OXALIPLATIN

Oxaliplatin for injection USP is an antineoplastic agent 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 for injection, USP is supplied in vials containing 50 mg or 100 mg of Oxaliplatin, USP as a sterile, preservative-free lyophilized powder for reconstitution. Lactose monohydrate is present as an inactive ingredient at 450 mg and 900 mg in the 50 mg and 100 mg dosage strengths, respectively. Oxaliplatin-image2

INDICATIONS & USAGE Oxaliplatin for injection USP, used in combination with infusional 5-fluorouracil/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 for injection USP is a platinum-based drug used in combination with infusional 5-fluorouracil/leucovorin, which 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. (1)

DOSAGE & ADMINISTRATION Oxaliplatin for injection should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available. - Administer oxaliplatin for injection in combination with 5-fluorouracil/leucovorin every 2 weeks. (2.1): - Day 1: Oxaliplatin for injection 85 mg/m 2 intravenous infusion in 250 to 500 mL 5% Dextrose Injection, USP and leucovorin 200 mg/m 2 intravenous infusion in 5% Dextrose Injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-fluorouracil 400 mg/m 2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m 2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion. - Day 2: leucovorin 200 mg/m 2 intravenous infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m 2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m 2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion. - Reduce the dose of oxaliplatin for injection to 75 mg/m 2 (adjuvant setting) or 65 mg/m 2 (advanced colorectal cancer) (2.2) : - if there are persistent grade 2 neurosensory events that do not resolve. - after recovery from grade 3/4 gastrointestinal toxicities (despite prophylactic treatment) or grade 4 neutropenia or febrile neutropenia or grade 3/4 thrombocytopenia. Delay next dose until neutrophils ≥1.5 x 10 9 /L and platelets ≥75 x 10 9 /L. - For patients with severe renal impairment (Creatinine clearance <30 mL/min), the initial recommended dose is 65 mg/m 2 . (2.2) - Discontinue oxaliplatin for injection if there are persistent Grade 3 neurosensory events. (2.2) - Never reconstitute or prepare final dilution with a sodium chloride solution or other chloride-containing solutions. (2.3) 2.1 Dosage Administer oxaliplatin for injection in combination with 5-fluorouracil/leucovorin every 2 weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles): Day 1: Oxaliplatin for injection 85 mg/m 2 intravenous infusion in 250 to 500 mL 5% Dextrose injection, USP and leucovorin 200 mg/m 2 intravenous infusion in 5% Dextrose Injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-fluorouracil 400 mg/m 2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m 2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion. Day 2: Leucovorin 200 mg/m 2 intravenous infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m 2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m 2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion. Figure 1 The administration of oxaliplatin for injection does not require prehydration. Premedication with antiemetics, including 5-HT 3 blockers with or without dexamethasone, is recommended. For information on 5-fluorouracil and leucovorin, see the respective package inserts. Oxaliplatin-image1 2.2 Dose Modification Recommendations Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory tests [see Warnings and Precautions (5.11)]. Prolongation of infusion time for oxaliplatin for injection from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5-fluorouracil and leucovorin do not need to be changed. Adjuvant Therapy in Patients with Stage III Colon Cancer Neuropathy and other toxicities were graded using the NCI CTC scale version 1 [see Warnings and Precautions (5.2)]. For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of oxaliplatin for injection to 75 mg/m 2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The infusional 5-fluorouracil/leucovorin regimen need not be altered. A dose reduction of oxaliplatin for injection to 75 mg/m 2 and infusional 5-fluorouracil to 300 mg/m 2 bolus and 500 mg/m 2 22 hour infusion is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or febrile neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 x 10 9 /L and platelets ≥75 x 10 9 /L. Dose Modifications in Therapy in Previously Untreated and Previously Treated Patients with Advanced Colorectal Cancer Neuropathy was graded using a study-specific neurotoxicity scale [see Warnings and Precautions (5.2)]. Other toxicities were graded by the NCI CTC, Version 2.0. For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of oxaliplatin for injection to 65 mg/m 2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The 5-fluorouracil/leucovorin regimen need not be altered. A dose reduction of oxaliplatin for injection to 65 mg/m 2 and 5-fluorouracil by 20% (300 mg/m 2 bolus and 500 mg/m 2 22-hour infusion) is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or febrile neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 x 10 9 /L and platelets ≥75 x 10 9 /L. Dose Modifications in Therapy for patient with renal impairment In a patients with normal renal fuction or mild to moderate renal impairment, the recommended dose of oxaliplatin for injections 85 mg/m 2 in patients with severe renal impairment, the initial recommended oxaliplatin for injection dose should be reduced to 65 mg/m 2 [ see Use in Specific Population (8.6) and Clinical Pharmacology (12.3)]. 2.3 Preparation of Infusion Solution Reconstitution or final dilution must never be performed with a sodium chloride solution or other chloride containing solutions. The lyophilized powder is reconstituted by adding 10 mL (for the 50 mg vial) or 20 mL (for the 100 mg vial) of Water for Injection, USP or 5% Dextrose Injection, USP. Do not administer the reconstituted solution without further dilution. The reconstituted solution must be further diluted in an infusion solution of 250 to 500 mL of 5% Dextrose Injection, USP. After reconstitution in the original vial, the solution may be stored up to 24 hours under refrigeration [2° to 8°C (36° to 46°F)]. After final dilution with 250 to 500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20° to 25°C (68° to 77°F)] or up to 24 hours under refrigeration [2° to 8°C (36° to 46°F)]. Oxaliplatin for injection is not light sensitive. Oxaliplatin for injection is incompatible in solution with alkaline medications or media such as basic solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection, USP prior to administration of any concomitant medication. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and discarded if present. Needles or intravenous administration sets containing aluminum parts that may come in contact with oxaliplatin for injection should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.

Oxaliplatin for injection should not be administered to patients with a history of known allergy to oxaliplatin for injection or other platinum compounds [see Warnings and Precautions (5.1)] . - Known allergy to oxaliplatin for injection or other platinum compounds. (4, 5.1)

The following serious adverse reactions are discussed in greaterdetail in other sections of the label: Anaphylaxis and Allergic reactions [see Boxed Warning, Warnings and Precautions (5.1).] Neuropathy [see Warnings and Precautions (5.2).] Severe Neutropenia [see Warnings and Precautions (5.3).] Pulmonary Toxicities [see Warnings and Precautions (5.4).] Hepatotoxicity [see Warnings and Precautions (5.5).] Cardiovascular Toxicities [see Warnings and Precautions (5.6).] Rhabdomyolysis [see Warnings and Precautions (5.7).] Most common adverse reactions (incidence ≥ 40%) were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, Fatigue and stomatitis. Other adverse reactions, including serious adverse reactions, have been reported. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Gland Pharma at 864-879-994 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. More than 1100 patients with stage II or III colon cancer and more than 4,000 patients with advanced colorectal cancer have been treated in clinical studies with oxaliplatin for injection. The most common adverse reactions in patients with stage II or III colon cancer receiving adjuvant therapy were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis. The most common adverse reactions in previously untreated and treated patients were peripheral sensory neuropathies, fatigue, neutropenia, nausea, emesis, and diarrhea [see Warnings and Precautions (5)]. Combination Adjuvant Therapy with Oxaliplatin for Injection and Infusional 5-fluorouracil/leucovorin in Patients with Colon Cancer One thousand one hundred and eight patients with stage II or III colon cancer, who had undergone complete resection of the primary tumor, have been treated in a clinical study with oxaliplatin for injection in combination with infusional 5-fluorouracil/leucovorin [see Clinical Studies (14)]. The incidence of grade 3 or 4 adverse reactions was 70% on the oxaliplatin for injection combination arm, and 31% on the infusional 5-fluorouracil/leucovorin arm. The adverse reactions in this trial are shown in the tables below. Discontinuation of treatment due to adverse reactions occurred in 15% of the patients receiving oxaliplatin for injection and infusional 5-fluorouracil/leucovorin. Both 5-fluorouracil/leucovorin and oxaliplatin for injection are associated with gastrointestinal or hematologic adverse reactions. When oxaliplatin for injection is administered in combination with infusional 5-fluorouracil/leucovorin, the incidence of these events is increased. The incidence of death within 28 days of last treatment, regardless of causality, was 0.5% (n=6) in both the oxaliplatin for injection combination and infusional 5-fluorouracil/leucovorin arms, respectively. Deaths within 60 days from initiation of therapy were 0.3% (n=3) in both the oxaliplatin for injection combination and infusional 5-fluorouracil/leucovorin arms, respectively. On the oxaliplatin for injection combination arm, 3 deaths were due to sepsis/neutropenic sepsis, 2 from intracerebral bleeding and one from eosinophilic pneumonia. On the 5-fluorouracil/leucovorin arm, one death was due to suicide, 2 from Steven-Johnson Syndrome (1 patient also had sepsis), 1 unknown cause, 1 anoxic cerebral infarction and 1 probable abdominal aorta rupture. The following table provides adverse reactions reported in the adjuvant therapy colon cancer clinical trial [see Clinical Studies (14)] by body system and decreasing order of frequency in the oxaliplatin for injection and infusional 5-fluorouracil/leucovorin arm for events with overall incidences ≥ 5% and for NCI grade 3/4 events with incidences ≥ 1%. Table 3 – Adverse Reactions Reported in Patients with Colon Cancer receiving Adjuvant Treatment (≥5% of all patients and with ≥1% NCI Grade 3/4 events) Oxaliplatin for Injection + 5-FU/LV N=1108 5-FU/LV N=1111 Adverse reaction (WHO/Pref) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) Any Event 100 70 99 31 Allergy/Immunology Allergic Reaction 10 3 2 <1 Constitutional Symptoms/Pain Fatigue 44 4 38 1 Abdominal Pain 18 1 17 2 Dermatology/Skin Skin Disorder 32 2 36 2 Injection Site Reaction 1 11 3 10 3 Gastrointestinal Nausea 74 5 61 2 Diarrhea 56 11 48 7 Vomiting 47 6 24 1 Stomatitis 42 3 40 2 Anorexia 13 1 8 <1 Fever/Infection Fever 27 1 12 1 Infection 25 4 25 3 Neurology Overall Peripheral Sensory Neuropathy 92 12 16 <1 1 Includes thrombosis related to the catheter The following table provides adverse reactions reported in the adjuvant therapy colon cancer clinical trial [see Clinical Studies (14)] by body system and decreasing order of frequency in the oxaliplatin for injection and infusional 5-fluorouracil/leucovorin arm for events with overall incidences ≥ 5% but with incidences <1% NCI grade 3/4 events. Table 4 - Adverse Reactions Reported in Patients with Colon Cancer receiving Adjuvant Treatment (≥ 5% of all patients, but with <1% NCI Grade 3/4 events) Adverse reaction (WHO/Pref) Oxaliplatin for Injection + 5-FU/LV N=1108 5-FU/LV N=1111 All Grades (%) All Grades (%) Allergy/Immunology Rhinitis 6 8 Constitutional Symptoms /Pain/Ocular/Visual Epistaxis 16 12 Weight Increase 10 10 Conjunctivitis 9 15 Headache 7 5 Dyspnea 5 3 Pain 5 5 Lacrimation Abnormal 4 12 Dermatology/Skin Alopecia 30 28 Gastrointestinal Constipation 22 19 Taste Perversion 12 8 Dyspepsia 8 5 Metabolic Phosphate Alkaline increased 42 20 Neurology Sensory Disturbance 8 1 Although specific events can vary, the overall frequency of adverse reactions was similar in men and women and in patients <65 and ≥65 years. However, the following grade 3/4 events were more common in females: diarrhea, fatigue, granulocytopenia, nausea and vomiting. In patients ≥65 years old, the incidence of grade 3/4 diarrhea and granulocytopenia was higher than in younger patients. Insufficient subgroup sizes prevented analysis of safety by race. The following additional adverse reactions, were reported in ≥2% and <5% of the patients in the oxaliplatin for injection and infusional 5-fluorouracil/leucovorin combination arm (listed in decreasing order of frequency): pain, leukopenia, weight decrease, coughing. The number of patients who developed secondary malignancies was similar; 62 in the oxaliplatin for injection combination arm and 68 in the infusional 5-fluorouracil/leucovorin arm. An exploratory analysis showed that the number of deaths due to secondary malignancies was 1.96% in the oxaliplatin for injection combination arm and 0.98% in infusional 5-fluorouracil/leucovorin arm. In addition, the number of cardiovascular deaths was 1.4% in the oxaliplatin for injection combination arm as compared to 0.7% in the infusional 5-fluorouracil/leucovorin arm. Clinical significance of these findings is unknown. Patients Previously Untreated for Advanced Colorectal Cancer Two hundred and fifty-nine patients were treated in the oxaliplatin for injection and 5- fluorouracil/leucovorin combination arm of the randomized trial in patients previously untreated for advanced colorectal cancer [see Clinical Studies (14)]. The adverse reaction profile in this study was similar to that seen in other studies and the adverse reactions in this trial are shown in the tables below. Both 5-fluorouracil and oxaliplatin for injection are associated with gastrointestinal and hematologic adverse reactions. When oxaliplatin for injection is administered in combination with 5-fluorouracil, the incidence of these events is increased. The incidence of death within 30 days of treatment in the previously untreated for advanced colorectal cancer study, regardless of causality, was 3% with the oxaliplatin for injection and 5-fluorouracil/leucovorin combination, 5% with irinotecan plus 5-fluorouracil/leucovorin, and 3% with oxaliplatin for injection plus irinotecan. Deaths within 60 days from initiation of therapy were 2.3% with the oxaliplatin for injection and 5-fluorouracil/leucovorin combination, 5.1% with irinotecan plus 5-fluorouracil/leucovorin, and 3.1% with oxaliplatin for injection plus irinotecan. The following table provides adverse reactions reported in the previously untreated for advanced colorectal cancer study [see Clinical Studies (14) ] by body system and decreasing order of frequency in the oxaliplatin for injection and 5-fluorouracil/leucovorin combination arm for events with overall incidences ≥5% and for grade 3/4 events with incidences ≥1%. Table 5 – Adverse Reactions Reported in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial (≥5% of all patients and with ≥1% NCI Grade 3/4 events) Oxaliplatin for Injection + 5-FU/LV N=259 Irinotecan + 5- FU/LV N=256 Oxaliplatin for Injection + Irinotecan N=258 Adverse reaction (WHO/Pref) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) Any Event 99 82 98 70 99 76 Allergy/Immunology Hypersensitivity 12 2 5 0 6 1 Cardiovascular Thrombosis 6 5 6 6 3 3 Hypotension 5 3 6 3 4 3 Constitutional Symptoms /Pain/Ocular/Visual Fatigue 70 7 58 11 66 16 Abdominal Pain 29 8 31 7 39 10 Myalgia 14 2 6 0 9 2 Pain 7 1 5 1 6 1 Vision abnormal 5 0 2 1 6 1 Neuralgia 5 0 0 0 2 1 Dermatology/Skin Skin reaction – hand/foot 7 1 2 1 1 0 Injection site reaction 6 0 1 0 4 1 Gastrointestinal Nausea 71 6 67 15 83 19 Diarrhea 56 12 65 29 76 25 Vomiting 41 4 43 13 64 23 Stomatitis 38 0 25 1 19 1 Anorexia 35 2 25 4 27 5 Constipation 32 4 27 2 21 2 Diarrhea-colostomy 13 2 16 7 16 3 Gastrointestinal NOS* 5 2 4 2 3 2 Hematology/Infection Infection normal ANC** 10 4 5 1 7 2 Infection low ANC** 8 8 12 11 9 8 Lymphopenia 6 2 4 1 5 2 Febrile neutropenia 4 4 15 14 12 11 Hepatic/Metabolic/Laboratory/Renal Hyperglycemia 14 2 11 3 12 3 Hypokalemia 11 3 7 4 6 2 Dehydration 9 5 16 11 14 7 Hypoalbuminemia 8 0 5 2 9 1 Hyponatremia 8 2 7 4 4 1 Urinary frequency 5 1 2 1 3 1 Neurology Overall Neuropathy 82 19 18 2 69 7 Paresthesias 77 18 16 2 62 6 Pharyngo-laryngeal dysesthesias 38 2 1 0 28 1 Neuro-sensory 12 1 2 0 9 1 Neuro NOS* 1 0 1 0 1 0 Pulmonary Cough 35 1 25 2 17 1 Dyspnea 18 7 14 3 11 2 Hiccups 5 1 2 0 3 2 * Not otherwise specified ** Absolute neutrophil count The following table provides adverse reactions reported in the previously untreated for advanced colorectal cancer study [see Clinical Studies (14)] by body system and decreasing order of frequency in the oxaliplatin for injection and 5-fluorouracil/leucovorin combination arm for events with overall incidences ≥5% but with incidences <1% NCI Grade 3/4 events. Table 6 - Adverse Reactions Reported in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial (≥5% of all patients but with < 1% NCI Grade 3/4 events) Oxaliplatin for Injection + 5- FU/LV N=259 Irinotecan + 5-FU/LV N=256 Oxaliplatin for Injection + Irinotecan N=258 Adverse reaction (WHO/Pref) All Grades (%) All Grades (%) All Grades (%) Allergy/Immunology Rash 11 4 7 Rhinitis allergic 10 6 6 Cardiovascular Edema 15 13 10 Constitutional Symptoms /Pain/Ocular/Visual Headache 13 6 9 Weight loss 11 9 11 Epistaxis 10 2 2 Tearing 9 1 2 Rigors 8 2 7 Dysphasia 5 3 3 Sweating 5 6 12 Arthralgia 5 5 8 Dermatology/Skin Alopecia 38 44 67 Flushing 7 2 5 Pruritis 6 4 2 Dry Skin 6 2 5 Gastrointestinal Taste perversion 14 6 8 Dyspepsia 12 7 5 Flatulence 9 6 5 Mouth Dryness 5 2 3 Hematology/Infection Fever normal ANC* 16 9 9 Hepatic/Metabolic/Laboratory/Renal Hypocalcemia 7 5 4 Elevated Creatinine 4 4 5 Neurology Insomnia 13 9 1 Depression 9 5 7 Dizziness 8 6 10 Anxiety 5 2 6 * Absolute neutrophil count Adverse reactions were similar in men and women and in patients <65 and ≥65 years, but older patients may have been more susceptible to diarrhea, dehydration, hypokalemia, leukopenia, fatigue and syncope. The following additional adverse reactions, at least possibly related to treatment and potentially important, were reported in ≥2% and <5% of the patients in the oxaliplatin for injection and 5- fluorouracil/leucovorin combination arm (listed in decreasing order of frequency): metabolic, pneumonitis, catheter infection, vertigo, prothrombin time, pulmonary, rectal bleeding, dysuria, nail changes, chest pain, rectal pain, syncope, hypertension, hypoxia, unknown infection, bone pain, pigmentation changes, and urticaria. Previously Treated Patients with Advanced Colorectal Cancer Four hundred and fifty patients (about 150 receiving the combination of oxaliplatin for injection and 5-fluorouracil/leucovorin) were studied in a randomized trial in patients with refractory and relapsed colorectal cancer [see Clinical Studies (14)]. The adverse reaction profile in this study was similar to that seen in other studies and the adverse reactions in this trial are shown in the tables below. Thirteen percent of patients in the oxaliplatin for injection and 5-fluorouracil/leucovorin combination arm and 18% in the 5-fluorouracil/leucovorin arm of the previously treated study had to discontinue treatment because of adverse effects related to gastrointestinal, or hematologic adverse reactions, or neuropathies. Both 5-fluorouracil and oxaliplatin for injection are associated with gastrointestinal and hematologic adverse reactions. When oxaliplatin for injection is administered in combination with 5-fluorouracil, the incidence of these events is increased. The incidence of death within 30 days of treatment in the previously treated study, regardless of causality was 5% with the oxaliplatin for injection and 5-fluorouracil/leucovorin combination, 8% with oxaliplatin for injection alone, and 7% with 5-fluorouracil/leucovorin. Of the 7 deaths that occurred on the oxaliplatin for injection and 5-fluorouracil/leucovorin combination arm within 30 days of stopping treatment, 3 may have been treatment related, associated with gastrointestinal bleeding or dehydration. The following table provides adverse reactions reported in the previously treated study [see Clinical Studies (14)] by body system and in decreasing order of frequency in the oxaliplatin for injection and 5-fluorouracil/leucovorin combination arm for events with overall incidences ≥5% and for grade 3/4 events with incidences ≥1%. This table does not include hematologic and blood chemistry abnormalities; these are shown separately below. Table 7 – Adverse Reactions Reported In Previously Treated Colorectal Cancer Clinical Trial (≥5% of all patients and with ≥1% NCI Grade 3/4 events) 5-FU/LV (N = 142) Oxaliplatin for Injection (N = 153) Oxaliplatin for Injection + 5- FU/LV (N = 150) Adverse reaction (WHO/Pref) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) Any Event 98 41 100 46 99 73 Cardiovascular Dyspnea 11 2 13 7 20 4 Coughing 9 0 11 0 19 1 Edema 13 1 10 1 15 1 Thromboembolism 4 2 2 1 9 8 Chest Pain 4 1 5 1 8 1 Constitutional Symptoms /Pain Fatigue 52 6 61 9 68 7 Back Pain 16 4 11 0 19 3 Pain 9 3 14 3 15 2 Dermatology/Skin Injection Site Reaction 5 1 9 0 10 3 Gastrointestinal Diarrhea 44 3 46 4 67 11 Nausea 59 4 64 4 65 11 Vomiting 27 4 37 4 40 9 Stomatitis 32 3 14 0 37 3 Abdominal Pain 31 5 31 7 33 4 Anorexia 20 1 20 2 29 3 Gastroesophageal Reflux 3 0 1 0 5 2 Hematology/Infection Fever 23 1 25 1 29 1 Febrile Neutropenia 1 1 0 0 6 6 Hepatic/Metabolic/Laboratory/Renal Hypokalemia 3 1 3 2 9 4 Dehydration 6 4 5 3 8 3 Neurology Neuropathy 17 0 76 7 74 7 Acute 10 0 65 5 56 2 Persistent 9 0 43 3 48 6 The following table provides adverse reactions reported in the previously treated study [see Clinical Studies (14)] by body system and in decreasing order of frequency in the oxaliplatin for injection and 5-fluorouracil/leucovorin combination arm for events with overall incidences ≥5% but with incidences <1% NCI Grade 3/4 events. Table 8 - Adverse Reactions Reported In Previously Treated Colorectal Cancer Clinical Trial (≥5% of all patients but with < 1% NCI Grade 3/4 events) 5-FU/LV (N = 142) Oxaliplatin for Injection (N = 153) Oxaliplatin for Injection + 5- FU/LV (N = 150) Adverse reaction(WHO/Pref) All Grades (%) All Grades (%) All Grades (%) Allergy/Immunology Rhinitis 4 6 15 Allergic Reaction 1 3 10 Rash 5 5 9 Cardiovascular Peripheral Edema 11 5 10 Constitutional Symptoms /Pain/Ocular/Visual Headache 8 13 7 Arthralgia 10 7 10 Epistaxis 1 2 9 Abnormal Lacrimation 6 1 7 Rigors 6 9 7 Dermatology/Skin Hand-Foot Syndrome 13 1 11 Flushing 2 3 10 Alopecia 3 3 7 Gastrointestinal Constipation 23 31 32 Dyspepsia 10 7 14 Taste Perversion 1 5 13 Mucositis 10 2 7 Flatulence 6 3 5 Hepatic/Metabolic/Laboratory/Renal Hematuria 4 0 6 Dysuria 1 1 6 Neurology Dizziness 8 7 13 Insomnia 4 11 9 Pulmonary Upper Resp Tract Infection 4 7 10 Pharyngitis 10 2 9 Hiccup 0 2 5 Adverse reactions were similar in men and women and in patients <65 and ≥65 years, but older patients may have been more susceptible to dehydration, diarrhea, hypokalemia and fatigue. The following additional adverse reactions, at least possibly related to treatment and potentially important, were reported in ≥2% and <5% of the patients in the oxaliplatin for injection and 5-fluorouracil/leucovorin combination arm (listed in decreasing order of frequency): 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, urinary incontinence. Hematologic Changes The following tables list the hematologic changes occurring in ≥5% of patients, based on laboratory values and NCI grade, with the exception of those events occurring in adjuvant patients and anemia in the patients previously untreated for advanced colorectal cancer, respectively, which are based on AE reporting and NCI grade alone. Table 9 - Adverse Hematologic Reactions in Patients with Colon Cancer Receiving Adjuvant Therapy (≥5% of patients) Hematology Parameter Oxaliplatin for Injection + 5-FU/LV (N=1108) 5-FU/LV (N=1111) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) Anemia 76 1 67 <1 Neutropenia 79 41 40 5 Thrombocytopenia 77 2 19 <1 Table 10 – Adverse Hematologic Reactions in Patients Previously Untreated for Advanced Colorectal Cancer (≥5% of patients) Hematology Parameter Oxaliplatin for Injection + 5-FU/LV N=259 Irinotecan+ 5-FU/LV N=256 Oxaliplatin for Injection + Irinotecan N=258 All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) Anemia 27 3 28 4 25 3 Leukopenia 85 20 84 23 76 24 Neutropenia 81 53 77 44 71 36 Thrombocytopenia 71 5 26 2 44 4 Table 11 – Adverse Hematologic Reactions in Previously Treated Patients (≥5% of patients) Hematology Parameter 5-FU/LV (N=142) Oxaliplatin for Injection (N=153) Oxaliplatin for Injection + 5-FU/LV (N=150) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) Anemia 68 2 64 1 81 2 Leukopenia 34 1 13 0 76 19 Neutropenia 25 5 7 0 73 44 Thrombocytopenia 20 0 30 3 64 4 Thrombocytopenia and Bleeding Thrombocytopenia was frequently reported with the combination of oxaliplatin for injection and infusional 5-fluorouracil/leucovorin. The incidence of all hemorrhagic events in the adjuvant and previously treated patients was higher on the oxaliplatin for injection combination arm compared to the infusional 5-fluorouracil/leucovorin arm. These events included gastrointestinal bleeding, hematuria, and epistaxis. In the adjuvant trial, two patients died from intracerebral hemorrhages. The incidence of Grade 3/4 thrombocytopenia was 2% in adjuvant patients with colon cancer. In patients treated for advanced colorectal cancer the incidence of Grade 3/4 thrombocytopenia was 3 to 5%, and the incidence of these events was greater for the combination of oxaliplatin for injection and 5-fluorouracil/leucovorin over the irinotecan plus 5-fluorouracil/leucovorin or 5-fluorouracil/leucovorin control groups. Grade 3/4 gastrointestinal bleeding was reported in 0.2% of adjuvant patients receiving oxaliplatin for injection and 5-fluorouracil/leucovorin. In the previously untreated patients, the incidence of epistaxis was 10% in the oxaliplatin for injection and 5-fluorouracil/leucovorin arm, and 2% and 1%, respectively, in the irinotecan plus 5-fluorouracil/leucovorin or irinotecan plus oxaliplatin for injection arms. Neutropenia Neutropenia was frequently observed with the combination of oxaliplatin for injection and 5- fluorouracil/leucovorin, with Grade 3 and 4 events reported in 29% and 12% of adjuvant patients with colon cancer, respectively. In the adjuvant trial, 3 patients died from sepsis/neutropenic sepsis. Grade 3 and 4 events were reported in 35% and 18% of the patients previously untreated for advanced colorectal cancer, respectively. Grade 3 and 4 events were reported in 27% and 17% of previously treated patients, respectively. In adjuvant patients the incidence of either febrile neutropenia (0.7%) or documented infection with concomitant grade 3/4 neutropenia (1.1%) was 1.8% in the oxaliplatin for injection and 5-fluorouracil/leucovorin arm. The incidence of febrile neutropenia in the patients previously untreated for advanced colorectal cancer was 15% (3% of cycles) in the irinotecan plus 5-fluorouracil/leucovorin arm and 4% (less than 1% of cycles) in the oxaliplatin for injection and 5-fluorouracil/leucovorin combination arm. Additionally, in this same population, infection with grade 3 or 4 neutropenia was 12% in the irinotecan plus 5-fluorouracil/leucovorin, and 8% in the oxaliplatin for injection and 5-fluorouracil/leucovorin combination. The incidence of febrile neutropenia in the previously treated patients was 1% in the 5-fluorouracil/leucovorin arm and 6% (less than 1% of cycles) in the oxaliplatin for injection and 5-fluorouracil/leucovorin combination arm. Gastrointestinal In patients receiving the combination of oxaliplatin for injection plus infusional 5-fluorouracil/leucovorin for adjuvant treatment for colon cancer the incidence of Grade 3/4 nausea and vomiting was greater than those receiving infusional 5-fluorouracil/leucovorin alone (see table). In patients previously untreated for advanced colorectal cancer receiving the combination of oxaliplatin for injection and 5-fluorouracil/leucovorin, the incidence of Grade 3 and 4 vomiting and diarrhea was less compared to irinotecan plus 5-fluorouracil/leucovorin controls (see table). In previously treated patients receiving the combination of oxaliplatin for injection and 5-fluorouracil/leucovorin, the incidence of Grade 3 and 4 nausea, vomiting, diarrhea, and mucositis/stomatitis increased compared to 5-fluorouracil/leucovorin controls (see table). The incidence of gastrointestinal adverse reactions in the previously untreated and previously treated patients appears to be similar across cycles. Premedication with antiemetics, including 5-HT3 blockers, is recommended. Diarrhea and mucositis may be exacerbated by the addition of oxaliplatin for injection to 5-fluorouracil/leucovorin, and should be managed with appropriate supportive care. Since cold temperature can exacerbate acute neurological symptoms, ice (mucositis prophylaxis) should be avoided during the infusion of oxaliplatin for injection. Dermatologic Oxaliplatin for injection did not increase the incidence of alopecia compared to 5-fluorouracil/leucovorin alone. No complete alopecia was reported. The incidence of Grade 3/4 skin disorders was 2% in both the oxaliplatin for injection plus infusional 5-fluorouracil/leucovorin and the infusional 5-fluorouracil/leucovorin alone arms in the adjuvant colon cancer patients. The incidence of hand-foot syndrome in patients previously untreated for advanced colorectal cancer was 2% in the irinotecan plus 5-fluorouracil/leucovorin arm and 7% in the oxaliplatin for injection and 5-fluorouracil/leucovorin combination arm. The incidence of hand-foot syndrome in previously treated patients was 13% in the 5-fluorouracil/leucovorin arm and 11% in the oxaliplatin for injection and 5-fluorouracil/leucovorin combination arm. Intravenous Site Reactions Extravasation, in some cases including necrosis, has been reported. Injection site reaction, including redness, swelling, and pain, has been reported. Anticoagulation and Hemorrhage There have been reports while on study and from post-marketing surveillance of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received oxaliplatin for injection plus 5-fluorouracil/leucovorin while on anticoagulants. Patients receiving oxaliplatin for injection plus 5-fluorouracil/leucovorin and requiring oral anticoagulants may require closer monitoring. Renal About 5 to 10% of patients in all groups had some degree of elevation of serum creatinine. The incidence of Grade 3/4 elevations in serum creatinine in the oxaliplatin for injection and 5- fluorouracil/leucovorin combination arm was 1% in the previously treated patients. Serum creatinine measurements were not reported in the adjuvant trial. Hepatic Hepatotoxicity (defined as elevation of liver enzymes) appears to be related to oxaliplatin for injection combination therapy [see Warnings and Precautions (5.6)]. The following tables list the clinical chemistry changes associated with hepatic toxicity occurring in ≥5% of patients, based on adverse reactions reported and NCI CTC grade for adjuvant patients and patients previously untreated for advanced colorectal cancer, laboratory values and NCI CTC grade for previously treated patients. Table 12 - Adverse Hepatic Reactions in Patients with Stage II or III Colon Cancer Receiving Adjuvant Therapy (≥5% of patients) Hepatic Parameter Oxaliplatin for Injection + 5-FU/LV (N=1108) 5-FU/LV (N=1111) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) Increase in transaminases 57 2 34 1 ALP increased 42 <1 20 <1 Bilirubinaemia 20 4 20 5 Table 13 – Adverse Hepatic Clinical Chemistry Abnormalities in Patients Previously Untreated for Advanced Colorectal Cancer (≥5% of patients) Clinical Chemistry Oxaliplatin for Injection + 5-FU/LV N=259 Irinotecan+ 5-FU/LV N=256 Oxaliplatin for Injection + Irinotecan N=258 All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) ALT (SGPT-ALAT) 6 1 2 0 5 2 AST (SGOT-ASAT) 17 1 2 1 11 1 Alkaline Phosphatase 16 0 8 0 14 2 Total Bilirubin 6 1 3 1 3 2 Table 14 – Adverse Hepatic Clinical Chemistry Abnormalities in Previously Treated Patients (≥5% of patients) Clinical Chemistry 5-FU/LV (N=142) Oxaliplatin for Injection (N=153) Oxaliplatin for Injection + 5-FU/LV (N=150) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) ALT (SGPT-ALAT) 28 3 36 1 31 0 AST (SGOT-ASAT) 39 2 54 4 47 0 Total Bilirubin 22 6 13 5 13 1 Thromboembolism The incidence of thromboembolic events in adjuvant patients with colon cancer was 6% (1.8% grade 3/4) in the infusional 5-fluorouracil/leucovorin arm and 6% (1.2% grade 3/4) in the oxaliplatin for injection and infusional 5-fluorouracil/leucovorin combined arm, respectively. The incidence was 6 and 9% of the patients previously untreated for advanced colorectal cancer and previously treated patients in the oxaliplatin for injection and 5-fluorouracil/leucovorin combination arm, respectively. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of oxaliplatin for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a whole: angioedema, anaphylactic shock Cardiovascular disorders: QT prolongation leading to ventricular arrhythmias including fatal Torsade de Pointes Central and peripheral nervous system disorders: loss of deep tendon reflexes, dysarthria, Lhermitte’s sign, cranial nerve palsies, fasciculations, convulsion, Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES). Hearing and vestibular system disorders: deafness Infections: septic shock, including fatal outcomes Infusion reactions/hypersensitivity: laryngospasm Liver and Gastrointestinal system disorders: severe diarrhea/vomiting resulting in hypokalemia, colitis (including Clostridium difficile diarrhea), metabolic acidosis; ileus; intestinal obstruction, pancreatitis; veno-occlusive disease of liver also known as sinusoidal obstruction syndrome, and perisinusoidal fibrosis which rarely may progress. Musculoskeletal and connective tissue disorders rhabdomyolysis, including fatal outcomes. Platelet, bleeding, and clotting disorders : immuno-allergic thrombocytopenia prolongation of prothrombin time and of INR in patients receiving anticoagulants Red Blood Cell disorders: hemolytic uremic syndrome, immuno-allergic hemolytic anemia Renal disorders: Acute tubular necrosis, acute interstitial nephritis and acute renal failure. Respiratory system disorders: pulmonary fibrosis, and other interstitial lung diseases (sometimes fatal) Vision disorders: decrease of visual acuity, visual field disturbance, optic neuritis and transient vision loss (reversible following therapy discontinuation)

No specific cytochrome P-450-based drug interaction studies have been conducted. No pharmacokinetic interaction between 85 mg/m2 oxaliplatin for injection and 5-fluorouracil/leucovorin has been observed in patients treated every 2 weeks. Increases of 5-fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m2 oxaliplatin for injection dosed every 3 weeks. Because platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by coadministration of potentially nephrotoxic compounds; although, this has not been specifically studied [ see Clinical Pharmacology (12.3)].