Oxaliplatin

Generic: OXALIPLATIN

Prescription DrugINTRAVENOUS

Drug Information

Brand Name: Oxaliplatin
Generic Name: OXALIPLATIN
Manufacturer: Meitheal Pharmaceuticals Inc.
Product Type: Prescription Drug
Route: INTRAVENOUS
Application Number: 11377169-7986-45b1-8298-6f0533efa3c3

Pharmacological Class

Platinum-based Drug [EPC]

Indications & Usage

1 INDICATIONS AND USAGE Oxaliplatin Injection, in combination with infusional fluorouracil and leucovorin, is indicated for: adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor. treatment of advanced colorectal cancer. Oxaliplatin Injection is a platinum-based drug used in combination with infusional fluorouracil and leucovorin, which is indicated for: adjuvant treatment of stage III colon cancer in patients who have undergone compl...

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Warnings

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5 WARNINGS AND PRECAUTIONS Peripheral Sensory Neuropathy : Acute and delayed neuropathy can occur. Avoid topical application of ice. Reduce the dose or permanently discontinue oxaliplatin as recommended. ( 5.2 ) Severe Myelosuppression : Delay oxaliplatin until neutrophils are greater than or equal to 1.5 × 10 9 /L and platelets are greater than or equal to 75 × 10 9 /L. Withhold oxaliplatin for sepsis or septic shock. Dose reduce after recovery from grade 4 neutropenia, febrile neutropenia, or grade 3 to 4 thrombocytopenia as recommended. ( 5.3 ) Posterior Reversible Encephalopathy Syndrome (PRES) : Permanently discontinue oxaliplatin in patients who develop PRES. ( 5.4 ) Pulmonary Toxicity : Withhold oxaliplatin until investigation excludes interstitial lung disease or pulmonary fibrosis. ( 5.5 ) Hepatotoxicity : Monitor liver function tests at baseline, before each subsequent cycle, and as clinically indicated. ( 5.6 ) QT Interval Prolongation : Avoid in patients with congenital long QT syndrome. Monitor electrocardiograms in patients with congestive heart failure, bradyarrhythmias, and electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Correct electrolyte abnormalities prior to initiating oxaliplatin and periodically during treatment. ( 5.7 ) Rhabdomyolysis : Permanently discontinue oxaliplatin if rhabdomyolysis occurs. ( 5.8 ) Hemorrhage : Increase frequency of monitoring in patients who are receiving oxaliplatin with fluorouracil/leucovorin and oral anticoagulants ( 5.9 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise males and females of reproductive potential to use an effective method of contraception. ( 5.10 , 8.1 , 8.3 ) 5.1 Hypersensitivity Reactions Serious and fatal hypersensitivity reactions, including anaphylaxis, can occur with oxaliplatin within minutes of administration and during any cycle. Grade 3 to 4 hypersensitivity reactions, including anaphylaxis, occurred in 2% to 3% of patients with colon cancer who received oxaliplatin. Hypersensitivity reactions, including rash, urticaria, erythema, pruritus, and rarely, bronchospasm and hypotension, were similar in nature and severity to those reported with other platinum-based drugs. Oxaliplatin is contraindicated in patients with hypersensitivity reactions to platinum-based drugs [see Contraindications ( 4 )] . Immediately and permanently discontinue oxaliplatin for hypersensitivity reactions and administer appropriate treatment for management of hypersensitivity reactions. 5.2 Peripheral Sensory Neuropathy Oxaliplatin can cause acute and delayed neuropathy. Reduce the dose or permanently discontinue oxaliplatin for persistent neurosensory reactions based on the severity of the adverse reaction [see Dosage and Administration ( 2.2 )] . Acute Neuropathy Acute neuropathy typically presents as a reversible, primarily peripheral sensory neuropathy that occurs within hours or 2 days following a dose, resolves within 14 days, and frequently recurs with further dosing. The symptoms can be precipitated or exacerbated by exposure to cold temperature or cold objects and they usually present as transient paresthesia, dysesthesia and hypoesthesia in the hands, feet, perioral area, or throat. Jaw spasm, abnormal tongue sensation, dysarthria, eye pain, and a feeling of chest pressure have also been observed. The acute, reversible pattern of sensory neuropathy was observed in about 56% of patients who received oxaliplatin with fluorouracil/leucovorin. In any individual cycle, acute neuropathy occurred in approximately 30% of patients. For grade 3 peripheral sensory neuropathy, the median time to onset was 9 cycles for adjuvant treatment and 6 cycles for previously treated advanced colorectal cancer. An acute syndrome of pharyngolaryngeal dysesthesia occurred in 1% to 2% (grade 3 to 4) of patients previously untreated for advanced colorectal cancer. Subjective sensations of dysphagia or dyspnea, without any laryngospasm or bronchospasm (no stridor or wheezing) occurred in patients previously treated for advanced colorectal cancer. Avoid topical application of ice for mucositis prophylaxis or other conditions, because cold temperature can exacerbate acute neurological symptoms. Delayed Neuropathy Delayed neuropathy typically presents as a persistent (greater than 14 days), primarily peripheral sensory neuropathy that is usually characterized by paresthesias, dysesthesias, and hypoesthesias, but may also include deficits in proprioception that can interfere with daily activities (e.g., writing, buttoning, swallowing, and difficulty walking from impaired proprioception). These forms of neuropathy occurred in 48% of patients receiving oxaliplatin. Delayed neuropathy can occur without any prior acute neuropathy. Most patients (80%) who developed grade 3 persistent neuropathy progressed from prior grade 1 or 2 reactions. These symptoms may improve in some patients upon discontinuation of oxaliplatin. Adjuvant treatment In the adjuvant treatment trial, neuropathy was graded using NCI CTC, version 1 as summarized in Table 3 . Table 3: Grading for Neuropathy in Adjuvant Treatment Trial Grade Definition 0 No change or none 1 Mild paresthesias, loss of deep tendon reflexes 2 Mild or moderate objective sensory loss, moderate paresthesias 3 Severe objective sensory loss or paresthesias that interfere with function 4 Not applicable Peripheral sensory neuropathy occurred in 92% of patients (all grades), including 13% of patients (grade 3) who received oxaliplatin with fluorouracil/leucovorin. At the 28-day follow-up after the last treatment cycle, 60% of patients had any grade (grade 1=40%, grade 2=16%, grade 3=5%) peripheral sensory neuropathy, decreasing to 39% at 6 months of follow-up (grade 1=31%, grade 2=7%, grade 3=1%) and 21% at 18 months of follow-up (grade 1=17%, grade 2=3%, grade 3=1%). Advanced colorectal cancer In the advanced colorectal cancer trials, neuropathy was graded using the neurotoxicity scale summarized in Table 4 . Table 4: Grading for Neuropathy in Advanced Colorectal Cancer Trials Grade Definition 1 Resolved and did not interfere with functioning 2 Interfered with function but not daily activities 3 Pain or functional impairment that interfered with daily activities 4 Persistent impairment that is disabling or life-threatening Neuropathy occurred in 82% (all grades) of patients previously untreated for advanced colorectal cancer, including 19% grade 3 to 4; and in 74% (all grades) of patients previously treated for advanced colorectal cancer, including 7% grade 3 to 4. 5.3 Severe Myelosuppression Grade 3 or 4 neutropenia occurred in 41% to 44% of patients with colorectal cancer who received oxaliplatin with fluorouracil/leucovorin. Sepsis, neutropenic sepsis and septic shock, including fatal outcomes, occurred in patients who received oxaliplatin [see Adverse Reactions ( 6.1 , 6.2 )] . Grade 3 or 4 thrombocytopenia occurred in 2% to 5% of patients with colorectal cancer who received oxaliplatin with fluorouracil/leucovorin. Monitor complete blood cell count at baseline, before each subsequent cycle and as clinically indicated. Delay oxaliplatin until neutrophils are greater than or equal to 1.5 × 10 9 /L and platelets are greater than or equal to 75 × 10 9 /L. Withhold oxaliplatin for sepsis or septic shock. Dose reduce oxaliplatin after recovery from grade 4 neutropenia, febrile neutropenia or grade 3 to 4 thrombocytopenia as recommended [see Dosage and Administration ( 2.2 )] . 5.4 Posterior Reversible Encephalopathy Syndrome PRES occurred in less than 0.1% of patients across clinical trials [see Adverse Reactions ( 6.1 )] . Signs and symptoms of PRES can include headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension. Confirm the diagnosis of PRES with magnetic resonance imaging. Permanently discontinue oxaliplatin in patients who develop PRES. 5.5 Pulmonary Toxicity Oxaliplatin has been associated with pulmonary fibrosis (less than 1% of patients), which may be fatal [see Adverse Reactions ( 6.1 )] . In the adjuvant treatment trial, the combined incidence of cough and dyspnea was 7.4% (any grade), including less than 1% (grade 3) in the oxaliplatin arm. One patient died from eosinophilic pneumonia in the oxaliplatin arm. In the previously untreated advanced colorectal cancer trial, the combined incidence of cough, dyspnea, and hypoxia was 43% (any grade), including 7% (grade 3 to 4) in the oxaliplatin with fluorouracil/leucovorin arm. In case of unexplained respiratory symptoms, such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, withhold oxaliplatin until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis. Permanently discontinue oxaliplatin for confirmed interstitial lung disease or pulmonary fibrosis. 5.6 Hepatotoxicity In the adjuvant treatment trial, increased transaminases (57% vs 34%) and alkaline phosphatase (42% vs 20%) occurred more commonly in the oxaliplatin arm than in the fluorouracil/leucovorin arm [see Adverse Reactions ( 6.1 )] . The incidence of increased bilirubin was similar on both arms. Changes noted on liver biopsies include: peliosis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive lesions. Consider evaluating patients who develop abnormal liver tests or portal hypertension, which cannot be explained by liver metastases, for hepatic vascular disorders. Monitor liver function tests at baseline, before each subsequent cycle, and as clinically indicated. 5.7 QT Interval Prolongation and Ventricular Arrhythmias QT prolongation and ventricular arrhythmias, including fatal torsade de pointes, have been reported with oxaliplatin [see Adverse Reactions ( 6.2 )] . Avoid oxaliplatin in patients with congenital long QT syndrome. Monitor electrocardiograms (ECG) in patients with congestive heart failure, bradyarrhythmias, and electrolyte abnormalities and in patients taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics [see Drug Interactions ( 7.1 )] . Monitor and correct electrolyte abnormalities prior to initiating oxaliplatin and periodically during treatment. 5.8 Rhabdomyolysis Rhabdomyolysis, including fatal cases, has been reported with oxaliplatin [see Adverse Reactions ( 6.2 )] . Permanently discontinue oxaliplatin for any signs or symptoms of rhabdomyolysis. 5.9 Hemorrhage The incidence of hemorrhage in clinical trials was higher on the oxaliplatin combination arm compared to the fluorouracil/leucovorin arm. These reactions included gastrointestinal bleeding, hematuria, and epistaxis. In the adjuvant treatment trial, 2 patients died from intracerebral hemorrhage [see Adverse Reactions ( 6.1 )] . Prolonged prothrombin time and INR occasionally associated with hemorrhage have been reported in patients who received oxaliplatin with fluorouracil/leucovorin while on anticoagulants [see Adverse Reactions ( 6.2 )] . Increase frequency of monitoring in patients who are receiving oxaliplatin with fluorouracil/leucovorin and oral anticoagulants [see Drug Interactions ( 7.3 )] . Thrombocytopenia and immune-mediated thrombocytopenia have been observed with oxaliplatin. Rapid onset of thrombocytopenia and greater risk of bleeding have been observed in immune-mediated thrombocytopenia. In this case, consider discontinuing oxaliplatin. 5.10 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, oxaliplatin can cause fetal harm when administered to a pregnant woman. The available human data do not establish the presence or absence of major birth defects or miscarriage related to the use of oxaliplatin. Reproductive toxicity studies demonstrated adverse effects on embryo-fetal development in rats at maternal doses that were below the recommended human dose based on body surface area. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with oxaliplatin and for 9 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with oxaliplatin and for 6 months after the final dose [see Use in Specific Populations ( 8.1 , 8.3 )].

Adverse Reactions

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6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] Peripheral Sensory Neuropathy [see Warnings and Precautions ( 5.2 )] Severe Myelosuppression [see Warnings and Precautions ( 5.3 )] Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions ( 5.4 )] Pulmonary Toxicity [see Warnings and Precautions ( 5.5 )] Hepatotoxicity [see Warnings and Precautions ( 5.6 )] QT Interval Prolongation and Ventricular Arrhythmias [see Warnings and Precautions ( 5.7 )] Rhabdomyolysis [see Warnings and Precautions ( 5.8 )] Hemorrhage [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (incidence greater than or equal to 40%) were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue, and stomatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals Inc. at 1-844-824-8426 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 were treated in trials with oxaliplatin. The most common adverse reactions in patients with stage II or III colon cancer receiving adjuvant treatment 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 with advanced colorectal cancer were peripheral sensory neuropathies, fatigue, neutropenia, nausea, emesis, and diarrhea. Adjuvant Treatment The safety of oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in patients with stage II or III colon cancer, who had undergone complete resection of the primary tumor in the adjuvant treatment trial [see Clinical Studies ( 14.1 )]. Fatal adverse reactions in patients who received oxaliplatin in the combination arm included sepsis/neutropenic sepsis (n=3), intracerebral hemorrhage (n=2), and eosinophilic pneumonia (n=1). Thromboembolic events occurred in 6% (grade 3 to 4, 1.2%) of patients in the oxaliplatin arm. Grade 3 or 4 adverse reactions occurred in 70% of patients in the oxaliplatin arm. Grade 3 to 4 gastrointestinal bleeding occurred in 0.2% of patients. Febrile neutropenia occurred in 0.7% and documented infection with concomitant grade 3 to 4 neutropenia occurred in 1.1%. Discontinuation due to an adverse reaction occurred in 15% of the patients in the oxaliplatin arm. Tables 5 , 6 , and 7 summarize the adverse reactions reported in patients with colon cancer receiving adjuvant treatment. Table 5: Adverse Reactions Reported in Patients with Colon Cancer Receiving Adjuvant Treatment (greater than or equal to 5% of all patients and with greater than or equal to 1% grade 3 to 4) * Event coded in WHO-ART dictionary † Includes thrombosis related to the catheter Adverse Reaction * Oxaliplatin + FU/LV N=1108 FU/LV N=1111 All Grades (%) Grade 3 to 4 (%) All Grades (%) Grade 3 to 4 (%) Neurology Peripheral Sensory Neuropathy 92 12 16 <1 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 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 † 11 3 10 3 Fever/Infection Fever 27 1 12 1 Infection 25 4 25 3 Allergy/Immunology Allergic Reaction 10 3 2 <1 Table 6: Adverse Reactions Reported in Patients with Colon Cancer Receiving Adjuvant Treatment (greater than or equal to 5% of all patients but with less than 1% grade 3 to 4) * Event coded in WHO-ART dictionary † No complete alopecia was reported Adverse Reaction * Oxaliplatin + FU/LV N=1108 FU/LV N=1111 All Grades (%) All Grades (%) Dermatology/Skin Alopecia † 30 28 Gastrointestinal Constipation 22 19 Taste Perversion 12 8 Dyspepsia 8 5 Constitutional Symptoms/Pain/Ocular/Visual Epistaxis 16 12 Weight Increase 10 10 Conjunctivitis 9 15 Headache 7 5 Dyspnea 5 3 Pain 5 5 Abnormal Lacrimation 4 12 Neurology Sensory Disturbance 8 1 Allergy/Immunology Rhinitis 6 8 In females, the following grade 3 to 4 adverse reactions were more frequent: diarrhea, fatigue, neutropenia, nausea, and vomiting. In patients greater than or equal to 65 years old, the incidence of grade 3 to 4 diarrhea and neutropenia was higher than in younger adults. Clinically relevant adverse reactions were reported in greater than or equal to 2% and less than 5% of the patients in the oxaliplatin arm (listed in decreasing order of frequency) were pain, leukopenia, weight loss, and cough. Table 7: Laboratory-Related Adverse Reactions Occurring in ≥5% of Patients with Colon Cancer Receiving Adjuvant Treatment Laboratory-Related Adverse Reaction Oxaliplatin with FU/LV N=1108 FU/LV N=1111 All Grades (%) Grades 3 to 4 (%) All Grades (%) Grades 3 to 4 (%) Hematology Neutropenia 79 41 40 5 Thrombocytopenia 77 2 19 <1 Anemia 76 1 67 <1 Hepatic Increased Transaminases 57 2 34 1 Increased Alkaline Phosphatase 42 <1 20 <1 Hyperbilirubinemia 20 4 20 5 Previously Untreated Advanced Colorectal Cancer The safety of oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in a randomized trial of patients with previously untreated advanced colorectal cancer [see Clinical Studies ( 14.2 )] . The adverse reaction profile in this trial was similar to that seen in other trials. Tables 8 , 9 , and 10 summarize the adverse reactions reported in the previously untreated advanced colorectal cancer trial. Table 8: Adverse Reactions Reported in Patients in the Previously Untreated Advanced Colorectal Cancer Clinical Trial (greater than or equal to 5% of all patients and with greater than or equal to 1% grade 3 to 4) * Event coded in WHO-ART dictionary † Not otherwise specified ‡ Absolute neutrophil count Adverse Reaction * Oxaliplatin + FU/LV N=259 Irinotecan + FU/LV N=256 Oxaliplatin + Irinotecan N=258 All Grades (%) Grades 3 to 4 (%) All Grades (%) Grades 3 to 4 (%) All Grades (%) Grades 3 to 4 (%) Neurology 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 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 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 Abnormal Vision 5 0 2 1 6 1 Neuralgia 5 0 0 0 2 1 Pulmonary Cough 35 1 25 2 17 1 Dyspnea 18 7 14 3 11 2 Hiccups 5 1 2 0 3 2 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 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 Dermatology/Skin Hand/Foot Syndrome 7 1 2 1 1 0 Injection Site Reaction 6 0 1 0 4 1 Cardiovascular Thrombosis 6 5 6 6 3 3 Hypotension 5 3 6 3 4 3 Table 9: Adverse Reactions Reported in Patients in the Previously Untreated Advanced Colorectal Cancer Clinical Trial (greater than or equal to 5% of all patients but with less than 1% grade 3 to 4) * Event coded in WHO-ART dictionary † No complete alopecia was reported ‡ Absolute neutrophil count Adverse Reaction * Oxaliplatin + FU/LV N=259 Irinotecan + FU/LV N=256 Oxaliplatin + Irinotecan N=258 All Grades (%) All Grades (%) All Grades (%) Dermatology/Skin Alopecia † 38 44 67 Flushing 7 2 5 Pruritus 6 4 2 Dry Skin 6 2 5 Hematology/Infection Fever Normal ANC ‡ 16 9 9 Cardiovascular Edema 15 13 10 Gastrointestinal Taste Perversion 14 6 8 Dyspepsia 12 7 5 Flatulence 9 6 5 Mouth Dryness 5 2 3 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 Neurology Insomnia 13 9 11 Depression 9 5 7 Dizziness 8 6 10 Anxiety 5 2 6 Allergy/Immunology Rash 11 4 7 Rhinitis Allergic 10 6 6 Hepatic/Metabolic/Laboratory/Renal Hypocalcemia 7 5 4 Elevated Creatinine 4 4 5 Clinically relevant adverse reactions that occurred in greater than or equal to 2% and less than 5% of the patients in the oxaliplatin and fluorouracil/leucovorin combination arm (listed in decreasing order of frequency) were: 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. Table 10: Laboratory-Related Adverse Reactions Occurring in ≥5% of Patients in the Previously Untreated Advanced Colorectal Cancer Trial * Aspartate transaminase † Alanine transaminase Laboratory-Related Adverse Reaction Oxaliplatin and FU/LV N=259 Irinotecan and FU/LV N=256 Oxaliplatin and Irinotecan N=258 All Grades (%) Grades 3 to 4 (%) All Grades (%) Grades 3 to 4 (%) All Grades (%) Grades 3 to 4 (%) Hematology Leukopenia 85 20 84 23 76 24 Neutropenia 81 53 77 44 71 36 Thrombocytopenia 71 5 26 2 44 4 Anemia 27 3 28 4 25 3 Hepatic Increased AST* 17 1 2 1 11 1 Increased Alkaline Phosphatase 16 0 8 0 14 2 Hyperbilirubinemia 6 1 3 1 3 2 Increased ALT † 6 1 2 0 5 2 Previously Treated Advanced Colorectal Cancer The safety of oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in a randomized trial in patients with refractory and relapsed colorectal cancer [see Clinical Studies ( 14.3 )] . The adverse reaction profile in this trial was similar to that seen in other trials. Three patients who received oxaliplatin in the combination arm experienced fatal adverse reactions: gastrointestinal bleeding and dehydration. Grade 3 and 4 neutropenia were reported in 27% and 17% of patients, respectively, in the oxaliplatin with fluorouracil/leucovorin combination arm. Grade 3 to 4 increased serum creatinine occurred in 1% of patients in the oxaliplatin with combination fluorouracil/leucovorin arm. Thirteen percent of patients in the oxaliplatin with fluorouracil/leucovorin combination arm discontinued treatment; the most frequent reasons were gastrointestinal adverse reactions, hematologic adverse reactions and neuropathies. Tables 11 , 12 , and 13 summarize the adverse reactions reported in the previously treated advanced colorectal cancer trial. Table 11: Adverse Reactions Reported in Patients in the Previously Treated Advanced Colorectal Cancer Trial (greater than or equal to 5% of all patients and with greater than or equal to 1% grade 3 to 4) * Event coded in WHO-ART dictionary Adverse Reaction * Oxaliplatin + FU/LV N=150 Oxaliplatin N=153 FU/LV N=142 All Grades (%) Grades 3 to 4 (%) All Grades (%) Grades 3 to 4 (%) All Grades (%) Grades 3 to 4 (%) Neurology Neuropathy 74 7 76 7 17 0 Acute 56 2 65 5 10 0 Persistent 48 6 43 3 9 0 Constitutional Symptoms/Pain Fatigue 68 7 61 9 52 6 Back Pain 19 3 11 0 16 4 Pain 15 2 14 3 9 3 Gastrointestinal Diarrhea 67 11 46 4 44 3 Nausea 65 11 64 4 59 4 Vomiting 40 9 37 4 27 4 Stomatitis 37 3 14 0 32 3 Abdominal Pain 33 4 31 7 31 5 Anorexia 29 3 20 2 20 1 Gastroesophageal Reflux 5 2 1 0 3 0 Hematology/Infection Fever 29 1 25 1 23 1 Febrile Neutropenia 6 6 0 0 1 1 Cardiovascular Dyspnea 20 4 13 7 11 2 Coughing 19 1 11 0 9 0 Edema 15 1 10 1 13 1 Thromboembolism 9 8 2 1 4 2 Chest Pain 8 1 5 1 4 1 Dermatology/Skin Injection Site Reaction 10 3 9 0 5 1 Hepatic/Metabolic/Laboratory/Renal Hypokalemia 9 4 3 2 3 1 Dehydration 8 3 5 3 6 4 Table 12: Adverse Reactions Reported in Patients in the Previously Treated Advanced Colorectal Cancer Clinical Trial (greater than or equal to 5% of all patients but with less than 1% grade 3 to 4) * Event coded in WHO-ART dictionary † No complete alopecia was reported Adverse Reaction * Oxaliplatin + FU/LV N=150 Oxaliplatin N=153 FU/LV N=142 All Grades (%) All Grades (%) All Grades (%) Gastrointestinal Constipation 32 31 23 Dyspepsia 14 7 10 Taste Perversion 13 5 1 Mucositis 7 2 10 Flatulence 5 3 6 Constitutional Symptoms/Pain/Ocular/Visual Headache 17 13 8 Arthralgia 10 7 10 Epistaxis 9 2 1 Abnormal Lacrimation 7 1 6 Rigors 7 9 6 Allergy/Immunology Rhinitis 15 6 4 Allergic Reaction 10 3 1 Rash 9 5 5 Neurology Dizziness 13 7 8 Insomnia 9 11 4 Dermatology/Skin Hand-Foot Syndrome 11 1 13 Flushing 10 3 2 Alopecia † 7 3 3 Pulmonary Upper Respiratory Tract Infection 10 7 4 Pharyngitis 9 2 10 Cardiovascular Peripheral Edema 10 5 11 Hepatic/Metabolic/Laboratory/Renal Hematuria 6 0 4 Dysuria 6 1 1 Clinically relevant adverse reactions in greater than or equal to 2% and less than 5% of the patients in the oxaliplatin and fluorouracil/leucovorin combination arm (listed in decreasing order of frequency) were: 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, and urinary incontinence. Table 13: Laboratory-Related Adverse Reactions Occurring in ≥5% of Patients with Previously Treated Advanced Colorectal Cancer * Alanine transaminase † Aspartate transaminase Laboratory-Related Adverse Reaction Oxaliplatin and FU/LV N=150 Oxaliplatin N=153 FU/LV N=142 All Grades (%) Grades 3 to 4 (%) All Grades (%) Grades 3 to 4 (%) All Grades (%) Grades 3 to 4 (%) Hematology Anemia 81 2 64 1 68 2 Leukopenia 76 19 13 0 34 1 Neutropenia 73 44 7 0 25 5 Thrombocytopenia 64 4 30 3 20 0 Hepatic Increased ALT* 31 0 36 1 28 3 Increased AST † 47 0 54 4 39 2 Increased Bilirubin 13 1 13 5 22 6 Additional Adverse Reactions The following adverse reactions were observed across clinical trials. Intravenous site reactions Injection site reaction, including redness, swelling, and pain, can occur with oxaliplatin. In some cases, skin necrosis has occurred with extravasation. PRES PRES occurred in less than 0.1% of patients. Pulmonary fibrosis and interstitial lung disease Pulmonary fibrosis, which may be fatal, occurred in less than 1% of patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of oxaliplatin. 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. General: angioedema, anaphylactic shock Cardiovascular: QT prolongation leading to ventricular arrhythmias, including fatal torsade de pointes; bradyarrhythmia Neurological: loss of deep tendon reflexes, dysarthria, Lhermitte's sign, cranial nerve palsies, fasciculations, convulsion Hearing and vestibular system: deafness Infections: septic shock, including fatal outcomes Infusion-related reactions and hypersensitivity reactions: laryngospasm Hepatic and gastrointestinal: severe diarrhea/vomiting resulting in hypokalemia, colitis (including Clostridium difficile diarrhea), metabolic acidosis, ileus, intestinal obstruction, pancreatitis, sinusoidal obstruction syndrome, perisinusoidal fibrosis which rarely may progress, focal nodular hyperplasia, esophagitis Musculoskeletal and connective tissue: rhabdomyolysis, including fatal outcomes Platelet, bleeding, and clotting disorders: immuno-allergic thrombocytopenia, prolonged prothrombin time and INR in patients receiving anticoagulants Blood disorders: secondary leukemia Red blood cell: hemolytic uremic syndrome, immuno-allergic hemolytic anemia Renal: acute tubular necrosis, acute interstitial nephritis, acute renal failure Respiratory: interstitial lung diseases (sometimes fatal) and pneumonia (including fatal outcomes) Vision: decrease of visual acuity, visual field disturbance, optic neuritis and transient vision loss (reversible following treatment discontinuation) Injury, poisoning, and procedural complications: fall-related injuries

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