This information is not for clinical use. These highlights do not include all the information needed to use Oxaliplatin safely and effectively. Before taking Oxaliplatin please consult with your doctor. See full prescribing information for Oxaliplatin.

Warning

WARNING: ANAPHYLACTIC REACTIONS Anaphylactic reactions to Oxaliplatin Injection, USP have been reported, and may occur within minutes of Oxaliplatin Injection, USP administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms of anaphylaxis [see Warnings and Precautions (5.1)]. WARNING: ANAPHYLACTIC REACTIONS See full prescribing information for complete boxed warning. Anaphylactic reactions to Oxaliplatin Injection, USP have been reported, and may occur within minutes of Oxaliplatin Injection, USP administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms. (5.1)

Recent Changes

Dosage and Administration (2.2) 10/2015
Warnings and Precautions (5.3, 5.4, 5.7, 5.8, 5.9) 10/2015

Indications And Usage

Oxaliplatin 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 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. (1) treatment of advanced colorectal cancer. (1)

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Dosage Forms And Strengths

Oxaliplatin Injection, USP is supplied in single-dose vials containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg per mL. Single-dose vials of 50 mg or 100 mg oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg per mL. (3)

Contraindications

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

Warning and Cautions

Allergic Reactions: Monitor for development of rash, urticaria, erythema, pruritis, bronchospasm, and hypotension. (5.1) Neuropathy: Reduce the dose or discontinue Oxaliplatin Injection, USP if necessary. (5.2) Severe Neutropenia: Delay Oxaliplatin Injection, USP until neutrophils are ≥1.5 × 109/L. Withhold Oxaliplatin Injection, USP for sepsis. (5.3) Pulmonary Toxicity: May need to discontinue Oxaliplatin Injection, USP until interstitial lung disease or pulmonary fibrosis are excluded. (5.4) Hepatotoxicity: Monitor liver function tests. (5.5) Cardiovascular Toxicity: Correct hypokalemia or hypomagnesemia prior to initiating Oxaliplatin Injection, USP. (5.6) Rhabdomyolysis: Discontinue Oxaliplatin Injection, USP if rhabdomyolysis occurs. (5.7) Pregnancy. Fetal harm can occur when administered to a pregnant woman. Women should be apprised of the potential harm to the fetus. (5.8, 8.1) 5.1 Allergic Reactions See boxed warning Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to Oxaliplatin Injection, USP has been observed in 2 to 3% of colon cancer patients. These allergic reactions which can be fatal, can occur within minutes of administration and at any cycle, and were similar in nature and severity to those reported with other platinum-containing compounds, such as rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension. The symptoms associated with hypersensitivity reactions reported in the previously untreated patients were urticaria, pruritus, flushing of the face, diarrhea associated with oxaliplatin infusion, shortness of breath, bronchospasm, diaphoresis, chest pains, hypotension, disorientation and syncope. These reactions are usually managed with standard epinephrine, corticosteroid, antihistamine therapy, and require discontinuation of therapy. Rechallenge is contraindicated in these patients [see Contraindications (4)]. Drug-related deaths associated with platinum compounds from anaphylaxis have been reported. 5.2 Neurologic Toxicity Neuropathy Oxaliplatin Injection, USP is associated with two types of neuropathy: An acute, reversible, primarily peripheral, sensory neuropathy that is of early onset, occurring within hours or one to two days of dosing, that resolves within 14 days, and that frequently recurs with further dosing. The symptoms may be precipitated or exacerbated by exposure to cold temperature or cold objects and they usually present as transient paresthesia, dysesthesia and hypoesthesia in the hands, feet, perioral area, or throat. Jaw spasm, abnormal tongue sensation, dysarthria, eye pain, and a feeling of chest pressure have also been observed. The acute, reversible pattern of sensory neuropathy was observed in about 56% of study patients who received Oxaliplatin Injection, USP with 5-fluorouracil/leucovorin. In any individual cycle acute neurotoxicity was observed in approximately 30% of patients. In adjuvant patients the median cycle of onset for grade 3 peripheral sensory neuropathy was 9 in the previously treated patients the median number of cycles administered on the Oxaliplatin Injection, USP with 5-fluorouracil/leucovorin combination arm was 6. An acute syndrome of pharyngolaryngeal dysesthesia seen in 1 to 2% (grade 3/4) of patients previously untreated for advanced colorectal cancer, and the previously treated patients, is characterized by subjective sensations of dysphagia or dyspnea, without any laryngospasm or bronchospasm (no stridor or wheezing). Ice (mucositis prophylaxis) should be avoided during the infusion of Oxaliplatin Injection, USP because cold temperature can exacerbate acute neurological symptoms. A persistent (>14 days), primarily peripheral, sensory neuropathy that is usually characterized by paresthesias, dysesthesias, hypoesthesias, but may also include deficits in proprioception that can interfere with daily activities (e.g., writing, buttoning, swallowing, and difficulty walking from impaired proprioception). These forms of neuropathy occurred in 48% of the study patients receiving Oxaliplatin Injection, USP with 5-fluorouracil/leucovorin. Persistent neuropathy can occur without any prior acute neuropathy event. The majority of the patients (80%) who developed grade 3 persistent neuropathy progressed from prior Grade 1 or 2 events. These symptoms may improve in some patients upon discontinuation of Oxaliplatin Injection, USP. In the adjuvant colon cancer trial, neuropathy was graded using a prelisted module derived from the Neuro-Sensory section of the National Cancer Institute Common Toxicity Criteria (NCI CTC) scale, Version 1, as follows: Table 1 - NCI CTC Grading for Neuropathy in Adjuvant Patients Grade Definition Grade 0 No change or none Grade 1 Mild paresthesias, loss of deep tendon reflexes Grade 2 Mild or moderate objective sensory loss, moderate paresthesias Grade 3 Severe objective sensory loss or paresthesias that interfere with function Grade 4 Not applicable Peripheral sensory neuropathy was reported in adjuvant patients treated with the Oxaliplatin Injection, USP combination with a frequency of 92% (all grades) and 13% (grade 3). At the 28-day follow-up after the last treatment cycle, 60% of all patients had any grade (Grade 1=40%, Grade 2=16%, Grade 3=5%) peripheral sensory neuropathy decreasing to 39% at 6 months follow-up (Grade 1=31%, Grade 2=7%, Grade 3=1%) and 21% at 18 months of follow-up (Grade 1=17%, Grade 2=3%, Grade 3=1%). In the advanced colorectal cancer studies, neuropathy was graded using a study-specific neurotoxicity scale, which was different from the NCI CTC scale, Version 2.0 (see below). Table 2 - Grading Scale for Paresthesias/Dysesthesias in Advanced Colorectal Cancer Patients Grade Definition Grade 1 Resolved and did not interfere with functioning Grade 2 Interfered with function but not daily activities Grade 3 Pain or functional impairment that interfered with daily activities Grade 4 Persistent impairment that is disabling or life-threatening Overall, neuropathy was reported in patients previously untreated for advanced colorectal cancer in 82% (all grades) and 19% (grade 3/4), and in the previously treated patients in 74% (all grades) and 7% (grade 3/4) events. Information regarding reversibility of neuropathy was not available from the trial for patients who had not been previously treated for colorectal cancer. Reversible Posterior Leukoencephalopathy Syndrome Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES, Posterior Reversible Encephalopathy Syndrome) has been observed in clinical trials (<0.1%) and postmarketing experience. Signs and symptoms of RPLS could be headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension [see Adverse Reactions (6.2)]. Diagnosis of RPLS is based upon confirmation by brain imaging. 5.3 Severe Neutropenia Grade 3 or 4 neutropenia occurred in 41 to 44% of patients with colorectal cancer treated with Oxaliplatin Injection, USP in combination with 5-flurouracil (5-FU) and leucovorin compared to 5% with 5-FU plus leucovorin alone. Sepsis, neutropenic sepsis and septic shock have been reported in patients treated with Oxaliplatin Injection, USP, including fatal outcomes [see Adverse Reactions (6.1)]. Delay Oxaliplatin Injection, USP until neutrophils are ≥1.5 × 109/L. Withhold Oxaliplatin Injection, USP for sepsis or septic shock. Dose reduce Oxaliplatin Injection, USP after recovery from Grade 4 neutropenia or febrile neutropenia [see Dosage and Administration (2.2)]. 5.4 Pulmonary Toxicity Oxaliplatin Injection, USP has been associated with pulmonary fibrosis (<1% of study patients), which may be fatal. The combined incidence of cough and dyspnea was 7.4% (any grade) and <1% (grade 3) with no grade 4 events in the Oxaliplatin Injection, USP plus infusional 5-fluorouracil/leucovorin arm compared to 4.5% (any grade) and no grade 3 and 0.1% grade 4 events in the infusional 5-fluorouracil/leucovorin alone arm in adjuvant colon cancer patients. In this study, one patient died from eosinophilic pneumonia in the Oxaliplatin Injection, USP combination arm. The combined incidence of cough, dyspnea and hypoxia was 43% (any grade) and 7% (grade 3 and 4) in the Oxaliplatin Injection, USP plus 5-fluorouracil/leucovorin arm compared to 32% (any grade) and 5% (grade 3 and 4) in the irinotecan plus 5-fluorouracil/leucovorin arm of unknown duration for patients with previously untreated colorectal cancer. In case of unexplained respiratory symptoms such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, Oxaliplatin Injection, USP should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis. 5.5 Hepatotoxicity Hepatotoxicity as evidenced in the adjuvant study, by increase in transaminases (57% vs. 34%) and alkaline phosphatase (42% vs. 20%) was observed more commonly in the Oxaliplatin Injection, USP combination arm than in the control arm. The incidence of increased bilirubin was similar on both arms. Changes noted on liver biopsies include: peliosis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive lesions. Hepatic vascular disorders should be considered, and if appropriate, should be investigated in case of abnormal liver function test results or portal hypertension, which cannot be explained by liver metastases [see Clinical Trials Experience (6.1)]. 5.6 Cardiovascular Toxicity QT prolongation and ventricular arrhythmias including fatal Torsade de Pointes have been reported in postmarketing experiences following Oxaliplatin Injection, USP administration. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating Oxaliplatin Injection, USP and monitor these electrolytes periodically during therapy. Avoid Oxaliplatin Injection, USP in patients with congenital long QT syndrome [see Adverse Reactions (6.2)]. 5.7 Rhabdomyolysis Rhabdomyolysis, including fatal cases, has been reported in patients treated with Oxaliplatin Injection, USP. Discontinue Oxaliplatin Injection, USP if any signs or symptoms of rhabdomyolysis occur [see Adverse Reactions (6.2)]. 5.8 Use in Pregnancy Pregnancy Category D Oxaliplatin Injection, USP may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Oxaliplatin Injection, USP in pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Oxaliplatin Injection, USP [see Use in Specific Populations (8.1)]. 5.9 Recommended Laboratory Tests Standard monitoring of the white blood cell count with differential, hemoglobin, platelet count, and blood chemistries (including ALT, AST, bilirubin and creatinine) is recommended before each Oxaliplatin Injection, USP cycle [see Dosage and Administration (2)]. 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 Injection, USP plus 5-fluorouracil/leucovorin while on anticoagulants. Patients receiving Oxaliplatin Injection, USP plus 5-fluorouracil/leucovorin and requiring oral anticoagulants may require closer monitoring.

Adverse Reactions

The following serious adverse reactions are discussed in greater detail 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 Breckenridge Pharmaceutical, Inc. at 1-800-367-3395 or go to www.bpirx.com 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 Injection, USP. 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 Injection, USP 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 Injection, USP 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 Injection, USP 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 Injection, USP and infusional 5-fluorouracil/leucovorin. Both 5-fluorouracil/leucovorin and Oxaliplatin Injection, USP are associated with gastrointestinal or hematologic adverse reactions. When Oxaliplatin Injection, USP 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 Injection, USP 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 Injection, USP combination and infusional 5-fluorouracil/leucovorin arms, respectively. On the Oxaliplatin Injection, USP 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 Injection, USP 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) Adverse reaction (WHO/Pref) Oxaliplatin Injection, USP + 5-FU/LV (N=1108) 5-FU/LV (N=1111) 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 ReactionIncludes thrombosis related to the catheter 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 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 Injection, USP 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 Injection, USP + 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 Injection, USP 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 Injection, USP 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 Injection, USP combination arm and 0.98% in infusional 5-fluorouracil/leucovorin arm. In addition, the number of cardiovascular deaths was 1.4% in the Oxaliplatin Injection, USP 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 Injection, USP 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 Injection, USP are associated with gastrointestinal and hematologic adverse reactions. When Oxaliplatin Injection, USP 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 Injection, USP and 5 fluorouracil/leucovorin combination, 5% with irinotecan plus 5-fluorouracil/leucovorin, and 3% with Oxaliplatin Injection, USP plus irinotecan. Deaths within 60 days from initiation of therapy were 2.3% with the Oxaliplatin Injection, USP and 5-fluorouracil/leucovorin combination, 5.1% with irinotecan plus 5-fluorouracil/leucovorin, and 3.1% with Oxaliplatin Injection, USP 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 Injection, USP 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) Adverse reaction (WHO/Pref) Oxaliplatin Injection, USP + 5-FU/LV (N=259) Irinotecan + 5-FU/LV (N=256) Oxaliplatin Injection, USP + Irinotecan (N=258) 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 NOSNot otherwise specified 5 2 4 2 3 2 Hematology/Infection Infection normal ANCAbsolute neutrophil count 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 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 Injection, USP 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) Adverse reaction (WHO/Pref) Oxaliplatin Injection, USP + 5-FU/LV (N=259) Irinotecan + 5-FU/LV (N=256) Oxaliplatin Injection, USP + Irinotecan (N=258) 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 ANCAbsolute neutrophil count 16 9 9 Hepatic/Metabolic/Laboratory/Renal Hypocalcemia 7 5 4 Elevated Creatinine 4 4 5 Neurology Insomnia 13 9 11 Depression 9 5 7 Dizziness 8 6 10 Anxiety 5 2 6 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 Injection, USP 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 Injection, USP 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 Injection, USP 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 Injection, USP are associated with gastrointestinal and hematologic adverse reactions. When Oxaliplatin Injection, USP 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 Injection, USP and 5-fluorouracil/leucovorin combination, 8% with Oxaliplatin Injection, USP alone, and 7% with 5-fluorouracil/leucovorin. Of the 7 deaths that occurred on the Oxaliplatin Injection, USP 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 Injection, USP 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) Adverse reaction (WHO/Pref) 5-FU/LV (N=142) Oxaliplatin Injection, USP (N=153) Oxaliplatin Injection, USP + 5-FU/LV (N=150) 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 Injection, USP 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) Adverse reaction (WHO/Pref) 5-FU/LV (N=142) Oxaliplatin Injection, USP (N=153) Oxaliplatin Injection, USP + 5-FU/LV (N=150) 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 17 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 13 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 Injection, USP 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) Oxaliplatin Injection, USP + 5-FU/LV (N=1108) 5-FU/LV (N=1111) Hematology Parameter 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) Oxaliplatin Injection, USP + 5-FU/LV (N=259) Irinotecan + 5-FU/LV (N=256) Oxaliplatin Injection, USP + Irinotecan (N=258) Hematology Parameter 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) 5-FU/LV (N=142) Oxaliplatin Injection, USP (N=153) Oxaliplatin Injection, USP + 5-FU/LV (N=150) Hematology Parameter 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 Injection, USP and infusional 5-fluorouracil/leucovorin. The incidence of all hemorrhagic events in the adjuvant and previously treated patients was higher on the Oxaliplatin Injection, USP 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 Injection, USP 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 Injection, USP and 5-fluorouracil/leucovorin. In the previously untreated patients, the incidence of epistaxis was 10% in the Oxaliplatin Injection, USP and 5-fluorouracil/leucovorin arm, and 2% and 1%, respectively, in the irinotecan plus 5-fluorouracil/leucovorin or irinotecan plus Oxaliplatin Injection, USP arms. Neutropenia Neutropenia was frequently observed with the combination of Oxaliplatin Injection, USP 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 Injection, USP 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 Injection, USP 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 Injection, USP 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 Injection, USP and 5-fluorouracil/leucovorin combination arm. Gastrointestinal In patients receiving the combination of Oxaliplatin Injection, USP 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 Injection, USP 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 Injection, USP 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 Injection, USP 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 Injection, USP. Dermatologic Oxaliplatin Injection, USP 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 Injection, USP 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 Injection, USP 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 Injection, USP 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 Injection, USP plus 5-fluorouracil/leucovorin while on anticoagulants. Patients receiving Oxaliplatin Injection, USP 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 Injection, USP 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 Injection, USP combination therapy [see Warnings and Precautions (5.5)]. 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) Oxaliplatin Injection, USP + 5-FU/LV (N=1108) 5-FU/LV (N=1111) Hepatic Parameter 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) Oxaliplatin Injection, USP + 5-FU/LV (N=259) Irinotecan + 5-FU/LV (N=256) Oxaliplatin Injection, USP + Irinotecan (N=258) Clinical Chemistry 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) 5-FU/LV (N=142) Oxaliplatin Injection, USP (N=153) Oxaliplatin Injection, USP + 5-FU/LV (N=150) Clinical Chemistry 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 Injection, USP 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 Injection, USP and 5-fluorouracil/leucovorin combination arm, respectively. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Oxaliplatin Injection, USP. 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)

Drug Interactions

No specific cytochrome P-450-based drug interaction studies have been conducted. No pharmacokinetic interaction between 85 mg/m2 Oxaliplatin Injection, USP 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 Injection, USP 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)].

Use In Specific Populations

8.1 Pregnancy Pregnancy Category D Based on direct interaction with DNA, Oxaliplatin Injection, USP may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Oxaliplatin Injection, USP in pregnant women. Reproductive toxicity studies in rats demonstrated adverse effects on fertility and embryo-fetal development at maternal doses that were below the recommended human dose based on body surface area. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant and use effective contraception while receiving treatment with Oxaliplatin Injection, USP. Pregnant rats were administered oxaliplatin at less than one-tenth the recommended human dose based on body surface area during gestation days 1 to 5 (pre-implantation), 6 to 10, or 11 to 16 (during organogenesis). Oxaliplatin caused developmental mortality (increased early resorptions) when administered on days 6 to 10 and 11 to 16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on days 6 to 10. Administration of oxaliplatin to male and female rats prior to mating resulted in 97% post-implantation loss in animals that received approximately one-seventh the recommended human dose based on the body surface area. 8.3 Nursing Mothers It is not known whether Oxaliplatin Injection, USP or its derivatives are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Oxaliplatin Injection, USP a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The effectiveness of oxaliplatin in children has not been established. Oxaliplatin has been tested in 2 Phase 1 and 2 Phase 2 trials in 235 patients ages 7 months to 22 years with solid tumors (see below) and no significant activity observed. In a Phase 1/2 study, oxaliplatin was administered as a 2-hour intravenous infusion on Days 1, 8 and 15 every 4 weeks (1 cycle), for a maximum of 6 cycles, to 43 patients with refractory or relapsed malignant solid tumors, mainly neuroblastoma and osteosarcoma. Twenty eight pediatric patients in the Phase 1 study received oxaliplatin at 6 dose levels starting at 40 mg/m2 with escalation to 110 mg/m2. The dose limiting toxicity (DLT) was sensory neuropathy at the 110 mg/m2 dose. Fifteen patients received oxaliplatin at a dose of 90 mg/m2 intravenous in the Phase 2 portion of the study. At this dose, paresthesia (60%, G3/4: 7%), fever (40%, G3/4: 7%) and thrombocytopenia (40%, G3/4: 27%) were the main adverse reactions. No responses were observed. In a second Phase 1 study, oxaliplatin was administered to 26 pediatric patients as a 2-hour intravenous infusion on day 1 every 3 weeks (1 cycle) at 5 dose levels starting at 100 mg/m2 with escalation to 160 mg/m2, for a maximum of 6 cycles. In a separate cohort, oxaliplatin 85 mg/m2 was administered on day 1 every 2 weeks, for a maximum of 9 doses. Patients had metastatic or unresectable solid tumors mainly neuroblastoma and ganglioneuroblastoma. No responses were observed. The DLT was sensory neuropathy at the 160 mg/m2 dose. Based on these studies, oxaliplatin 130 mg/m2 as a 2-hour intravenous infusion on day 1 every 3 weeks (1 cycle) was used in subsequent Phase II studies. A dose of 85 mg/m2 on day 1 every 2 weeks was also found to be tolerable. In one Phase 2 study, 43 pediatric patients with recurrent or refractory embryonal CNS tumors received oxaliplatin 130 mg/m2 every 3 weeks for a maximum of 12 months in absence of progressive disease or unacceptable toxicity. In patients <10 kg the oxaliplatin dose used was 4.3 mg/kg. The most common adverse reactions reported were leukopenia (67%, G3/4: 12%), anemia (65%, G3/4: 5%), thrombocytopenia (65%, G3/4: 26%), vomiting (65%, G3/4: 7%), neutropenia (58%, G3/4: 16%) and sensory neuropathy (40%, G3/4: 5%). One partial response was observed. In a second Phase 2 study, 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 of interest received oxaliplatin 130 mg/m2 every 3 weeks for a maximum of 12 months or 17 cycles. In patients ≤12 months old the oxaliplatin dose used was 4.3 mg/kg. The most common adverse reactions reported were sensory neuropathy (52%, G3/4: 12%), thrombocytopenia (37%, G3/4: 17%), anemia (37%, G3/4: 9%), vomiting (26%, G3/4: 4%), ALT increased (24%, G3/4: 6%), AST increased (24%, G3/4: 2%), and nausea (23%, G3/4: 3%). Two partial responses were observed. The pharmacokinetic parameters of ultrafiltrable platinum have been 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. The inter-patient variability of platinum clearance in pediatric cancer patients was 41%. Mean platinum pharmacokinetic parameters in ultrafiltrate were Cmax of 0.75 ± 0.24 mcg/mL, AUC0-48 of 7.52 ± 5.07 mcg∙h/mL and AUCinf of 8.83 ± 1.57 mcg∙h/mL at 85 mg/m2 of oxaliplatin and Cmax of 1.10 ± 0.43 mcg/mL, AUC0-48 of 9.74 ± 2.52 mcg∙h/mL and AUCinf of 17.3 ± 5.34 mcg∙h/mL at 130 mg/m2 of oxaliplatin. 8.5 Geriatric Use No significant effect of age on the clearance of ultrafilterable platinum has been observed. In the adjuvant therapy colon cancer randomized clinical trial, [see Clinical Studies (14)] 723 patients treated with Oxaliplatin Injection, USP and infusional 5-fluorouracil/leucovorin were <65 years and 400 patients were ≥65 years. A descriptive subgroup analysis demonstrated that the improvement in DFS for the Oxaliplatin Injection, USP combination arm compared to the infusional 5-fluorouracil/leucovorin alone arm appeared to be maintained across genders. The effect of Oxaliplatin Injection, USP in patients ≥65 years of age was not conclusive. Insufficient subgroup sizes prevented analysis by race. Patients ≥65 years of age receiving the Oxaliplatin Injection, USP combination therapy experienced more grade 3 to 4 granulocytopenia than patients <65 years of age (45% versus 39%). In the previously untreated for advanced colorectal cancer randomized clinical trial [see Clinical Studies (14)] of Oxaliplatin Injection, USP, 160 patients treated with Oxaliplatin Injection, USP and 5-fluorouracil/leucovorin were <65 years and 99 patients were ≥65 years. The same efficacy improvements in response rate, time to tumor progression, and overall survival were observed in the ≥65 year old patients as in the overall study population. In the previously treated for advanced colorectal cancer randomized clinical trial [see Clinical Studies (14)] of Oxaliplatin Injection, USP, 95 patients treated with Oxaliplatin Injection, USP and 5-fluorouracil/leucovorin were <65 years and 55 patients were ≥65 years. The rates of overall adverse reactions, including grade 3 and 4 events, were similar across and within arms in the different age groups in all studies. The incidence of diarrhea, dehydration, hypokalemia, leukopenia, fatigue and syncope were higher in patients ≥65 years old. No adjustment to starting dose was required in patients ≥65 years old. 8.6 Patients with Renal Impairment The exposure (AUC) of unbound platinum in plasma ultrafiltrate tends to increase in renally impaired patients [see Pharmacokinetics (12.3)]. Caution and close monitoring should be exercised when Oxaliplatin Injection, USP is administered to patients with renal impairment. The starting Oxaliplatin Injection, USP dose does not need to be reduced in patients with mild (creatinine clearance=50 to 80 mL/min) or moderate (creatinine clearance=30 to 49 mL/min) renal impairment. However, the starting dose of Oxaliplatin Injection, USP should be reduced in patients with severe renal impairment (creatinine clearance <30 mL/min) [see Dosage and Administration (2.2)].