 0 9 1 Neuro NOS* 1 0 1 0 1 0 Pulmonary Cough 35 1 25 2 17 1 Dyspnea 18 7 14 3 11 2 Hiccups 5 1 2 0 3 2 The following table provides adverse reactions reported in the previously untreated for advanced colorectal cancer study [see Clinical Studies (14) ] by body system and decreasing order of frequency in the Oxaliplatin for Injection and 5- fluorouracil/leucovorin combination arm for events with overall incidences ≥5% but with incidences <1% NCI Grade 3/4 events. Table 6 - Adverse Reactions Reported in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial (≥5% of all patients but with < 1% NCI Grade 3/4 events) * Absolute neutrophil count Oxaliplatin for Injection + irinotecan + 5-FU/LV Oxaliplatin for Injection + 5-FU/LV N=256 irinotecan N=259 N=258 Adverse reaction All Grades All Grades All Grades (WHO/Pref) (%) (%) (%) Allergy/Immunology Rash 11 4 7 Rhinitis allergic 10 6 6 Cardiovascular Edema 15 13 10 Constitutional Symptoms/Pain/Ocular/Visual Headache 13 6 9 Weight loss 11 9 11 Epistaxis 10 2 2 Tearing 9 1 2 Rigors 8 2 7 Dysphasia 5 3 3 Sweating 5 6 12 Arthralgia 5 5 8 Dermatology/Skin Alopecia 38 44 67 Flushing 7 2 5 Pruritis 6 4 2 Dry Skin 6 2 5 Gastrointestinal Taste perversion 14 6 8 Dyspepsia 12 7 5 Flatulence 9 6 5 Mouth Dryness 5 2 3 Hematology/Infection Fever normal ANC* 16 9 9 Hepatic/Metabolic/Laboratory/Renal Hypocalcemia 7 5 4 Elevated Creatinine 4 4 5 Neurology Insomnia 13 9 11 Depression 9 5 7 Dizziness 8 6 10 Anxiety 5 2 6 Adverse reactions were similar in men and women and in patients <65 and ≥65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, leukopenia, fatigue and syncope. The following additional adverse reactions, at least possibly related to treatment and potentially important, were reported in ≥2% and <5% of the patients in the Oxaliplatin for Injection and 5- fluorouracil/leucovorin combination arm (listed in decreasing order of frequency): metabolic, pneumonitis, catheter infection, vertigo, prothrombin time, pulmonary, rectal bleeding, dysuria, nail changes, chest pain, rectal pain, syncope, hypertension, hypoxia, unknown infection, bone pain, pigmentation changes, and urticaria. Previously Treated Patients with Advanced Colorectal Cancer Four hundred and fifty patients (about 150 receiving the combination of Oxaliplatin for Injection and 5- fluorouracil/leucovorin) were studied in a randomized trial in patients with refractory and relapsed colorectal cancer [see Clinical Studies (14) ] . The adverse reaction profile in this study was similar to that seen in other studies and the adverse reactions in this trial are shown in the tables below. Thirteen percent of patients in the Oxaliplatin for Injection and 5- fluorouracil/leucovorin combination arm and 18% in the 5- fluorouracil/leucovorin arm of the previously treated study had to discontinue treatment because of adverse effects related to gastrointestinal, or hematologic adverse reactions, or neuropathies. Both 5- fluorouracil and Oxaliplatin for Injection are associated with gastrointestinal and hematologic adverse reactions. When Oxaliplatin for Injection is administered in combination with 5- fluorouracil, the incidence of these events is increased. The incidence of death within 30 days of treatment in the previously treated study, regardless of causality, was 5% with the Oxaliplatin for Injection and 5- fluorouracil/leucovorin combination, 8% with Oxaliplatin for Injection alone, and 7% with 5- fluorouracil/leucovorin. Of the 7 deaths that occurred on the Oxaliplatin for Injection and 5- fluorouracil/leucovorin combination arm within 30 days of stopping treatment, 3 may have been treatment related, associated with gastrointestinal bleeding or dehydration. The following table provides adverse reactions reported in the previously treated study [see Clinical Studies (14) ] by body system and in decreasing order of frequency in the Oxaliplatin for Injection and 5- fluorouracil/leucovorin combination arm for events with overall incidences ≥5% and for grade 3/4 events with incidences ≥1%. This table does not include hematologic and blood chemistry abnormalities; these are shown separately below. Table 7 – Adverse Reactions Reported In Previously Treated Colorectal Cancer Clinical Trial (≥5% of all patients and with ≥1% NCI Grade 3/4 events) 5-FU/LV (N=142) Oxaliplatin for Injection (N=153) Oxaliplatin for Injection + 5-FU/LV (N=150) Adverse reaction (WHO/Pref) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) Any Event 98 41 100 46 99 73 Cardiovascular Dyspnea 11 2 13 7 20 4 Coughing 9 0 11 0 19 1 Edema 13 1 10 1 15 1 Thromboembolism 4 2 2 1 9 8 Chest Pain 4 1 5 1 8 1 Constitutional Symptoms/Pain Fatigue 52 6 61 9 68 7 Back Pain 16 4 11 0 19 3 Pain 9 3 14 3 15 2 Dermatology/Skin Injection Site Reaction 5 1 9 0 10 3 Gastrointestinal Diarrhea 44 3 46 4 67 11 Nausea 59 4 64 4 65 11 Vomiting 27 4 37 4 40 9 Stomatitis 32 3 14 0 37 3 Abdominal Pain 31 5 31 7 33 4 Anorexia 20 1 20 2 29 3 Gastroesophageal Reflux 3 0 1 0 5 2 Hematology/Infection Fever 23 1 25 1 29 1 Febrile Neutropenia 1 1 0 0 6 6 Hepatic/Metabolic/Laboratory/Renal Hypokalemia 3 1 3 2 9 4 Dehydration 6 4 5 3 8 3 Neurology Neuropathy 17 0 76 7 74 7 Acute 10 0 65 5 56 2 Persistent 9 0 43 3 48 6 The following table provides adverse reactions reported in the previously treated study [see Clinical Studies (14) ] by body system and in decreasing order of frequency in the Oxaliplatin for Injection and 5- fluorouracil/leucovorin combination arm for events with overall incidences ≥5% but with incidences <1% NCI Grade 3/4 events. Table 8 - Adverse Reactions Reported In Previously Treated Colorectal Cancer Clinical Trial (≥5% of all patients but with < 1% NCI Grade 3/4 events) 5-FU/LV Oxaliplatin for Oxaliplatin for Injection Injection (N=153) + 5-FU/LV (N=142) (N=150) Adverse reaction All All All (WHO/Pref) Grades (%) Grades (%) Grades (%) Allergy/Immunology Rhinitis 4 6 15 Allergic Reaction 1 3 10 Rash 5 5 9 Cardiovascular Peripheral Edema 11 5 10 Constitutional Symptoms/Pain/Ocular/Visual Headache 8 13 17 Arthralgia 10 7 10 Epistaxis 1 2 9 Abnormal Lacrimation 6 1 7 Rigors 6 9 7 Dermatology/Skin Hand-Foot Syndrome 13 1 11 Flushing 2 3 10 Alopecia 3 3 7 Gastrointestinal Constipation 23 31 32 Dyspepsia 10 7 14 Taste Perversion 1 5 13 Mucositis 10 2 7 Flatulence 6 3 5 Hepatic/Metabolic/Laboratory/Renal Hematuria 4 0 6 Dysuria 1 1 6 Neurology Dizziness 8 7 13 Insomnia 4 11 9 Pulmonary Upper Resp Tract Infection 4 7 10 Pharyngitis 10 2 9 Hiccup 0 2 5 Adverse reactions were similar in men and women and in patients <65 and ≥65 years, but older patients may have been more susceptible to dehydration, diarrhea, hypokalemia and fatigue. The following additional adverse reactions, at least possibly related to treatment and potentially important, were reported in ≥2% and <5% of the patients in the Oxaliplatin for Injection and 5- fluorouracil/leucovorin combination arm (listed in decreasing order of frequency): anxiety, myalgia, erythematous rash, increased sweating, conjunctivitis, weight decrease, dry mouth, rectal hemorrhage, depression, ataxia, ascites, hemorrhoids, muscle weakness, nervousness, tachycardia, abnormal micturition frequency, dry skin, pruritus, hemoptysis, purpura, vaginal hemorrhage, melena, somnolence, pneumonia, proctitis, involuntary muscle contractions, intestinal obstruction, gingivitis, tenesmus, hot flashes, enlarged abdomen, urinary incontinence. Hematologic Changes The following tables list the hematologic changes occurring in ≥5% of patients, based on laboratory values and NCI grade, with the exception of those events occurring in adjuvant patients and anemia in the patients previously untreated for advanced colorectal cancer, respectively, which are based on AE reporting and NCI grade alone. Table 9 - Adverse Hematologic Reactions in Patients with Colon Cancer Receiving Adjuvant Therapy (≥5% of patients) Oxaliplatin for Injection + 5- 5-FU/LV FU/LV (N=1111) (N=1108) Hematology Parameter All Grades Grade 3/4 All Grade 3/4 (%) (%) Grades (%) (%) Anemia 76 1 67 <1 Neutropenia 79 41 40 5 Thrombocytopenia 77 2 19 <1 Table 10 – Adverse Hematologic Reactions in Patients Previously Untreated for Advanced Colorectal Cancer (≥5% of patients) Oxaliplatin for Injection Irinotecan Oxaliplatin for + 5-FU/LV + 5-FU/LV Injection + irinotecan (N=259) (N=256) (N=258) All Grade All Grade All Grade Hematology Grades 3/4 Grades 3/4 Grades 3/4 Parameter (%) (%) (%) (%) (%) (%) 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 11 – Adverse Hematologic Reactions in Previously Treated Patients (≥5% of patients) 5-FU/LV Oxaliplatin for Injection Oxaliplatin for Injection (N=142) (N=153) + 5-FU/LV Hematology (N=150) Parameter All Grades Grade 3/4 All Grades Grade 3/4 All Grade 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 and Bleeding Thrombocytopenia was frequently reported with the combination of Oxaliplatin for Injection and infusional 5- fluorouracil/leucovorin. The incidence of all hemorrhagic events in the adjuvant and previously treated patients was higher on the Oxaliplatin for Injection combination arm compared to the infusional 5- fluorouracil/leucovorin 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 Oxaliplatin for Injection and 5- fluorouracil/leucovorin over the irinotecan plus 5- fluorouracil/leucovorin or 5- fluorouracil/leucovorin control groups. Grade 3/4 gastrointestinal bleeding was reported in 0.2% of adjuvant patients receiving Oxaliplatin for Injection and 5- fluorouracil/leucovorin. In the previously untreated patients, the incidence of epistaxis was 10% in the Oxaliplatin for Injection and 5- fluorouracil/leucovorin arm, and 2% and 1%, respectively, in the irinotecan plus 5- fluorouracil/leucovorin or irinotecan plus Oxaliplatin for Injection arms. Neutropenia Neutropenia was frequently observed with the combination of Oxaliplatin for Injection and 5- fluorouracil/leucovorin, 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 Oxaliplatin for Injection and 5- fluorouracil/leucovorin 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- fluorouracil/leucovorin arm and 4% (less than 1% of cycles) in the Oxaliplatin for Injection and 5- fluorouracil/leucovorin combination arm. Additionally, in this same population, infection with grade 3 or 4 neutropenia was 12% in the irinotecan plus 5- fluorouracil/leucovorin, and 8% in the Oxaliplatin for Injection and 5- fluorouracil/leucovorin combination. The incidence of febrile neutropenia in the previously treated patients was 1% in the 5- fluorouracil/leucovorin arm and 6% (less than 1% of cycles) in the Oxaliplatin for Injection and 5- fluorouracil/leucovorin combination arm. Gastrointestinal In patients receiving the combination of Oxaliplatin for Injection plus infusional 5- fluorouracil/leucovorin for adjuvant treatment for colon cancer the incidence of Grade 3/4 nausea and vomiting was greater than those receiving infusional 5- fluorouracil/leucovorin alone (see table). In patients previously untreated for advanced colorectal cancer receiving the combination of Oxaliplatin for Injection and 5- fluorouracil/leucovorin, the incidence of Grade 3 and 4 vomiting and diarrhea was less compared to irinotecan plus 5- fluorouracil/leucovorin controls (see table). In previously treated patients receiving the combination of Oxaliplatin for Injection and 5- fluorouracil/leucovorin, the incidence of Grade 3 and 4 nausea, vomiting, diarrhea, and mucositis/stomatitis increased compared to 5- fluorouracil/leucovorin controls (see table). The incidence of gastrointestinal adverse reactions in the previously untreated and previously treated patients appears to be similar across cycles. Premedication with antiemetics, including 5-HT 3 blockers, is recommended. Diarrhea and mucositis may be exacerbated by the addition of Oxaliplatin for Injection to 5- fluorouracil/leucovorin, 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 Oxaliplatin for Injection. Dermatologic Oxaliplatin for Injection did not increase the incidence of alopecia compared to 5- fluorouracil/leucovorin alone. No complete alopecia was reported. The incidence of Grade 3/4 skin disorders was 2% in both the Oxaliplatin for Injection plus infusional 5- fluorouracil/leucovorin and the infusional 5- fluorouracil/leucovorin 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- fluorouracil/leucovorin arm and 7% in the Oxaliplatin for Injection and 5- fluorouracil/leucovorin combination arm. The incidence of hand-foot syndrome in previously treated patients was 13% in the 5- fluorouracil/leucovorin arm and 11% in the Oxaliplatin for Injection and 5- fluorouracil/leucovorin combination arm. Intravenous Site Reactions Extravasation, in some cases including necrosis, has been reported. Injection site reaction, including redness, swelling, and pain, has been reported. 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 Oxaliplatin for Injection plus 5- fluorouracil/leucovorin while on anticoagulants. Patients receiving Oxaliplatin for Injection plus 5- fluorouracil/leucovorin 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 Oxaliplatin for Injection and 5- fluorouracil/leucovorin 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 Oxaliplatin for Injection combination therapy [see Warnings and Precautions (5.4) ] . The following tables list the clinical chemistry changes associated with hepatic toxicity occurring in ≥5% of patients, based on adverse reactions 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 12 - Adverse Hepatic Reactions in Patients with Stage II or III Colon Cancer Receiving Adjuvant Therapy (≥5% of patients) Hepatic Parameter Oxaliplatin for Injection + 5-FU/LV (N=1111) 5-FU/LV (N=1108) All Grades (%) Grade ¾ (%) All Grades (%) Grade ¾ (%) Increase in transaminases 57 2 34 1 ALP increased 42 <1 20 <1 Bilirubinaemia 20 4 20 5 Table 13 – Adverse Hepatic – Clinical Chemistry Abnormalities in Patients Previously Untreated for Advanced Colorectal Cancer (≥5% of patients) Clinical Chemistry Oxaliplatin for Injection + 5-FU/LV irinotecan + 5-FU/LV (N=256) Oxaliplatin for Injection + irinotecan (N=258) (N=259) All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 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 14 – Adverse Hepatic – Clinical Chemistry Abnormalities in Previously Treated Patients (≥5% of patients) 5-FU/LV (N=142) Oxaliplatin for Injection Oxaliplatin for Injection (N=153) + 5-FU/LV (N=150) Clinical All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Chemistry (%) (%) (%) (%) (%) (%) 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- fluorouracil/leucovorin arm and 6% (1.2% grade 3/4) in the Oxaliplatin for Injection and infusional 5- fluorouracil/leucovorin combined arm, respectively. The incidence was 6 and 9% of the patients previously untreated for advanced colorectal cancer and previously treated patients in the Oxaliplatin for Injection and 5- fluorouracil/leucovorin combination arm, respectively. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Oxaliplatin for Injection. 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 drug exposure. Body as a whole: angioedema, anaphylactic shock Central and peripheral nervous system disorders: loss of deep tendon reflexes, dysarthria, Lhermitte's sign, cranial nerve palsies, fasciculations, convulsion, Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES). Liver and Gastrointestinal system disorders: severe diarrhea/vomiting resulting in hypokalemia, colitis (including Clostridium difficile diarrhea), metabolic acidosis; ileus; intestinal obstruction, pancreatitis; veno-occlusive disease of liver also known as sinusoidal obstruction syndrome, and perisinusoidal fibrosis which rarely may progress. Hearing and vestibular system disorders: deafness Platelet, bleeding, and clotting disorders: immuno-allergic thrombocytopenia prolongation of prothrombin time and of INR in patients receiving anticoagulants Red Blood Cell disorders: hemolytic uremic syndrome, immuno-allergic hemolytic anemia Renal disorders: Acute tubular necrosis, acute interstitial nephritis and acute renal failure. Respiratory system disorders: pulmonary fibrosis, and other interstitial lung diseases (sometimes fatal) Vision disorders: decrease of visual acuity, visual field disturbance, optic neuritis and transient vision loss (reversible following therapy discontinuation)