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adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: Anaphylaxis and Allergic reactions [ see Boxed Warning, Warnings and Precautions ( 5.1 ).] Neuropathy [see Warnings and Precautions ( 5.2 ).] Severe Neutropenia [see Warnings and Precautions ( 5.3 ).] Pulmonary Toxicities [see Warnings and Precautions ( 5.4 ).] Hepatotoxicity [see Warnings and Precautions ( 5.5 ).] Cardiovascular Toxicities [see Warnings and Precautions ( 5.6 ).] Rhabdomyolysis [see Warnings and Precautions ( 5.7 ).] 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 NorthStar Rx LLC at 1-800-206-7821 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. 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 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 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 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 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 injection and infusional 5-fluorouracil/leucovorin. Both 5‑fluorouracil/leucovorin and oxaliplatin are associated with gastrointestinal or hematologic adverse reactions. When oxaliplatin 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 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 injection combination and infusional 5-fluorouracil/leucovorin arms, respectively. On the oxaliplatin 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 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 + 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 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 (WHO/Pref) Oxaliplatin + 5‑FU/LV N=1108 5-FU/LV 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 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 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 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 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 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 are associated with gastrointestinal and hematologic adverse reactions. When oxaliplatin 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 and 5‑fluorouracil/leucovorin combination, 5% with irinotecan plus 5-fluorouracil/leucovorin, and 3% with oxaliplatin plus irinotecan. Deaths within 60 days from initiation of therapy were 2.3% with the oxaliplatin and 5‑fluorouracil/leucovorin combination, 5.1% with irinotecan plus 5‑fluorouracil/leucovorin, and 3.1% with oxaliplatin 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 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 + 5‑FU/LV N=259 Irinotecan + 5‑FU/LV N=256 Oxaliplatin + 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 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 Adverse reaction (WHO/Pref) Oxaliplatin + 5-FU/LV N=259 Irinotecan + 5‑FU/LV N=256 Oxaliplatin + irinotecan N=258 All Grades (%) All Grades (%) All Grades (%) 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 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 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 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 are associated with gastrointestinal and hematologic adverse reactions. When oxaliplatin 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 and 5-fluorouracil/leucovorin combination, 8% with oxaliplatin alone, and 7% with 5-fluorouracil/leucovorin. Of the 7 deaths that occurred on the oxaliplatin 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 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 (N = 153) Oxaliplatin + 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 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of oxaliplatin 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 Cardiovascular disorders: QT prolongation leading to ventricular arrhythmias including fatal Torsade de Pointes 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). Hearing and vestibular system disorders: deafness Infections: septic shock, including fatal outcomes Infusion reactions/hypersensitivity: laryngospasm 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. Musculoskeletal and connective tissue disorders rhabdomyolysis, including fatal outcomes. 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)