ADVERSE REACTIONS SECTION.

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 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 or 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 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 61 Diarrhea 56 11 48 Vomiting 47 24 Stomatitis 42 40 Anorexia 13 8 <1 Constitutional Symptoms/Pain Fatigue 44 38 Abdominal Pain 18 17 Dermatology/Skin Skin Disorder 32 36 Injection Site Reaction 11 10 Fever/Infection Fever 27 12 Infection 25 25 Allergy/Immunology Allergic Reaction 10 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 Dyspepsia 5 Constitutional Symptoms/Pain/Ocular/Visual Epistaxis 16 12 Weight Increase 10 10 Conjunctivitis 15 Headache 5 Dyspnea 3 Pain 5 Abnormal Lacrimation 12 Neurology Sensory Disturbance 1 Allergy/Immunology Rhinitis 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 Thrombocytopenia 77 19 <1 Anemia 76 67 <1 Hepatic Increased Transaminases 57 34 Increased Alkaline Phosphatase 42 <1 20 <1 Hyperbilirubinemia 20 20 Previously Untreated Advanced Colorectal Cancer The safety of oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in 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 69 Paresthesias 77 18 16 62 Pharyngo-laryngeal Dysesthesias 38 1 28 Neuro-sensory 12 2 9 Neuro NOS 1 1 1 Gastrointestinal Nausea 71 67 15 83 19 Diarrhea 56 12 65 29 76 25 Vomiting 41 43 13 64 23 Stomatitis 38 25 19 Anorexia 35 25 27 Constipation 32 27 21 Diarrhea-colostomy 13 16 16 Gastrointestinal NOS 2 2 2 Constitutional Symptoms/Pain/Ocular/Visual Fatigue 70 58 11 66 16 Abdominal Pain 29 31 39 10 Myalgia 14 6 9 Pain 1 1 1 Abnormal Vision 0 1 1 Neuralgia 0 0 1 Pulmonary Cough 35 25 17 Dyspnea 18 14 11 Hiccups 1 0 2 Hepatic/Metabolic/Laboratory/Renal Hyperglycemia 14 11 12 Hypokalemia 11 7 6 Dehydration 5 16 11 14 Hypoalbuminemia 0 2 1 Hyponatremia 2 4 1 Urinary Frequency 1 1 1 Hematology/Infection Infection Normal ANC 10 5 7 Infection Low ANC 8 12 11 8 Lymphopenia 2 1 2 Febrile Neutropenia 4 15 14 12 11 Dermatology/Skin Hand/Foot Syndrome 1 1 0 Injection Site Reaction 0 0 1 Cardiovascular Thrombosis 5 6 3 Hypotension 3 3 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 2 Pruritus 4 Dry Skin 2 Hematology/Infection Fever Normal ANC 16 9 Cardiovascular Edema 15 13 10 Gastrointestinal Taste Perversion 14 8 Dyspepsia 12 5 Flatulence 6 Mouth Dryness 2 Constitutional Symptoms/Pain/Ocular/Visual Headache 13 9 Weight Loss 11 11 Epistaxis 10 2 Tearing 1 Rigors 2 Dysphasia 3 Sweating 6 12 Arthralgia 5 Neurology Insomnia 13 11 Depression 5 Dizziness 6 10 Anxiety 2 Allergy/Immunology Rash 11 7 Rhinitis Allergic 10 6 Hepatic/Metabolic/Laboratory/Renal Hypocalcemia 5 Elevated Creatinine 4 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 26 44 Anemia 27 28 25 Hepatic Increased AST 17 2 11 Increased Alkaline Phosphatase 16 8 14 Hyperbilirubinemia 1 1 2 Increased ALT 6 2 5 Aspartate transaminase +Alanine transaminase Previously Treated Advanced Colorectal Cancer The safety of oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in 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 and 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 76 17 Acute 56 65 10 Persistent 48 43 9 Constitutional Symptoms/Pain Fatigue 68 61 52 Back Pain 19 11 16 Pain 15 14 9 Gastrointestinal Diarrhea 67 11 46 44 Nausea 65 11 64 59 Vomiting 40 37 27 Stomatitis 37 14 32 Abdominal Pain 33 31 31 Anorexia 29 20 20 Gastroesophageal Reflux 2 0 0 Hematology/Infection Fever 29 25 23 Febrile Neutropenia 6 0 1 Cardiovascular Dyspnea 20 13 11 Coughing 19 11 9 Edema 15 10 13 Thromboembolism 8 1 2 Chest Pain 1 1 1 Dermatology/Skin Injection Site Reaction 10 9 5 Hepatic/Metabolic/Laboratory/Renal Hypokalemia 4 2 1 Dehydration 3 3 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 10 Taste Perversion 13 1 Mucositis 2 10 Flatulence 3 Constitutional Symptoms/Pain/Ocular/Visual Headache 17 13 Arthralgia 10 10 Epistaxis 2 Abnormal Lacrimation 1 Rigors 9 Allergy/Immunology Rhinitis 15 4 Allergic Reaction 10 1 Rash 5 Neurology Dizziness 13 8 Insomnia 11 Dermatology/Skin Hand-Foot Syndrome 11 13 Flushing 10 2 Alopecia 7 3 Pulmonary Upper Respiratory Tract Infection 10 4 Pharyngitis 2 10 Cardiovascular Peripheral Edema 10 11 Hepatic/Metabolic/Laboratory/Renal Hematuria 0 Dysuria 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 64 68 Leukopenia 76 19 13 34 Neutropenia 73 44 0 25 Thrombocytopenia 64 30 20 Hepatic Increased ALT 31 36 28 Increased AST 47 54 39 Increased Bilirubin 13 13 22 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.o General: angioedema, anaphylactic shock Cardiovascular: QT prolongation leading to ventricular arrhythmias, including fatal torsade de pointes; bradyarrhythmia Neurological: loss of deep tendon reflexes, dysarthria, Lhermittes 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 difficilediarrhea), 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed, including monoaquo and diaquo DACH platinum, which covalently bind with macromolecules. Both inter- and intrastrand Pt-DNA crosslinks are formed. Crosslinks are formed between the N7positions of two adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide (GNG). These crosslinks inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific. In vivostudies have shown antitumor activity of oxaliplatin against colon carcinoma. In combination with fluorouracil, oxaliplatin exhibits in vitroand in vivoantiproliferative activity greater than either compound alone in several tumor models (HT29 [colon], GR [mammary], and L1210 [leukemia]). 12.2 Pharmacodynamics. pharmacodynamic relationship between platinum ultrafiltrate levels and clinical safety and effectiveness has not been established.. 12.3 Pharmacokinetics. The reactive oxaliplatin derivatives are present as fraction of the unbound platinum in plasma ultrafiltrate. After single 2-hour intravenous infusion of oxaliplatin at dose of 85 mg/m 2, pharmacokinetic parameters expressed as ultrafiltrable platinum were Cmax of 0.814 mcg/mL and volume of distribution of 440 L. Interpatient and intrapatient variability in ultrafiltrable platinum exposure (AUC 0-48hr) assessed over cycles was 23% and 6%, respectively. Distribution At the end of 2-hour infusion of oxaliplatin, approximately 15% of the administered platinum is present in the systemic circulation. The remaining 85% is rapidly distributed into tissues or eliminated in the urine. The decline of ultrafiltrable platinum levels following oxaliplatin administration is triphasic, including two distribution phases (t 1/2; 0.43 hours and 1/2; 16.8 hours). In patients, plasma protein binding of platinum is irreversible and is greater than 90%. The main binding proteins are albumin and gamma-globulins. Platinum also binds irreversibly and accumulates (approximately 2-fold) in erythrocytes, where it appears to have no relevant activity. No platinum accumulation was observed in plasma ultrafiltrate following 85 mg/m 2every two weeks. Elimination The decline of ultrafiltrable platinum concentrations from plasma is characterized by long terminal elimination phase (t 1/2; 391 hours). Metabolism Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation. There is no evidence of cytochrome P450-mediated metabolism in vitro. Up to 17 platinum-containing derivatives have been observed in plasma ultrafiltrate samples from patients, including several cytotoxic species (monochloro DACH platinum, dichloro DACH platinum, and monoaquo and diaquo DACH platinum) and number of noncytotoxic, conjugated species. Excretion The major route of platinum elimination is renal excretion. At five days after single 2-hour infusion of oxaliplatin, urinary elimination accounted for about 54% of the platinum eliminated, with fecal excretion accounting for only about 2%. Platinum was cleared from plasma at rate (10-17 L/h) that was similar to or exceeded the average human glomerular filtration rate (GFR; 7.5 L/h). The renal clearance of ultrafiltrable platinum is significantly correlated with GFR. Special Populations Sex There was no significant effect of sex on the clearance of ultrafiltrable platinum. Patients with renal impairment Patients with normal function (CLcr greater than 80 mL/min) and patients with mild (CLcr=50- 80 mL/min) and moderate (CLcr equal to 30-49 mL/min) renal impairment received oxaliplatin 85 mg/m 2and those with severe (CLcr less than 30 mL/min) renal impairment received oxaliplatin 65 mg/m 2. Mean dose adjusted AUC of unbound platinum was 40%, 95%, and 342% higher for patients with mild, moderate, and severe renal impairment, respectively, compared to patients with normal renal function. Mean dose adjusted maxof unbound platinum appeared to be similar among the normal, mild and moderate renal function groups, but was 38% higher in the severe group than in the normal group [see Dosage and Administration 2.3)]. Drug Interaction Studies No pharmacokinetic interaction between oxaliplatin 85 mg/m 2and infusional fluorouracil has been observed in patients treated every weeks, but increases of fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m 2of oxaliplatin administered every weeks. In vitroplatinum was not displaced from plasma proteins by the following medications: erythromycin, salicylate, sodium valproate, granisetron, and paclitaxel. In vitrooxaliplatin does not inhibit human cytochrome P450 isoenzymes.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Adjuvant Treatment with Oxaliplatin in Combination with Fluorouracil and Leucovorin. The efficacy of oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in an international, multicenter, randomized (1:1) trial (The Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer [MOSAIC], NCT00275210) in patients with stage II (Dukes B2) or III (Dukes C) colon cancer who had undergone complete resection of the primary tumor. Patients were randomized to receive oxaliplatin with fluorouracil/leucovorin or fluorouracil/leucovorin alone for total of months (i.e., 12 cycles). Table 14 shows the dosing regimens for the two arms. Eligible patients were between 18 and 75 years of age, had histologically proven stage II (T 3-T 4N0 M0; Dukes B2) or III (any N 1-2M0; Dukes C) colon carcinoma (with the inferior pole of the tumor above the peritoneal reflection, i.e., greater than or equal to 15 cm from the anal margin) and had undergone (within weeks prior to randomization) complete resection of the primary tumor without gross or microscopic evidence of residual disease and carcino-embyrogenic antigen (CEA) less than 10 ng/mL. Additional eligibility criteria were no prior chemotherapy, immunotherapy or radiotherapy; Eastern Cooperative Oncology Group performance status of 0, 1, or (Karnofsky Performance Status greater than or equal to 60%); no pre-existing neuropathy; and absolute neutrophil count (ANC) greater than or equal to 1.5 10 9/L, platelets greater than or equal to 100 10 9/L, serum creatinine less than or equal to 1.25 upper limit normal (ULN), total bilirubin less than x ULN, and aspartate transaminase (AST)/alanine transaminase (ALT) less than x ULN. The major efficacy outcome was 3-year disease-free survival (DFS). Table 14: Dosing Regimens in Adjuvant Treatment Study Treatment Arm Dose Regimen Oxaliplatin FU/LV (FOLFOX4) (N=1123) Day 1: Oxaliplatin: 85 mg/m 2(2-hour infusion) LV: 200 mg/m 2(2-hour infusion), followed by FU: 400 mg/m 2(bolus), 600 mg/m 2(22-hour infusion) Day 2: LV: 200 mg/m 2(2-hour infusion), followed by FU: 400 mg/m (bolus), 600 mg/m (22-hour infusion) every weeks 12 cycles FU/LV (N=1123) Day 1: LV: 200 mg/m (2-hour infusion), followed by FU: 400 mg/m (bolus), 600 mg/m (22-hour infusion) Day 2: LV: 200 mg/m (2-hour infusion), followed by FU: 400 mg/m (bolus), 600 mg/m (22-hour infusion) every weeks 12 cycles There were 2246 patients enrolled, of whom 1347 (60%) had Stage III disease. Tables 15 and 16 show the baseline characteristics and exposure to oxaliplatin. Table 15: Baseline Characteristics in Adjuvant Treatment Study Oxaliplatin Infusional FU/LV N=1123 Infusional FU/LV N=1123 Sex: Male (%) 56.1 52.4 Female (%) 43.9 47.6 Median age (years) 61.0 60.0 <65 years of age (%) 64.4 66.2 >=65 years of age (%) 35.6 33.8 KPS (%) 100 29.7 30.5 90 52.2 53.9 80 4.4 3.3 70 13.2 11.9 <=60 0.6 0.4 Primary site (%) Colon including cecum 54.6 54.4 Sigmoid 31.9 33.8 Recto sigmoid 12.9 10.9 Other including rectum 0.6 0.9 Bowel obstruction (%) Yes 17.9 19.3 Perforation (%) Yes 6.9 6.9 Stage at Randomization (%) II (T=3,4 N=0, M=0) 40.1 39.9 III (T=any, N=1,2, M=0) 59.6 59.3 IV (T=any, N=any, M=1) 0.4 0.8 Staging T (%) T1 0.5 0.7 T2 4.5 4.8 T3 76.0 75.9 T4 19.0 18.5 Staging N (%) N0 40.2 39.9 N1 39.4 39.4 N2 20.4 20.7 Staging M (%) M1 0.4 0.8 Table 16: Exposure to Oxaliplatin in Adjuvant Treatment Study Oxaliplatin Infusional FU/LV N=1108 Infusional FU/LV N=1111 Median Relative Dose Intensity (%) FU 84.4 97.7 Oxaliplatin 80.5 N/A Median Number of Cycles 12 12 Median Number of Cycles with Oxaliplatin 11 N/A The median duration of follow-up was approximately 77 months. In the overall and the stage III colon cancer populations, DFS was statistically significantly improved in the oxaliplatin- containing arm compared to fluorouracil/leucovorin alone; however, statistically significant improvement in DFS was not observed in Stage II patients. No significant differences in overall survival (OS) were detected in the overall population or those with Stage III disease. Table 17 and Figures and summarize the 5-year DFS rates in the overall randomized population and in patients with stage II and III disease based on an intention-to-treat (ITT) analysis. Table 17: Summary of DFS Analysis in Adjuvant Treatment Study ITT Population Parameter Oxaliplatin Infusional FU/LV Infusional FU/LV Overall Number of patients 1123 1123 Number of events relapse or death (%) 304 (27.1) 360 (32.1) 5-yr Disease-free survival (95% CI) 73.3 (70.7, 76.0) 67.4 (64.6, 70.2) Hazard ratio (95% CI) 0.80 (0.68, 0.93) Stratified Log rank test p=0.003 Stage III (Dukes C) Number of patients 672 675 Number of events relapse or death (%) 226 (33.6) 271 (40.1) 5-yr Disease-free survival (95% CI) 66.4 (62.7, 70.0) 58.9 (55.2, 62.7) Hazard ratio (95% CI) 0.78 (0.65, 0.93) Log rank test p=0.005 Stage II (Dukes B2) Number of patients 451 448 Number of events relapse or death (%) 78 (17.3) 89 (19.9) 5-yr Disease-free survival (95% CI) 83.7 (80.2, 87.1) 79.9 (76.2, 83.7) Hazard ratio (95% CI) 0.84 (0.62, 1.14) Log rank test p=0.258 hazard ratio of less than favors Oxaliplatin Infusional FU/LV Data cut off for disease-free survival June 1, 2006 Figure 1: Kaplan-Meier Curves of Disease-Free Survival (cutoff: June 2006) in Adjuvant Treatment Trial ITT Population Figure 2: Kaplan-Meier Curves of Disease-Free Survival in Stage III Patients (cutoff: June 2006) in Adjuvant Treatment Trial ITTPopulationTable 18 summarizes the OS results in the overall randomized population and in patients with stage II and III disease, based on the ITT analysis. Table 18: Summary of OS Analysis in Adjuvant Treatment ITT Population Parameter Oxaliplatin Infusional FU/LV Infusional FU/LV Overall Number of patients 1123 1123 Number of death events (%) 245 (21.8) 283 (25.2) Hazard ratio (95% CI) 0.84 (0.71 1.00) Stage III (Dukes C) Number of patients 672 675 Number of death events (%) 182 (27.1) 220 (32.6) Hazard ratio (95% CI) 0.80 (0.65 0.97) Stage II (Dukes B2) Number of patients 451 448 Number of death events (%) 63 (14.0) 63 (14.1) Hazard ratio (95% CI) 1.00 (0.70, 1.41) hazard ratio of less than favors Oxaliplatin Infusional FU/LV Data cut off for overall survival January 16, 2007 oxaliplatinfigure1. oxaliplatinfigure2. 14.2 Previously Untreated Advanced Colorectal Cancer. The efficacy of oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in North American, multicenter, open-label, randomized, active-controlled trial (A Randomized Phase III Trial of Three Different Regimens of CPT-11 Plus 5-Fluorouracil and Leucovorin Compared to 5-Fluorouracil and Leucovorin in Patients with Advanced Adenocarcinoma of the Colon and Rectum; NCT00003594). The trial included arms at different times during its conduct, four of which were closed due to either changes in the standard of care, toxicity, or simplification. During the trial, the control arm was changed to irinotecan with fluorouracil/leucovorin. The results reported below compared the efficacy of oxaliplatin with fluorouracil/leucovorin and oxaliplatin with irinotecan to an approved control regimen of irinotecan with fluorouracil/leucovorin in 795 concurrently randomized patients previously untreated for locally advanced or metastatic colorectal cancer. Table 19 presents the dosing regimens for the three arms. After completion of enrollment, the dose of irinotecan with fluorouracil/leucovorin was decreased due to toxicity. Eligible patients were at least 18 years of age; had known locally advanced, locally recurrent, or metastatic colorectal adenocarcinoma not curable by surgery or amenable to radiation therapy; with an Eastern Cooperative Oncology Group (ECOG) performance status <=0, 1, or 2. Patients had to have absolute neutrophil count (ANC) greater than or equal to 1.5 10 9/L, platelets greater than or equal to 100 10 9/L, hemoglobin greater than or equal to 9.0 g/dL, creatinine less than or equal to 1.5 upper limit of normal (ULN), total bilirubin less than or equal to 1.5 mg/dL, aspartate transaminase (AST) less than or equal to x ULN, and alkaline phosphatase less than or equal to x ULN. Patients may have received adjuvant treatment for resected Stage II or III disease without recurrence within 12 months. Randomization was stratified by ECOG performance status (0, vs 2), prior adjuvant chemotherapy (yes vs no), prior immunotherapy (yes vs no), and age (less than 65 vs greater than or equal to 65 years). Although no post study treatment was specified in the protocol, 65% to 72% of patients received additional post study chemotherapy after study treatment discontinuation on all arms. Fifty-eight percent of patients on the oxaliplatin with fluorouracil/leucovorin arm received an irinotecan-containing regimen and 23% of patients on the irinotecan with fluorouracil/leucovorin arm received an oxaliplatin- containing regimen. The main efficacy outcome measure was 3-year disease-free survival (DFS) and additional efficacy outcome measures were overall survival (OS). Table 19: Dosing Regimens for Previously Untreated Advanced Colorectal Cancer Clinical Trial Treatment Arm Dose Regimen Oxaliplatin FU/LV (FOLFOX4) (N=267) Day 1: Oxaliplatin: 85 mg/m (2-hour infusion) LV 200 mg/m (2-hour infusion), followed by FU: 400 mg/m (bolus), 600 mg/m 2(22-hour infusion) Day 2: LV 200 mg/m 2(2-hour infusion), followed by FU: 400 mg/m 2(bolus), 600 mg/m 2(22-hour infusion) every weeks Irinotecan FU/LV (IFL) (N=264) Day 1: irinotecan 125 mg/m 2as 90-min infusion LV 20 mg/m 2as 15-min infusion or intravenous push, followed by FU 500 mg/m intravenous bolus weekly 4 every weeks Oxaliplatin Irinotecan (IROX) (N=264) Day 1: Oxaliplatin: 85 mg/m 2intravenous (2-hour infusion) irinotecan 200 mg/m 2intravenous over 30 minutes every weeks Table 20 presents the baseline characteristics. Table 20: Baseline Characteristics for Previously Untreated Advanced Colorectal Cancer Clinical Trial Oxaliplatin FU/LV N=267 Irinotecan FU/LV N=264 Oxaliplatin Irinotecan N=264 Sex: Male (%) 58.8 65.2 61.0 Female (%) 41.2 34.8 39.0 Median age (years) 61.0 61.0 61.0 <65 years of age (%) 61 62 63 >=65 years of age (%) 39 38 37 ECOG (%) 0-1 94.4 95.5 94.7 5.6 4.5 5.3 Involved organs (%) Colon only 0.7 0.8 0.4 Liver only 39.3 44.3 39.0 Liver other 41.2 38.6 40.9 Lung only 6.4 3.8 5.3 Other (including lymph nodes) 11.6 11.0 12.9 Not reported 0.7 1.5 1.5 Prior radiation (%) 3.0 1.5 3.0 Prior surgery (%) 74.5 79.2 81.8 Prior adjuvant (%) 15.7 14.8 15.2 The median number of cycles administered per patient was 10 (23.9 weeks) for the oxaliplatin plus fluorouracil/leucovorin regimen, (23.6 weeks) for the irinotecan plus fluorouracil/leucovorin regimen, and (21.0 weeks) for the oxaliplatin plus irinotecan regimen. Patients who received oxaliplatin with fluorouracil/leucovorin had significantly longer time to tumor progression based on investigator assessment, longer OS, and significantly higher confirmed response rate based on investigator assessment compared to patients who received irinotecan with fluorouracil/leucovorin. Efficacy results are summarized in Table 21 and Figure 3. Table 21: Efficacy Results for Previously Untreated Advanced Colorectal Cancer Trial Oxaliplatin FU/LV N=267 Irinotecan FU/LV N=264 Oxaliplatin Irinotecan N=264 Survival (ITT) Number of deaths (%) 155 (58.1) 192 (72.7) 175 (66.3) Median survival (months) 19.4 14.6 17.6 Hazard ratio (95% CI) 0.65 (0.53, 0.80) - P-value <0.0001 - TTP (ITT, investigator assessment) Percentage of progressors 82.8 81.8 89.4 Median TTP (months) 8.7 6.9 6.5 Hazard ratio (95% CI) 0.74 (0.61, 0.89) - P-value 0.0014 - Response Rate (investigator assessment) Patients with measurable disease 210 212 215 Complete response, (%) 13 (6.2) (2.4) (3.3) Partial response, (%) 82 (39.0) 64 (30.2) 67 (31.2) Complete and partial response, (%) 95 (45.2) 69 (32.5) 74 (34.4) 95% CI (38.5, 52.0) (26.2, 38.9) (28.1, 40.8) P-value 0.0080 - Compared to irinotecan plus fluorouracil/leucovorin (IFL) arm. A hazard ratio of less than favors oxaliplatin Infusional FU/LV. Based on all patients with measurable disease at baseline. The numbers in the response rate and TTP analysis are based on unblinded investigator assessment. Figure 3: Kaplan-Meier Curves for Overall Survival in Previously Untreated Advanced Colorectal Cancer Trial In descriptive subgroup analyses, the improvement in overall survival (OS) for oxaliplatin with fluorouracil/leucovorin compared to irinotecan with fluorouracil/leucovorin appeared to be maintained across age groups, prior adjuvant treatment, number of organs involved and both sexes; however, the effect appeared larger among women than men.. oxaliplatinfigure3. 14.3 Previously Treated Advanced Colorectal Cancer. The efficacy of oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in multicenter, open-label, randomized, three-arm controlled trial was conducted in the US and Canada in patients with advanced colorectal cancer who had relapsed/progressed during or within months of first-line treatment with bolus fluorouracil/leucovorin and irinotecan (A multicenter, open-label, randomized, three-arm study of 5-fluorouracil (5-FU) leucovorin (LV) or oxaliplatin or combination of 5-FU/LV oxaliplatin as second-line treatment of metastatic colorectal carcinoma: NCT00008281). Patients were randomized to one of three regimens; the dosing regimens are presented in Table 22. Eligible patients were at least 18 years of age, had unresectable, measurable, histologically proven colorectal adenocarcinoma, with Karnofsky performance status (KPS) greater than 50%. Patients had to have aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase less than or equal to 2x upper limit of normal (ULN), unless liver metastases were present and documented at baseline by CT or MRI scan, in which case less than or equal to 5x ULN was permitted. Prior radiotherapy was permitted if it had been completed at least weeks before randomization. The main efficacy outcome measure was 3-year disease-free survival (DFS) and an additional outcome measure was overall survival (OS). Table 22: Dosing Regimens in Refractory and Relapsed Colorectal Cancer Trial Treatment Arm Dose Regimen Oxaliplatin FU/LV (N=152) Day 1: Oxaliplatin: 85 mg/m 2(2-hour infusion) LV 200 mg/m 2(2-hour infusion), followed by FU: 400 mg/m 2(bolus), 600 mg/m 2(22-hour infusion) Day 2: LV 200 mg/m 2(2-hour infusion), followed by FU: 400 mg/m 2(bolus), 600 mg/m 2(22-hour infusion) every weeks FU/LV (N=151) Day 1: LV 200 mg/m 2(2-hour infusion), followed by FU: 400 mg/m 2(bolus), 600 mg/m 2(22-hour infusion) Day 2: LV 200 mg/m 2(2-hour infusion), followed by FU: 400 mg/m 2(bolus), 600 mg/m 2(22-hour infusion) every weeks Oxaliplatin (N=156) Day 1: Oxaliplatin 85 mg/m 2(2-hour infusion) every weeks Patients must have had at least one unidimensional lesion measuring greater than or equal to 20 mm using conventional CT or MRI scans or greater than or equal to 10 mm using spiral CT scan. Tumor response and progression were assessed every cycles (6 weeks) using the Response Evaluation Criteria in Solid Tumors (RECIST) until radiological documentation of progression or for 13 months following the first dose of study drug(s), whichever came first. Confirmed responses were based on two tumor assessments separated by at least weeks. Baseline characteristics are shown in Table 23. Table 23: Baseline Characteristics in Refractory and Relapsed Colorectal Cancer Trial Oxaliplatin FU/LV N=152 Oxaliplatin N=156 FU/LV N=151 Sex: Male (%) 57.2 60.9 54.3 Female (%) 42.8 39.1 45.7 Median age (years) 59.0 61.0 60.0 Range 22-88 27-79 21-80 Race (%) Caucasian 88.8 84.6 87.4 Black 5.9 7.1 7.9 Asian 2.6 2.6 1.3 Other 2.6 5.8 3.3 KPS (%) 70-100 95.4 92.3 94.7 50-60 2.0 4.5 2.6 Not reported 2.6 3.2 2.6 Prior radiotherapy (%) 25.0 19.2 25.2 Prior pelvic radiation (%) 21.1 13.5 18.5 Number of metastatic sites (%) 25.7 31.4 27.2 >= 74.3 67.9 72.2 Liver involvement (%) Liver only 18.4 25.6 22.5 Liver other 53.3 59.0 60.3 The median number of cycles administered per patient was for the oxaliplatin and fluorouracil/leucovorin combination and each for fluorouracil/leucovorin alone and oxaliplatin alone. Patients treated with the combination of oxaliplatin and fluorouracil/leucovorin had an increased response rate compared to patients given fluorouracil/leucovorin or oxaliplatin alone. Efficacy results are summarized in Tables 24 and 25. Table 24: Response Rates in Refractory and Relapsed Colorectal Cancer Clinical Trial ITT Analysis Best Response Oxaliplatin FU/LV N=152 Oxaliplatin N=156 FU/LV N=151 Complete Response 0 Partial Response 13 (9%) (1%) P-value 0.0002 FU/LV vs Oxaliplatin FU/LV 95% CI 4.6%, 14.2% 0.2%, 4.6% 0, 2.4% Table 25: Radiographic Time to Progression (TTP) in Refractory and Relapsed Colorectal Cancer Clinical Trial Arm Oxaliplatin FU/LV N=152 Oxaliplatin N=156 FU/LV N=151 Number of progressors 50 101 74 Number of patients with no radiological evaluation beyond baseline 17 (11%) 16 (10%) 22 (15%) Median TTP (months) 4.6 1.6 2.7 95% CI 4.2, 6.1 1.4, 2.7 1.8, 3.0 This is not an ITT analysis. Events were limited to radiographic disease progression documented by independent review of radiographs. Clinical progression was not included in this analysis, and 18% of patients were excluded from the analysis based on unavailability of the radiographs for independent review. At the time of the interim analysis 49% of the radiographic progression events had occurred. In this interim analysis an estimated 2-month increase in median time to radiographic progression was observed compared to fluorouracil/leucovorin alone.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administer oxaliplatin injection 85 mg/m 2as an intravenous infusion over 120 minutes concurrently with leucovorin over 120 minutes in separate bags, followed by fluorouracil on Day of each 14-day cycle. Administer fluorouracil and leucovorin on Day as recommended. 2.1) Adjuvant Treatment:Continue treatment for up to 12 cycles or unacceptable toxicity. 2.1) Advanced Colorectal Cancer:Continue treatment until disease progression or unacceptable toxicity. 2.1) 2.1 Recommended Dosage. Administer oxaliplatin injection in combination with fluorouracil and leucovorin every weeks. For adjuvant treatment, continue treatment for up to 12 cycles or unacceptable toxicity. For advanced colorectal cancer, continue treatment until disease progression or unacceptable toxicity. Day Administer oxaliplatin injection 85 mg/m 2as an intravenous infusion over 120 minutes and leucovorin 200 mg/m 2as an intravenous infusion over 120 minutes at the same time in separate bags, followed by fluorouracil 400 mg/m 2as intravenous bolus over 2-4 minutes, followed by fluorouracil 600 mg/m 2as 22-hour continuous infusion. Day Administer leucovorin 200 mg/m 2as an intravenous infusion over 120 minutes, followed by fluorouracil 400 mg/m 2as intravenous bolus over 2-4 minutes, followed by fluorouracil 600 mg/m 2as 22-hour continuous infusion. Refer to the prescribing information for fluorouracil and leucovorin for additional information. 2.2 Dose Modifications for Adverse Reactions. Prolongation of infusion time for oxaliplatin injection from hours to hours may mitigate acute toxicities, such as non-life-threatening infusion-related reactions. Permanently discontinue oxaliplatin injection for any of the following: Hypersensitivity Reactions [see Warnings and Precautions 5.1)] Posterior reversible encephalopathy syndrome (PRES) [see Warnings and Precautions 5.4)] Confirmed interstitial lung disease or pulmonary fibrosis [see Warnings and Precautions 5.5)] Rhabdomyolysis [see Warnings and Precautions 5.8)] Refer to the fluorouracil and leucovorin prescribing information for dosage modifications for adverse reactions. Dosage Modifications for Adjuvant Treatment Dosage modifications for adverse reactions for adjuvant treatment are presented in Table 1. Table 1: Dosage Modifications for Adjuvant Treatment in Patients with Stage III Colon CancerAdverse ReactionsSeverityOxaliplatin Injection Dosage Modifications Peripheral Sensory Neuropathy [see Warnings and Precautions (5.2)] Persistent Grade Consider reducing oxaliplatin injection dose to 75 mg/m 2. Persistent Grade Consider discontinuing oxaliplatin injection. Grade Discontinue oxaliplatin injection. Myelosuppression [see Warnings and Precautions (5.3), Adverse Reactions (6.1)]. Grade neutropenia or febrile neutropenia Delay the next dose until neutrophils greater than or equal to 1.5 10 9/L and platelets greater than or equal to 75 10 9/L. Reduce oxaliplatin injection dose to 75 mg/m 2. Grade to thrombocytopenia Gastrointestinal Adverse Reactions [see Adverse Reactions (6.1)] Grade to After recovery, reduce oxaliplatin injection dose to 75 mg/m 2along with dose reduction of fluorouracil to 300 mg/m 2as an intravenous bolus and 500 mg/m 2as 22-hour continuous infusion. Dosage Modifications for Advanced Colorectal CancerDosage modifications for adverse reactions for advanced colorectal cancer are presented in Table 2. Table 2: Dosage Modifications for Advanced Colorectal Cancer Adverse ReactionsSeverityOxaliplatin Injection Dosage ModificationsNeuropathy [see Warnings and Precautions (5.2)] Persistent Grade Consider reducing oxaliplatin injection dose to 65 mg/m 2. Persistent Grade Consider discontinuing oxaliplatin injection. Grade Discontinue oxaliplatin injection. Myelosuppression [see Warnings and Precautions (5.3), Adverse Reactions (6.1)] Grade neutropenia or febrile neutropenia Delay the next dose until neutrophils greater than or equal to 1.5 10 9/L and platelets greater than or equal to 75 10 9/L. Reduce oxaliplatin injection dose to 65 mg/m 2. Grade to thrombocytopenia Gastrointestinal Adverse Reactions [see Adverse Reactions (6.1)] Grade to After recovery, reduce oxaliplatin injection dose to 65 mg/m 2along with dose reduction of fluorouracil to 300 mg/m 2as an intravenous bolus and 500 mg/m 2as 22-hour continuous infusion . 2.3 Dose Modifications for Patients with Renal Impairment. In patients with severe renal impairment (creatinine clearance [CLcr] less than 30 mL/min, calculated by the Cockcroft-Gault equation), reduce the oxaliplatin injection dose to 65 mg/m [see Use in Specific Populations (8.6), Clinical Pharmacology 12.3)]. 2.4 Preparation and Administration. Oxaliplatin injection is cytotoxic drug. Follow applicable special handling and disposal procedures. o Do not freeze. Protect the concentrated solution from light. Dilute concentrated solution with 250 to 500 mL of 5% Dextrose Injection, USP. Do not dilute with sodium chloride solution or other chloride-containing solutions. Store diluted solution for no more than hours at room temperature (20C to 25C [68F to 77F]) or 24 hours under refrigeration (2C to 8C [36F to 46F]). Protection from light is not required. Visually inspect for particulate matter and discoloration prior to administration and discard if present. Do not mix oxaliplatin injection or administer oxaliplatin injection through the same infusion line concurrently with alkaline medications or media (such as basic solutions of fluorouracil). Flush the infusion line with 5% Dextrose Injection, USP prior to administration of any concomitant medication. Do not use needles or intravenous administration sets containing aluminum parts for the preparation or mixing of oxaliplatin injection. Aluminum has been reported to cause degradation of platinum compounds. Administer oxaliplatin injection as an intravenous infusion over 120 minutes concurrently with leucovorin over 120 minutes in separate bags.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Hypersensitivity Reactions Advise patients of the potential risk of hypersensitivity and that oxaliplatin injection is contraindicated in patients with history of hypersensitivity reactions to oxaliplatin and other platinum-based drugs. Instruct patients to seek immediate medical attention for signs of severe hypersensitivity reaction such as chest tightness; shortness of breath; wheezing; dizziness or faintness; or swelling of the face, eyelids, or lips [see Warnings and Precautions 5.1)]. Peripheral Sensory Neuropathy Advise patients of the risk of acute reversible or persistent-type neurosensory toxicity. Advise patients to avoid cold drinks, use of ice, and exposure of skin to cold temperature or cold objects [see Warnings and Precautions 5.2)]. Myelosuppression Inform patients that oxaliplatin injection can cause low blood cell counts and the need for frequent monitoring of blood cell counts. Advise patients to contact their healthcare provider immediately for bleeding, fever, particularly if associated with persistent diarrhea, or symptoms of infection develop [see Warnings and Precautions 5.3)]. Posterior Reversible Encephalopathy Syndrome Advise patients of the potential effects of vision abnormalities, in particular transient vision loss (reversible following therapy discontinuation), which may affect the patients ability to drive and use machines [see Warnings and Precautions 5.4)]. Pulmonary Toxicity Advise patients to report immediately to their healthcare provider any persistent or recurrent respiratory symptoms, such as non-productive cough and dyspnea [see Warnings and Precautions 5.5)]. Hepatotoxicity Advise patients to report signs or symptoms of hepatic toxicity to their healthcare provider [see Warnings and Precautions 5.6)]. QT Interval Prolongation Advise patients that oxaliplatin injection can cause QTc interval prolongation and to inform their physician if they have any symptoms, such as syncope [see Warnings and Precautions 5.7)]. Rhabdomyolysis Advise patients to contact their healthcare provider immediately for new or worsening signs or symptoms of muscle toxicity, dark urine, decreased urine output, or the inability to urinate [see Warnings and Precautions 5.8)]. Hemorrhage Advise patients that oxaliplatin injection may increase the risk of bleeding and to promptly inform their healthcare provider of any bleeding episodes [see Warnings and Precautions 5.9)]. Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions 5.10), Use in Specific Populations 8.1)]. Advise females of reproductive potential to use effective contraception during treatment with oxaliplatin injection and for months after the final dose [see Use in Specific Populations 8.3)]. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with oxaliplatin injection and for months after the final dose [see Use in Specific Populations 8.3), Nonclinical Toxicology 13.1)]. Lactation Advise women not to breastfeed during treatment with oxaliplatin injection and for months after the final dose [see Use in Specific Populations 8.2)]. Infertility Advise females and males of reproductive potential that oxaliplatin injection may impair fertility [see Use in Specific Populations 8.3), Nonclinical Toxicology 13.1)]. Gastrointestinal Advise patients to contact their healthcare provider for persistent vomiting, diarrhea, or signs of dehydration [see Adverse Reactions 6.1)]. Drug Interactions Inform patients about the risk of drug interactions and the importance of providing list of prescription and nonprescription drugs to their healthcare provider [see Drug Interactions 7)]. Manufactured for:Camber Pharamceuticals, Inc. Piscataway, NJ 08854 Manufactured by:HETERO LABS LIMITED Unit VI, Polepally, Jadcherla, Mahabubnagar 509 301, India Revised: 06/2025 camberlogo.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The reactive oxaliplatin derivatives are present as fraction of the unbound platinum in plasma ultrafiltrate. After single 2-hour intravenous infusion of oxaliplatin at dose of 85 mg/m 2, pharmacokinetic parameters expressed as ultrafiltrable platinum were Cmax of 0.814 mcg/mL and volume of distribution of 440 L. Interpatient and intrapatient variability in ultrafiltrable platinum exposure (AUC 0-48hr) assessed over cycles was 23% and 6%, respectively. Distribution At the end of 2-hour infusion of oxaliplatin, approximately 15% of the administered platinum is present in the systemic circulation. The remaining 85% is rapidly distributed into tissues or eliminated in the urine. The decline of ultrafiltrable platinum levels following oxaliplatin administration is triphasic, including two distribution phases (t 1/2; 0.43 hours and 1/2; 16.8 hours). In patients, plasma protein binding of platinum is irreversible and is greater than 90%. The main binding proteins are albumin and gamma-globulins. Platinum also binds irreversibly and accumulates (approximately 2-fold) in erythrocytes, where it appears to have no relevant activity. No platinum accumulation was observed in plasma ultrafiltrate following 85 mg/m 2every two weeks. Elimination The decline of ultrafiltrable platinum concentrations from plasma is characterized by long terminal elimination phase (t 1/2; 391 hours). Metabolism Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation. There is no evidence of cytochrome P450-mediated metabolism in vitro. Up to 17 platinum-containing derivatives have been observed in plasma ultrafiltrate samples from patients, including several cytotoxic species (monochloro DACH platinum, dichloro DACH platinum, and monoaquo and diaquo DACH platinum) and number of noncytotoxic, conjugated species. Excretion The major route of platinum elimination is renal excretion. At five days after single 2-hour infusion of oxaliplatin, urinary elimination accounted for about 54% of the platinum eliminated, with fecal excretion accounting for only about 2%. Platinum was cleared from plasma at rate (10-17 L/h) that was similar to or exceeded the average human glomerular filtration rate (GFR; 7.5 L/h). The renal clearance of ultrafiltrable platinum is significantly correlated with GFR. Special Populations Sex There was no significant effect of sex on the clearance of ultrafiltrable platinum. Patients with renal impairment Patients with normal function (CLcr greater than 80 mL/min) and patients with mild (CLcr=50- 80 mL/min) and moderate (CLcr equal to 30-49 mL/min) renal impairment received oxaliplatin 85 mg/m 2and those with severe (CLcr less than 30 mL/min) renal impairment received oxaliplatin 65 mg/m 2. Mean dose adjusted AUC of unbound platinum was 40%, 95%, and 342% higher for patients with mild, moderate, and severe renal impairment, respectively, compared to patients with normal renal function. Mean dose adjusted maxof unbound platinum appeared to be similar among the normal, mild and moderate renal function groups, but was 38% higher in the severe group than in the normal group [see Dosage and Administration 2.3)]. Drug Interaction Studies No pharmacokinetic interaction between oxaliplatin 85 mg/m 2and infusional fluorouracil has been observed in patients treated every weeks, but increases of fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m 2of oxaliplatin administered every weeks. In vitroplatinum was not displaced from plasma proteins by the following medications: erythromycin, salicylate, sodium valproate, granisetron, and paclitaxel. In vitrooxaliplatin does not inhibit human cytochrome P450 isoenzymes.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Females: Advise female patients of reproductive potential to use effective contraception while receiving oxaliplatin and for months after the final dose. 8.3) Males:Based on its mechanism action as genotoxic drug, advise males with female partners of reproductive potential to use effective contraception while receiving oxaliplatin and for months after the final dose [see Nonclinical Toxicology (13.1)]. 8.1 Pregnancy. Risk Summary Based on its direct interaction with DNA, oxaliplatin can cause fetal harm when administered to 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 (see Data).Advise pregnant woman of the potential risk to fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal data Pregnant rats were administered oxaliplatin at less than one-tenth the recommended human dose based on body surface area during gestation days (GD)1-5 (preimplantation), GD 6-10, or GD 11-16 (during organogenesis). Oxaliplatin caused developmental mortality (increased early resorptions) when administered on days GD 6-10 and GD 11-16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on days GD 6-10. 8.2 Lactation. Risk Summary There are no data on the presence of oxaliplatin or its metabolites in human or animal milk or its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with oxaliplatin and for months after the final dose. 8.3 Females and Males of Reproductive Potential. Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating oxaliplatin [see Use in Specific Populations 8.1)]. Contraception Oxaliplatin can cause embryo-fetal harm when administered to pregnant woman [see Use in Specific Populations 8.1)]. Females Advise female patients of reproductive potential to use effective contraception while receiving oxaliplatin and for months after the final dose. Males Based on its mechanism action as genotoxic drug, advise males with female partners of reproductive potential to use effective contraception while receiving oxaliplatin and for months after the final dose [see Nonclinical Toxicology 13.1)]. Infertility Based on animal studies, oxaliplatin may impair fertility in males and females [see Nonclinical Toxicology 13.1)]. 8.4 Pediatric Use. The safety and effectiveness of oxaliplatin in pediatrics have not been established. Safety and effectiveness were assessed across open-label studies in 235 patients aged months to 22 years with solid tumors. In multicenter, open-label, non-comparative, non-randomized study (ARD5531), oxaliplatin was administered to 43 patients with refractory or relapsed malignant solid tumors, mainly neuroblastoma and osteosarcoma. The dose limiting toxicity (DLT) was sensory neuropathy at dose of 110 mg/m 2. The main adverse reactions were: paresthesia (60%, grade 3-4: 7%), fever (40%, grade 3-4: 7%), and thrombocytopenia (40%, grade 3-4: 27%). No responses were observed. In an open-label non-randomized study (DFI7434), oxaliplatin was administered to 26 pediatric patients with metastatic or unresectable solid tumors, mainly neuroblastoma and ganglioneuroblastoma. The DLT was sensory neuropathy at dose of 160 mg/m 2. No responses were observed. In an open-label, single-agent study (ARD5021), oxaliplatin was administered to 43 pediatric patients with recurrent or refractory embryonal CNS tumors. The most common adverse reactions reported were: leukopenia (67%, grade 3-4: 12%), anemia (65%, grade 3-4: 5%), thrombocytopenia (65%, grade 3-4: 26%), vomiting (65%, grade 3-4: 7%), neutropenia (58%, grade 3-4: 16%), and sensory neuropathy (40%, grade 3-4: 5%). In an open-label single-agent study (ARD5530), oxaliplatin was administered to 123 pediatric patients with recurrent solid tumors, including neuroblastoma, osteosarcoma, Ewing sarcoma or peripheral PNET, ependymoma, rhabdomyosarcoma, hepatoblastoma, high grade astrocytoma, brain stem glioma, low grade astrocytoma, malignant germ cell tumor and other tumors. The most common adverse reactions reported were: sensory neuropathy (52%, grade 3-4: 12%), thrombocytopenia (37%, grade 3-4: 17%), anemia (37%, grade 3-4: 9%), vomiting (26%, grade 3-4: 4%), increased ALT (24%, grade 3-4: 6%), increased AST (24%, grade 3-4: 2%), and nausea (23%, grade 3-4: 3%). The pharmacokinetic parameters of ultrafiltrable platinum were evaluated in 105 pediatric patients during the first cycle. The mean clearance in pediatric patients estimated by the population pharmacokinetic analysis was 4.7 L/h (%CV, 41%). Mean platinum pharmacokinetic parameters in ultrafiltrate were maxof 0.75 +- 0.24 mcg/mL, AUC 0-48hof 7.52 +- 5.07 mcg h/mL and AUC infof 8.83 +- 1.57 mcg h/mL at 85 mg/m 2of oxaliplatin and maxof 1.10 +- 0.43 mcg/mL, AUC 0-48hof 9.74 +- 2.52 mcg h/mL and AUC infof 17.3 +- 5.34 mcg h/mL at 130 mg/m 2of oxaliplatin. 8.5 Geriatric Use. In the adjuvant treatment trial [see Clinical Studies 14.1)], 400 patients who received oxaliplatin with fluorouracil/leucovorin were greater than or equal to 65 years. The effect of oxaliplatin in patients greater than or equal to 65 years was not conclusive. Patients greater than or equal to 65 years receiving oxaliplatin experienced more diarrhea and grade 3-4 neutropenia (45% vs 39%) compared to patients less than 65 years. In the previously untreated advanced colorectal cancer trial [see Clinical Studies 14.2)], 99 patients who received oxaliplatin with fluorouracil and leucovorin were greater than or equal to 65 years. The same efficacy improvements in response rate, time to tumor progression, and overall survival were observed in the greater than or equal to 65 years patients as in the overall study population. Adverse reactions were similar in patients less than 65 and greater than or equal to 65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, leukopenia, fatigue, and syncope. In the previously treated advanced colorectal cancer trial [see Clinical Studies 14.3)], 55 patients who received oxaliplatin with fluorouracil and leucovorin were greater than or equal to 65 years. No overall differences in effectiveness were observed between these patients and younger adults. Adverse reactions were similar in patients less than 65 and greater than or equal to 65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, and fatigue. No significant effect of age on the clearance of ultrafiltrable platinum has been observed [see Clinical Pharmacology 12.3)]. 8.6 Patients with Renal Impairment. The AUC of unbound platinum in plasma ultrafiltrate was increased in patients with renal impairment [see Clinical Pharmacology 12.3)]. No dose reduction is recommended for patients with mild (creatinine clearance 50 to 79 mL/min) or moderate (creatinine clearance 30 to 49 mL/min) renal impairment, calculated by Cockcroft-Gault equation. Reduce the dose of oxaliplatin in patients with severe renal impairment (creatinine clearance less than 30 mL/min) [see Dosage and Administration 2.3)].

WARNINGS AND PRECAUTIONS SECTION.

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 neutropenia, febrile neutropenia, or grade 3-4 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 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 3-4 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 reversible, primarily peripheral sensory neuropathy that occurs within hours or days following 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 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 peripheral sensory neuropathy, the median time to onset was cycles for adjuvant treatment and cycles for previously treated advanced colorectal cancer. An acute syndrome of pharyngolaryngeal dysesthesia occurred in 1% to 2% (grade 3-4) 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 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 persistent neuropathy progressed from prior grade or 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 as summarized in Table 3. Table 3: Grading for Neuropathy in Adjuvant Treatment Trial GradeDefinition0 No change or none Mild paresthesias, loss of deep tendon reflexes Mild or moderate objective sensory loss, moderate paresthesias Severe objective sensory loss or paresthesias that interfere with function 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 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 GradeDefinition1 Resolved and did not interfere with functioning Interfered with function but not daily activities Pain or functional impairment that interfered with daily activities 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 3-4; and in 74% (all grades) of patients previously treated for advanced colorectal cancer, including 7% grade 3-4.. 5.3 Severe Myelosuppression. Grade or 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 or 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 neutropenia, febrile neutropenia or grade 3-4 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 3-4) 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, 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 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 fetus. Advise females of reproductive potential to use effective contraception during treatment with oxaliplatin and for months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with oxaliplatin and for months after the final dose [see Use in Specific Populations 8.1, 8.3)].