Oxaliplatin

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 Fresenius Kabi USA, LLC, Vigilance & Medical Affairs at 1-800-551-7176 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 1,100 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) * 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 3-4 (%) 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 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) * 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. 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 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) * 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 3-4 (%) 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 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) * Event coded in WHO-ART dictionary † No complete alopecia was reported. ‡ Absolute neutrophil count 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 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 3-4 (%) 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 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) * Event coded in WHO-ART dictionary 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 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) * Event coded in WHO-ART dictionary † No complete alopecia was reported. 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 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 3-4 (%) 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 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, 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

4 CONTRAINDICATIONS Oxaliplatin is contraindicated in patients with a history of a hypersensitivity reaction to oxaliplatin or other platinum-based drugs. Reactions have included anaphylaxis [see Warnings and Precautions ( 5.1 )] . History of hypersensitivity reaction to oxaliplatin or other platinum-based drugs. ( 4 , 5.1 )

11 DESCRIPTION Oxaliplatin is a platinum-based drug with the molecular formula C 8 H 14 N 2 O 4 Pt and the chemical name of cis -[(1 R ,2 R )-1,2-cyclohexanediamine- N,N' ] [oxalato(2-)- O,O' ] platinum. Oxaliplatin is an organoplatinum complex in which the platinum atom is complexed with 1,2-diaminocyclohexane (DACH) and with an oxalate ligand as a leaving group. The molecular weight is 397.3. Oxaliplatin is slightly soluble in water at 6 mg/mL, very slightly soluble in methanol, and practically insoluble in ethanol and acetone. Oxaliplatin Injection, USP, for intravenous use is supplied in vials containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL. Water for Injection, USP is present as an inactive ingredient. Structural Formula

2 DOSAGE AND ADMINISTRATION Administer Oxaliplatin Injection 85 mg/m 2 as an intravenous infusion over 120 minutes concurrently with leucovorin over 120 minutes in separate bags, followed by fluorouracil on Day 1 of each 14-day cycle. Administer fluorouracil and leucovorin on Day 2 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 2 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 1 Administer Oxaliplatin 85 mg/m 2 as an intravenous infusion over 120 minutes and leucovorin 200 mg/m 2 as an intravenous infusion over 120 minutes at the same time in separate bags, followed by fluorouracil 400 mg/m 2 as intravenous bolus over 2 to 4 minutes, followed by fluorouracil 600 mg/m 2 as a 22-hour continuous infusion. Day 2 Administer leucovorin 200 mg/m 2 as an intravenous infusion over 120 minutes, followed by fluorouracil 400 mg/m 2 as intravenous bolus over 2 to 4 minutes, followed by fluorouracil 600 mg/m 2 as a 22-hour continuous infusion. Refer to the prescribing information for fluorouracil and leucovorin for additional information. 2.2 Dosage Modification for Adverse Reactions Prolongation of infusion time for Oxaliplatin from 2 hours to 6 hours may mitigate acute toxicities, such as non-life threatening infusion-related reactions. Permanently discontinue Oxaliplatin 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 Cancer Adverse Reactions Severity Oxaliplatin Injection Dosage Modifications Peripheral Sensory Neuropathy [see Warnings and Precautions ( 5.2 )] Persistent Grade 2 Consider reducing Oxaliplatin Injection dose to 75 mg/m 2 . Persistent Grade 3 Consider discontinuing Oxaliplatin Injection. Grade 4 Discontinue Oxaliplatin Injection. Myelosuppression [see Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6.1 )]. Grade 4 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 3 to 4 thrombocytopenia Gastrointestinal Adverse Reactions [see Adverse Reactions ( 6.1 )] Grade 3-4 After recovery, reduce Oxaliplatin Injection dose to 75 mg/m 2 along with a dose reduction of fluorouracil to 300 mg/m 2 as an intravenous bolus and 500 mg/m 2 as a 22-hour continuous infusion. Dosage Modifications for Advanced Colorectal Cancer Dosage modifications for adverse reactions for advanced colorectal cancer are presented in Table 2 . Table 2: Dosage Modifications for Advanced Colorectal Cancer Adverse Reactions Severity Oxaliplatin Dosage Modifications Neuropathy [see Warnings and Precautions ( 5.2 )] Persistent Grade 2 Consider reducing Oxaliplatin Injection dose to 65 mg/m 2 . Persistent Grade 3 Consider discontinuing Oxaliplatin Injection. Grade 4 Discontinue Oxaliplatin Injection Myelosuppression Grade 4 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 . [see Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6.1 )] Grade 3-4 thrombocytopenia Gastrointestinal Adverse Reactions [see Adverse Reactions ( 6.1 )] Grade 3-4 After recovery, reduce Oxaliplatin Injection dose to 65 mg/ m 2 along with a dose reduction of fluorouracil to 300 mg/m 2 as an intravenous bolus and 500 mg/m 2 as a 22-hour continuous infusion. 2.3 Dosage 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 2 [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )] . 2.4 Preparation and Administration Oxaliplatin Injection is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 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 6 hours at room temperature (20°C to 25°C [68°F to 77°F]) or 24 hours under refrigeration (2°C to 8°C [36°F to 46°F]). Protection from light is not required. Visually inspect for particulate matter and discoloration prior to administration and discard if present. Do not mix Oxaliplatin or administer Oxaliplatin 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. Aluminum has been reported to cause degradation of platinum compounds. Administer Oxaliplatin as an intravenous infusion over 120 minutes concurrently with leucovorin over 120 minutes in separate bags.

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 )

10 OVERDOSAGE The maximum dose of oxaliplatin that has been administered in a single infusion is 825 mg. Several cases of overdoses have been reported with Oxaliplatin. Adverse reactions observed following an overdosage were grade 4 thrombocytopenia (less than 25,000/mm 3 ) without bleeding, anemia, sensory neuropathy (including paresthesia, dysesthesia, laryngospasm and facial muscle spasms), gastrointestinal disorders (including nausea, vomiting, stomatitis, flatulence, abdomen enlarged and grade 4 intestinal obstruction), grade 4 dehydration, dyspnea, wheezing, chest pain, respiratory failure, severe bradycardia and death. Closely monitor patients suspected of receiving an overdose, including for the adverse reactions described above and administer appropriate supportive treatment.

7 DRUG INTERACTIONS 7.1 Drugs that Prolong the QT Interval QT interval prolongation and ventricular arrhythmias can occur with Oxaliplatin [see Warnings and Precautions ( 5.7 )] . Avoid coadministration of Oxaliplatin with medicinal products with a known potential to prolong the QT interval. 7.2 Use with Nephrotoxic Drugs Because platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by coadministration of potentially nephrotoxic compounds [see Clinical Pharmacology ( 12.3 )] . Avoid coadministration of Oxaliplatin with medicinal products known to cause nephrotoxicity. 7.3 Use with Anticoagulants Prolonged prothrombin time and INR occasionally associated with hemorrhage have been reported in patients who received Oxaliplatin with fluorouracil/leucovorin while on anticoagulants [see Warnings and Precautions ( 5.10 ), Adverse Reactions ( 6.2 )] . Increase frequency of monitoring in patients who are receiving Oxaliplatin with fluorouracil/leucovorin and oral anticoagulants.

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 N7 positions 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 vivo studies have shown antitumor activity of oxaliplatin against colon carcinoma. In combination with fluorouracil, oxaliplatin exhibits in vitro and in vivo antiproliferative activity greater than either compound alone in several tumor models (HT29 [colon], GR [mammary], and L1210 [leukemia]). 12.2 Pharmacodynamics A 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 a fraction of the unbound platinum in plasma ultrafiltrate. After a single 2-hour intravenous infusion of Oxaliplatin at a dose of 85 mg/m 2 , pharmacokinetic parameters expressed as ultrafiltrable platinum were C max 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 3 cycles was 23% and 6%, respectively. Distribution At the end of a 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 1/2α ; 0.43 hours and t 1/2β ; 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 2 every two weeks. Elimination The decline of ultrafiltrable platinum concentrations from plasma is characterized by a long terminal elimination phase (t1/2 γ ; 392 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 a number of noncytotoxic, conjugated species. Excretion The major route of platinum elimination is renal excretion. At five days after a 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 a rate (10 to 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 2 and 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 C max of 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 2 and infusional fluorouracil has been observed in patients treated every 2 weeks, but increases of fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m 2 of Oxaliplatin administered every 3 weeks. In vitro platinum was not displaced from plasma proteins by the following medications: erythromycin, salicylate, sodium valproate, granisetron, and paclitaxel. In vitro Oxaliplatin does not inhibit human cytochrome P450 isoenzymes.

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 N7 positions 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 vivo studies have shown antitumor activity of oxaliplatin against colon carcinoma. In combination with fluorouracil, oxaliplatin exhibits in vitro and in vivo antiproliferative activity greater than either compound alone in several tumor models (HT29 [colon], GR [mammary], and L1210 [leukemia]).

12.2 Pharmacodynamics A 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 a fraction of the unbound platinum in plasma ultrafiltrate. After a single 2-hour intravenous infusion of Oxaliplatin at a dose of 85 mg/m 2 , pharmacokinetic parameters expressed as ultrafiltrable platinum were C max 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 3 cycles was 23% and 6%, respectively. Distribution At the end of a 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 1/2α ; 0.43 hours and t 1/2β ; 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 2 every two weeks. Elimination The decline of ultrafiltrable platinum concentrations from plasma is characterized by a long terminal elimination phase (t1/2 γ ; 392 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 a number of noncytotoxic, conjugated species. Excretion The major route of platinum elimination is renal excretion. At five days after a 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 a rate (10 to 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 2 and 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 C max of 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 2 and infusional fluorouracil has been observed in patients treated every 2 weeks, but increases of fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m 2 of Oxaliplatin administered every 3 weeks. In vitro platinum was not displaced from plasma proteins by the following medications: erythromycin, salicylate, sodium valproate, granisetron, and paclitaxel. In vitro Oxaliplatin does not inhibit human cytochrome P450 isoenzymes.

20211007

14

3 DOSAGE FORMS AND STRENGTHS Injection: 50 mg (5 mg/mL) or 100 mg (5 mg/mL) clear, colorless solution in a single-dose vial. Injection: 50 mg (5 mg/mL) or 100 mg (5 mg/mL) in a single-dose vial ( 3 )

Oxaliplatin Oxaliplatin OXALIPLATIN OXALIPLATIN WATER

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential of oxaliplatin. Oxaliplatin was not mutagenic to bacteria (Ames test) but was mutagenic to mammalian cells in vitro (L5178Y mouse lymphoma assay). Oxaliplatin was clastogenic both in vitro (chromosome aberration in human lymphocytes) and in vivo (mouse bone marrow micronucleus assay). In a fertility study, male rats were given oxaliplatin at 0, 0.5, 1, or 2 mg/kg/day for five days every 21 days for a total of three cycles prior to mating with females that received two cycles of oxaliplatin on the same schedule. A dose of 2 mg/kg/day (less than one-seventh the recommended human dose on a body surface area basis) did not affect pregnancy rate, but resulted in 97% postimplantation loss (increased early resorptions, decreased live fetuses, decreased live births) and delayed growth (decreased fetal weight). Testicular damage, characterized by degeneration, hypoplasia, and atrophy, was observed in dogs administered oxaliplatin at 0.75 mg/kg/day (approximately one-sixth of the recommended human dose on a body surface area basis) x 5 days every 28 days for three cycles. A no effect level was not identified.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential of oxaliplatin. Oxaliplatin was not mutagenic to bacteria (Ames test) but was mutagenic to mammalian cells in vitro (L5178Y mouse lymphoma assay). Oxaliplatin was clastogenic both in vitro (chromosome aberration in human lymphocytes) and in vivo (mouse bone marrow micronucleus assay). In a fertility study, male rats were given oxaliplatin at 0, 0.5, 1, or 2 mg/kg/day for five days every 21 days for a total of three cycles prior to mating with females that received two cycles of oxaliplatin on the same schedule. A dose of 2 mg/kg/day (less than one-seventh the recommended human dose on a body surface area basis) did not affect pregnancy rate, but resulted in 97% postimplantation loss (increased early resorptions, decreased live fetuses, decreased live births) and delayed growth (decreased fetal weight). Testicular damage, characterized by degeneration, hypoplasia, and atrophy, was observed in dogs administered oxaliplatin at 0.75 mg/kg/day (approximately one-sixth of the recommended human dose on a body surface area basis) x 5 days every 28 days for three cycles. A no effect level was not identified.

ANDA078811

Oxaliplatin

Oxaliplatin

63323-750

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE LABEL PRINCIPAL DISPLAY PANEL- 50 mg per 10 mL- Vial Label NDC 63323-750-10 775010 Oxaliplatin Injection, USP 50 mg per 10 mL (5 mg per mL) For intravenous use only. MUST BE DILUTED WITH 5% DEXTROSE INJECTION BEFORE USE. Preservative free. Cytotoxic agent. Do not mix or add to sodium chloride/chloride-containing solutions. Rx only Single Dose Vial PACKAGE LABEL PRINCIPAL DISPLAY PANEL- 50 mg per 10 mL- Vial Label

17 PATIENT COUNSELING INFORMATION Hypersensitivity Reactions Advise patients of the potential risk of hypersensitivity and that Oxaliplatin is contraindicated in patients with a 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 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 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 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 a fetus. Advise females to inform their healthcare provider of a 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 and for 9 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 and for 6 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 and for 3 months after the final dose [see Use in Specific Populations ( 8.2 )] . Infertility Advise females and males of reproductive potential that Oxaliplatin 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 a list of prescription and nonprescription drugs to their healthcare provider [see Drug Interactions ( 7 )] . For Product Inquiry: 1-800-551-7176 or www.fresenius-kabi.com/us 451426C

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 a total of 6 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 4 N0 M0; Dukes' B2) or III (any T N 1-2 M0; 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 7 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 2 (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 2 × ULN, and aspartate transaminase (AST)/alanine transaminase (ALT) less than 2 × 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 2 (bolus), 600 mg/m 2 (22-hour infusion) every 2 weeks 12 cycles FU/LV (N=1123) 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 2 weeks 12 cycles There were 2,246 patients enrolled, of whom 1,347 (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, a 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 1 and 2 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 A hazard ratio of less than 1 favors Oxaliplatin + Infusional FU/LV Data cut off for disease-free survival June 1, 2006 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 Figure 1: Kaplan-Meier Curves of Disease-Free Survival (cutoff: 1 June 2006) in Adjuvant Treatment Trial – ITT Population Figure 2: Kaplan-Meier Curves of Disease-Free Survival in Stage III Patients (cutoff: 1 June 2006) in Adjuvant Treatment Trial - ITT Population Table 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 A hazard ratio of less than 1 favors Oxaliplatin + Infusional FU/LV Data cut off for overall survival January 16, 2007 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) Figure 1 Figure 2 14.2 Previously Untreated Advanced Colorectal Cancer The efficacy of Oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in a 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 7 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 5 × ULN, and alkaline phosphatase less than or equal to 5 × 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, 1 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 (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 2 weeks Irinotecan + FU/LV (IFL) (N=264) Day 1: irinotecan 125 mg/m 2 as a 90-min infusion + LV 20 mg/m 2 as a 15-min infusion or intravenous push, followed by FU 500 mg/m 2 intravenous bolus weekly x 4 every 6 weeks Oxaliplatin+ Irinotecan (IROX) (N=264) Day 1: Oxaliplatin: 85 mg/m 2 intravenous(2-hour infusion) + irinotecan 200 mg/m 2 intravenous over 30 minutes every 3 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 2 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, 4 (23.6 weeks) for the irinotecan plus fluorouracil/leucovorin regimen, and 7 (21.0 weeks) for the Oxaliplatin plus irinotecan regimen. Patients who received Oxaliplatin with fluorouracil/leucovorin had a significantly longer time to tumor progression based on investigator assessment, longer OS, and a 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 * Compared to irinotecan plus fluorouracil/leucovorin (IFL) arm. † A hazard ratio of less than 1 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. 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, N (%) 13 (6.2) 5 (2.4) 7 (3.3) Partial response, N (%) 82 (39.0) 64 (30.2) 67 (31.2) Complete and partial response, N (%) 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* - Figure 3: Kaplan-Meier Curves for Overall Survival in Previously Untreated Advanced Colorectal Cancer Trial *Log rank test comparing Oxaliplatin plus 5-FU/LV to irinotecan plus 5-FU/LV 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. Figure 3 14.3 Previously Treated Advanced Colorectal Cancer The efficacy of Oxaliplatin in combination with fluorouracil (FU)/leucovorin (LV) was evaluated in a 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 6 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 a 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 a 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 2× 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 5× ULN was permitted. Prior radiotherapy was permitted if it had been completed at least 3 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 2 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 2 weeks Oxaliplatin (N=156) Day 1: Oxaliplatin 85 mg/m 2 (2-hour infusion) every 2 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 to10 mm using a spiral CT scan. Tumor response and progression were assessed every 3 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 4 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 (%) 1 25.7 31.4 27.2 ≥ 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 6 for the Oxaliplatin and fluorouracil/leucovorin combination and 3 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 0 0 Partial Response 13 (9%) 2 (1%) 0 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 * 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. 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 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.

15 REFERENCES “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

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 )] .

8.4 Pediatric Use The safety and effectiveness of Oxaliplatin in pediatrics have not been established. Safety and effectiveness were assessed across 4 open-label studies in 235 patients aged 7 months to 22 years with solid tumors. In a 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 a 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 a 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 C max of 0.75 ± 0.24 mcg/mL, AUC 0-48h of 7.52 ± 5.07 mcg∙h/mL and AUC inf of 8.83 ± 1.57 mcg∙h/mL at 85 mg/m 2 of oxaliplatin and C max of 1.10 ± 0.43 mcg/mL, AUC 0-48h of 9.74 ± 2.52 mcg∙h/mL and AUC inf of 17.3 ± 5.34 mcg∙h/mL at 130 mg/m 2 of oxaliplatin.

8.1 Pregnancy Risk Summary Based on its direct interaction with DNA, 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 (see Data ) . Advise a pregnant woman of the potential risk to a 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 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. 8.1 Pregnancy Risk Summary Based on its direct interaction with DNA, 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 (see Data ) . Advise a pregnant woman of the potential risk to a 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 3 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 a 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 9 months after the final dose. Males Based on its mechanism action as a genotoxic drug, advise males with female partners of reproductive potential to use effective contraception while receiving Oxaliplatin and for 6 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 4 open-label studies in 235 patients aged 7 months to 22 years with solid tumors. In a 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 a 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 a 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 C max of 0.75 ± 0.24 mcg/mL, AUC 0-48h of 7.52 ± 5.07 mcg∙h/mL and AUC inf of 8.83 ± 1.57 mcg∙h/mL at 85 mg/m 2 of oxaliplatin and C max of 1.10 ± 0.43 mcg/mL, AUC 0-48h of 9.74 ± 2.52 mcg∙h/mL and AUC inf of 17.3 ± 5.34 mcg∙h/mL at 130 mg/m 2 of 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 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING Oxaliplatin Injection, USP is supplied in clear, glass, single-dose vials containing 50 mg or 100 mg of oxaliplatin as a clear, colorless, sterile, preservative-free, aqueous solution at a concentration of 5 mg per mL. Water for Injection USP is present as an inactive ingredient. Product Code Unit of Sale Strength Each 775010 NDC 63323-750-10 Individually packaged 50 mg per 10 mL (5 mg per mL) 10 mL Single Dose Vial 775020 NDC 63323-750-20 Individually packaged 100 mg per 20 mL (5 mg per mL) 20 mL Single Dose Vial The container closure is not made with natural rubber latex. Store at 20°C to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Do not freeze and protect from light (keep in original outer carton). Oxaliplatin is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 The use of gloves is recommended. If a solution of Oxaliplatin contacts the skin, wash the skin immediately and thoroughly with soap and water. If Oxaliplatin contacts the mucous membranes, flush thoroughly with water.

WARNING: HYPERSENSITIVITY REACTIONS, INCLUDING ANAPHYLAXIS Serious and fatal hypersensitivity adverse reactions, including anaphylaxis, can occur with Oxaliplatin Injection within minutes of administration and during any cycle. Oxaliplatin Injection is contraindicated in patients with hypersensitivity reactions to oxaliplatin and other platinum-based drugs [see Contraindications ( 4 )] . Immediately and permanently discontinue Oxaliplatin Injection for hypersensitivity reactions and administer appropriate treatment for management of the hypersensitivity reaction [see Warnings and Precautions ( 5.1 )]. WARNING: HYPERSENSITIVITY REACTIONS, INCLUDING ANAPHYLAXIS See full prescribing information for complete boxed warning. Serious and fatal hypersensitivity adverse reactions, including anaphylaxis, can occur with OXALIPLATIN INJECTION, USP within minutes of administration and during any cycle. OXALIPLATIN INJECTION, USP is contraindicated in patients with hypersensitivity reactions to oxaliplatin and other platinum-based drugs. Immediately and permanently discontinue OXALIPLATIN INJECTION, USP for hypersensitivity reactions and administer appropriate treatment. ( 4 , 5.1 )