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 complete resection of the primary tumor.

( 1 ) • treatment of advanced colorectal cancer.

( 1 )

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 Hetero Labs Limited at 1-866-495-1995 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 3-4, 1.2%) of patients in the oxaliplatin arm.

Grade 3 or 4 adverse reactions occurred in 70% of patients in the oxaliplatin arm.

Grade 3-4 gastrointestinal bleeding occurred in 0.2% of patients.

Febrile neutropenia occurred in 0.7% and documented infection with concomitant grade 3-4 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 3-4) Adverse Reaction* Oxaliplatin + FU/LV N=1108 FU/LV N=1111 All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) 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 * Event coded in WHO-ART dictionary † Includes thrombosis related to the catheter 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 3-4) 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 * Event coded in WHO-ART dictionary † No complete alopecia was reported.

In females, the following grade 3-4 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 3-4 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 3-4 (%) All Grades (%) Grades 3-4 (%) 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 3-4) Adverse Reaction* Oxaliplatin + FU/LV N=259 Irinotecan + FU/LV N=256 Oxaliplatin + Irinotecan N=258 All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) 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 * Event coded in WHO-ART dictionary † Not otherwise specified ‡ Absolute neutrophil count 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 3-4) Adverse Reaction* Oxaliplatin + 5-FU/LV N=259 Irinotecan + 5-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 *Event coded in WHO-ART dictionary † No complete alopecia was reported.

‡ Absolute neutrophil count 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 Laboratory-Related Adverse Reaction Oxaliplatin and FU/LV N=259 Irinotecan and FU/LV N=256 Oxaliplatin and Irinotecan N=258 All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) 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 * Aspartate transaminase † Alanine transaminase 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 3-4 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 3-4 ) Adverse Reaction* Oxaliplatin + FU/LV N=150 Oxaliplatin N=153 FU/LV N=142 All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) 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 * Event coded in WHO-ART dictionary 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 3-4) Adverse Reaction* Oxaliplatin + FU/LV N=150 Oxaliplatin N=153 5-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 * Event coded in WHO-ART dictionary † No complete alopecia was reported.

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 Laboratory-Related Adverse Reaction Oxaliplatin and FU/LV N=150 Oxaliplatin N=153 FU/LV N=142 All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) 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 * Alanine transaminase † Aspartate transaminase 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