2.1 Dosage

Administer Oxaliplatin Injection in combination with 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 Injection 85 mg/m2 intravenous infusion in 250 to 500 mL 5% Dextrose Injection and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection both given over 120 minutes at the same time in separate bags using a Y-line, followed by fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection (recommended) as a 22-hour continuous infusion.

Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection (recommended) as a 22-hour continuous infusion.

Figure 1

The administration of Oxaliplatin Injection does not require prehydration. Premedication with antiemetics, including 5-HT3 blockers with or without dexamethasone, is recommended.

For information on fluorouracil and leucovorin, see the respective package inserts.

2.2 Dose Modification Recommendations

Prior to subsequent therapy cycles, evaluate patients for clinical toxicities and recommended laboratory tests [see Warnings and Precautions (5.9)]. Prolongation of infusion time for Oxaliplatin Injection from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 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, consider a dose reduction of Oxaliplatin Injection to 75 mg/m2. For patients with persistent Grade 3 neurosensory events, consider discontinuing therapy. The infusional fluorouracil/leucovorin regimen need not be altered.

A dose reduction of Oxaliplatin Injection to 75 mg/m2 and infusional fluorouracil to 300 mg/m2 bolus and 500 mg/m2 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. Delay the next dose until: neutrophils ≥ 1.5 × 109/L and platelets ≥ 75 × 109/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, consider a dose reduction of Oxaliplatin Injection to 65 mg/m2. For patients with persistent Grade 3 neurosensory events, consider discontinuing therapy. The fluorouracil/leucovorin regimen need not be altered.

A dose reduction of Oxaliplatin Injection to 65 mg/m2 and fluorouracil by 20% (300 mg/m2 bolus and 500 mg/m2 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. Delay the next dose until: neutrophils ≥ 1.5 × 109/L and platelets ≥ 75 × 109/L.

Dose Modifications in Therapy for Patients with Renal Impairment

In patients with normal renal function or mild to moderate renal impairment, the recommended dose of Oxaliplatin Injection is 85 mg/m2. In patients with severe renal impairment, the recommended Oxaliplatin Injection dose is 65 mg/m2 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

2.3 Preparation of Infusion Solution

Oxaliplatin Injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

Do not freeze and protect from light the concentrated solution.

A final dilution must never be performed with a sodium chloride solution or other chloride-containing solutions.

The solution must be further diluted in an infusion solution of 250 to 500 mL of 5% Dextrose Injection.

After dilution with 250 to 500 mL of 5% Dextrose Injection, the shelf life is 6 hours at room temperature [20°C to 25°C (68°F to 77°F)] or up to 24 hours under refrigeration [2°C to 8°C (36°F to 46°F)]. After final dilution, protection from light is not required.

Oxaliplatin Injection is incompatible in solution with alkaline medications or media (such as basic solutions of 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 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 Injection should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.

Discard unused portion.

5.1 Allergic Reactions

Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to oxaliplatin 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 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 with 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 with 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 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 with 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.

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:

Peripheral sensory neuropathy was reported in adjuvant patients treated with the oxaliplatin 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).

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 in combination with fluorouracil (FU) and leucovorin compared to 5% with FU plus leucovorin alone. Sepsis, neutropenic sepsis and septic shock have been reported in patients treated with oxaliplatin, including fatal outcomes [see Adverse Reactions (6.1)].

Delay Oxaliplatin Injection until neutrophils are ≥ 1.5 x 109/L. Withhold Oxaliplatin Injection for sepsis or septic shock. Reduce the dose of Oxaliplatin Injection after recovery from Grade 4 neutropenia or febrile neutropenia [see Dosage and Administration (2.2)].

5.4 Pulmonary Toxicity

Oxaliplatin 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 plus infusional fluorouracil/leucovorin arm compared to 4.5% (any grade) and no Grade 3 and 0.1% Grade 4 events in the infusional fluorouracil/leucovorin alone arm in adjuvant colon cancer patients. In this study, one patient died from eosinophilic pneumonia in the oxaliplatin combination arm. The combined incidence of cough, dyspnea and hypoxia was 43% (any grade) and 7% (Grade 3 and 4) in the oxaliplatin plus fluorouracil/leucovorin arm compared to 32% (any grade) and 5% (Grade 3 and 4) in the irinotecan plus 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 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 combination arm than in the control arm. The incidence of increased bilirubin was similar in both arms. Changes noted on liver biopsies included: 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 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 and monitor these electrolytes periodically during therapy. Avoid Oxaliplatin Injection 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. Discontinue Oxaliplatin Injection if any signs or symptoms of rhabdomyolysis occur [see Adverse Reactions (6.2)].

5.8 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, Oxaliplatin Injection can cause fetal harm when administered to a pregnant woman. The available human data do not establish the presence or absence of major birth defects or miscarriage related to the use of oxaliplatin. Reproductive toxicity studies demonstrated adverse effects on embryo-fetal development in rats at maternal doses that were below the recommended human dose based on body surface area.  Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during treatment with Oxaliplatin Injection and for at least 9 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Oxaliplatin Injection and for 6 months after the final dose [see Use in Specific Populations (8.1, 8.3)].

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 cycle [see Dosage and Administration (2)].

There have been reports while on study and from postmarketing surveillance of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received oxaliplatin plus fluorouracil/leucovorin while on anticoagulants. Patients receiving Oxaliplatin Injection plus fluorouracil/leucovorin and requiring oral anticoagulants may require closer monitoring.

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. 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 and Infusional 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 in combination with infusional fluorouracil/leucovorin [see Clinical Studies (14)]. The incidence of Grade 3 or 4 adverse reactions was 70% on the oxaliplatin combination arm, and 31% on the infusional 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 and infusional fluorouracil/leucovorin. Both fluorouracil/leucovorin and oxaliplatin are associated with gastrointestinal or hematologic adverse reactions. When oxaliplatin is administered in combination with infusional 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 combination and infusional fluorouracil/leucovorin arms, respectively. Deaths within 60 days from initiation of therapy were 0.3% (n=3) in both the oxaliplatin combination and infusional fluorouracil/leucovorin arms, respectively. On the oxaliplatin combination arm, 3 deaths were due to sepsis/neutropenic sepsis, 2 from intracerebral bleeding and one from eosinophilic pneumonia. On the fluorouracil/leucovorin arm, one death was due to suicide, 2 from Stevens-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 and infusional fluorouracil/leucovorin arm for events with overall incidences ≥ 5% and for NCI Grade 3/4 events with incidences ≥ 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 and infusional fluorouracil/leucovorin arm for events with overall incidences ≥ 5% but with incidences < 1% NCI Grade 3/4 events.

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 and infusional 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 combination arm and 68 in the infusional fluorouracil/leucovorin arm. An exploratory analysis showed that the number of deaths due to secondary malignancies was 1.96% in the oxaliplatin combination arm and 0.98% in infusional fluorouracil/leucovorin arm. In addition, the number of cardiovascular deaths was 1.4% in the oxaliplatin combination arm as compared to 0.7% in the infusional 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 and 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 fluorouracil and oxaliplatin are associated with gastrointestinal and hematologic adverse reactions. When oxaliplatin is administered in combination with 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 and fluorouracil/leucovorin combination, 5% with irinotecan plus fluorouracil/leucovorin, and 3% with oxaliplatin plus irinotecan. Deaths within 60 days from initiation of therapy were 2.3% with the oxaliplatin and fluorouracil/leucovorin combination, 5.1% with irinotecan plus fluorouracil/leucovorin, and 3.1% with oxaliplatin 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 and fluorouracil/leucovorin combination arm for events with overall incidences ≥ 5% and for Grade 3/4 events with incidences ≥ 1%.

* 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 and fluorouracil/leucovorin combination arm for events with overall incidences ≥ 5% but with incidences < 1% NCI Grade 3/4 events.

* 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 and 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 and 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 and fluorouracil/leucovorin combination arm and 18% in the 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 fluorouracil and oxaliplatin are associated with gastrointestinal and hematologic adverse reactions. When oxaliplatin is administered in combination with 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 and fluorouracil/leucovorin combination, 8% with oxaliplatin alone, and 7% with fluorouracil/leucovorin. Of the 7 deaths that occurred on the oxaliplatin and 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 and 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.

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 and fluorouracil/leucovorin combination arm for events with overall incidences ≥ 5% but with incidences < 1% NCI Grade 3/4 events.

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 and 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.

Thrombocytopenia and Bleeding

Thrombocytopenia was frequently reported with the combination of oxaliplatin and infusional fluorouracil/leucovorin. The incidence of all hemorrhagic events in the adjuvant and previously treated patients was higher on the oxaliplatin combination arm compared to the infusional 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 and fluorouracil/leucovorin over the irinotecan plus fluorouracil/leucovorin or fluorouracil/leucovorin control groups. Grade 3/4 gastrointestinal bleeding was reported in 0.2% of adjuvant patients receiving oxaliplatin and fluorouracil/leucovorin. In the previously untreated patients, the incidence of epistaxis was 10% in the oxaliplatin and fluorouracil/leucovorin arm, and 2% and 1%, respectively, in the irinotecan plus fluorouracil/leucovorin or irinotecan plus oxaliplatin arms.

Neutropenia

Neutropenia was frequently observed with the combination of oxaliplatin and 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 and 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 fluorouracil/leucovorin arm and 4% (less than 1% of cycles) in the oxaliplatin and fluorouracil/leucovorin combination arm. Additionally, in this same population, infection with Grade 3 or 4 neutropenia was 12% in the irinotecan plus fluorouracil/leucovorin, and 8% in the oxaliplatin and fluorouracil/leucovorin combination. The incidence of febrile neutropenia in the previously treated patients was 1% in the fluorouracil/leucovorin arm and 6% (less than 1% of cycles) in the oxaliplatin and fluorouracil/leucovorin combination arm.

Gastrointestinal

In patients receiving the combination of oxaliplatin plus infusional fluorouracil/leucovorin for adjuvant treatment for colon cancer the incidence of Grade 3/4 nausea and vomiting was greater than those receiving infusional fluorouracil/leucovorin alone (see table). In patients previously untreated for advanced colorectal cancer receiving the combination of oxaliplatin and fluorouracil/leucovorin, the incidence of Grade 3 and 4 vomiting and diarrhea was less compared to irinotecan plus fluorouracil/leucovorin controls (see table). In previously treated patients receiving the combination of oxaliplatin and fluorouracil/leucovorin, the incidence of Grade 3 and 4 nausea, vomiting, diarrhea, and mucositis/stomatitis increased compared to 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 to 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.

Dermatologic

Oxaliplatin did not increase the incidence of alopecia compared to fluorouracil/leucovorin alone. No complete alopecia was reported. The incidence of Grade 3/4 skin disorders was 2% in both the oxaliplatin plus infusional fluorouracil/leucovorin and the infusional 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 fluorouracil/leucovorin arm and 7% in the oxaliplatin and fluorouracil/leucovorin combination arm. The incidence of hand-foot syndrome in previously treated patients was 13% in the fluorouracil/leucovorin arm and 11% in the oxaliplatin and 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 plus fluorouracil/leucovorin while on anticoagulants. Patients receiving Oxaliplatin Injection plus 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 and 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 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.

Thromboembolism

The incidence of thromboembolic events in adjuvant patients with colon cancer was 6% (1.8% Grade 3/4) in the infusional fluorouracil/leucovorin arm and 6% (1.2% grade 3/4) in the oxaliplatin and infusional 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 and fluorouracil/leucovorin combination arm, respectively.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of oxaliplatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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)

8.1 Pregnancy

Risk Summary

Based on direct interaction with DNA, Oxaliplatin Injection can cause fetal harm when administered to a pregnant woman. The available human data do not establish the presence or absence of major birth defects or miscarriage related to the use of oxaliplatin. Reproductive toxicity studies demonstrated adverse effects on embryo-fetal development in rats at maternal doses that were below the recommended human dose based on body surface area (see Data). Advise a pregnant woman of the potential hazard to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Pregnant rats were administered oxaliplatin at less than one-tenth the recommended human dose based on body surface area during gestation days (GD) 1 to 5 (preimplantation), GD 6 to 10, or GD 11 to 16 (during organogenesis). Oxaliplatin caused developmental mortality (increased early resorptions) when administered on GD 6 to 10 and GD 11 to 16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on GD 6 to 10.

8.2 Lactation

Risk Summary

There are no data on the presence of oxaliplatin or its metabolites in human or animal milk or its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with Oxaliplatin Injection and for 3 months after the final dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating Oxaliplatin Injection [see Use in Specific Populations (8.1)].

Contraception

Oxaliplatin Injection can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

Advise females of reproductive potential to use effective contraception while receiving Oxaliplatin Injection and for 9 months after the final dose.

Males

Based on its mechanism action as a genotoxic drug, advise males with female partners of reproductive potential to use effective contraception while receiving Oxaliplatin Injection and for 6 months after the final dose [see Nonclinical Toxicology (13.1)].

Infertility

Based on animal studies, Oxaliplatin Injection may impair fertility in males and females [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The effectiveness of Oxaliplatin Injection 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 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 and infusional fluorouracil/leucovorin were < 65 years and 400 patients were ≥ 65 years.

A descriptive subgroup analysis demonstrated that the improvement in DFS for the oxaliplatin combination arm compared to the infusional fluorouracil/leucovorin alone arm appeared to be maintained across genders. The effect of oxaliplatin in patients ≥ 65 years of age was not conclusive. Insufficient subgroup sizes prevented analysis by race.

Patients ≥ 65 years of age receiving the oxaliplatin 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, 160 patients treated with oxaliplatin and 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, 95 patients treated with oxaliplatin and 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 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 is administered to patients with renal impairment. The starting Oxaliplatin Injection 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 should be reduced in patients with severe renal impairment (creatinine clearance < 30 mL/min) [see Dosage and Administration (2.2)].

12.1 Mechanism of Action

Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed, including monoaquo and diaquo DACH platinum, which covalently bind with macromolecules. Both inter- and intrastrand Pt-DNA crosslinks are formed. Crosslinks are formed between the N7 positions of two adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide (GNG). These crosslinks inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific.

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

12.3 Pharmacokinetics

The reactive oxaliplatin derivatives are present as a fraction of the unbound platinum in plasma ultrafiltrate. The decline of ultrafilterable platinum levels following oxaliplatin administration is triphasic, characterized by two relatively short distribution phases (t1/2α; 0.43 hours and t1/2β; 16.8 hours) and a long terminal elimination phase (t1/2γ; 391 hours). Pharmacokinetic parameters obtained after a single 2-hour intravenous infusion of oxaliplatin at a dose of 85 mg/m2 expressed as ultrafilterable platinum were Cmax of 0.814 mcg/mL and volume of distribution of 440 L.

Interpatient and intrapatient variability in ultrafilterable platinum exposure (AUC0-48hr) assessed over 3 cycles was moderate to low (23% and 6%, respectively). A pharmacodynamic relationship between platinum ultrafiltrate levels and clinical safety and effectiveness has not been established.

Distribution

At the end of a 2-hour infusion of oxaliplatin, approximately 15% of the administered platinum is present in the systemic circulation. The remaining 85% is rapidly distributed into tissues or eliminated in the urine. In patients, plasma protein binding of platinum is irreversible and is greater than 90%. The main binding proteins are albumin and gamma-globulins. Platinum also binds irreversibly and accumulates (approximately 2-fold) in erythrocytes, where it appears to have no relevant activity. No platinum accumulation was observed in plasma ultrafiltrate following 85 mg/m2 every two weeks.

Metabolism

Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation. There is no evidence of cytochrome P450-mediated metabolism in vitro.

Up to 17 platinum-containing derivatives have been observed in plasma ultrafiltrate samples from patients, including several cytotoxic species (monochloro DACH platinum, dichloro DACH platinum, and monoaquo and diaquo DACH platinum) and a number of noncytotoxic, conjugated species.

Elimination

The major route of platinum elimination is renal excretion. At five days after a single 2-hour infusion of oxaliplatin, urinary elimination accounted for about 54% of the platinum eliminated, with fecal excretion accounting for only about 2%. Platinum was cleared from plasma at a rate (10 to 17 L/h) that was similar to or exceeded the average human glomerular filtration rate (GFR; 7.5 L/h). There was no significant effect of gender on the clearance of ultrafilterable platinum. The renal clearance of ultrafilterable platinum is significantly correlated with GFR.

Pharmacokinetics in Special Populations

Renal Impairment

A study was conducted in 38 patients with advanced GI cancer and varying degrees of renal impairment. Patients in the normal (creatinine clearance (CrCL) > 80 mL/min, N=11), mild (CrCL=50 to 80 mL/min, N=13), and moderate (CrCL=30 to 49 mL/min, N=10) groups were treated with 85 mg/m2 oxaliplatin and those in the severe (CrCL < 30 mL/min, N=4) group were treated with 65 mg/m2 oxaliplatin. The mean AUC of unbound platinum was 40%, 95%, and 342% higher in the mild, moderate, and severe groups, respectively, than in the normal group. Mean Cmax of unbound platinum appeared to be similar among the normal, mild and moderate renal function groups, but was 38% higher in the severe group than in the normal group. Caution should be exercised in renally impaired patients [see Use in Specific Populations (8.6)]. The starting dose of Oxaliplatin Injection should be reduced in patients with severe renal impairment [see Dosage and Administration (2.2)].

Drug - Drug Interactions

No pharmacokinetic interaction between 85 mg/m2 of oxaliplatin and infusional fluorouracil has been observed in patients treated every 2 weeks, but increases of fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m2 of oxaliplatin administered every 3 weeks. In vitro, platinum was not displaced from plasma proteins by the following medications: erythromycin, salicylate, sodium valproate, granisetron, and paclitaxel. In vitro, oxaliplatin is not metabolized by, nor does it inhibit, human cytochrome P450 isoenzymes. No P450-mediated drug-drug interactions are therefore anticipated in patients. Since platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by co-administration of potentially nephrotoxic compounds, although this has not been specifically studied.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of oxaliplatin. Oxaliplatin was not mutagenic to bacteria (Ames test) but was mutagenic to mammalian cells in vitro (L5178Y mouse lymphoma assay). Oxaliplatin was clastogenic both in vitro (chromosome aberration in human lymphocytes) and in vivo (mouse bone marrow micronucleus assay).

In a fertility study, male rats were given oxaliplatin at 0, 0.5, 1, or 2 mg/kg/day for five days every 21 days for a total of three cycles prior to mating with females that received two cycles of oxaliplatin on the same schedule. A dose of 2 mg/kg/day (less than one-seventh the recommended human dose on a body surface area basis) did not affect pregnancy rate, but resulted in 97% postimplantation loss (increased early resorptions, decreased live fetuses, decreased live births) and delayed growth (decreased fetal weight).

The evaluation of ovaries and testes from mice that received oxaliplatin in a single intraperitoneal dose of 15 mg/kg (approximately one-half the recommended human dose based on body surface area) showed a decreased number of growing follicles in the ovaries 1 month after dosing and decreased spermatagonia,  spermatocyte numbers, and sperm mobility in testes 1 week after dosing. Testicular damage, characterized by degeneration, hypoplasia, and atrophy, was observed in dogs administered oxaliplatin at 0.75 mg/kg/day (approximately one-sixth of the recommended human dose on a body surface area basis) x 5 days every 28 days for three cycles. A no effect level was not identified.

14.1 Combination Adjuvant Therapy with Oxaliplatin and Infusional Fluorouracil/Leucovorin in Patients with Colon Cancer

An international, multicenter, randomized study compared the efficacy and evaluated the safety of oxaliplatin in combination with an infusional schedule of fluorouracil/leucovorin to infusional fluorouracil/leucovorin alone, in patients with Stage II (Dukes' B2) or III (Dukes' C) colon cancer who had undergone complete resection of the primary tumor. The primary objective of the study was to compare the 3-year disease-free survival (DFS) in patients receiving oxaliplatin and infusional fluorouracil/leucovorin to those receiving fluorouracil/leucovorin alone. Patients were to be treated for a total of 6 months (i.e., 12 cycles). A total of 2246 patients were randomized; 1123 patients per study arm. Patients in the study had to be between 18 and 75 years of age, have histologically proven Stage II (T3 to T4 N0 M0; Dukes' B2) or III (any T N1-2 M0; Dukes' C) colon carcinoma (with the inferior pole of the tumor above the peritoneal reflection, i.e., ≥ 15 cm from the anal margin) and undergone (within 7 weeks prior to randomization) complete resection of the primary tumor without gross or microscopic evidence of residual disease. Patients had to have had no prior chemotherapy, immunotherapy or radiotherapy, and have an ECOG performance status of 0, 1, or 2 (KPS ≥ 60%), absolute neutrophil count (ANC) > 1.5 × 109/L, platelets ≥ 100 × 109/L, serum creatinine ≤ 1.25 × ULN total bilirubin < 2 × ULN, AST/ALT < 2 × ULN and carcinoembyrogenic antigen (CEA) < 10 ng/mL. Patients with preexisting peripheral neuropathy (NCI Grade ≥ 1) were ineligible for this trial.

The following table shows the dosing regimens for the two arms of the study.

The following tables show the baseline characteristics and dosing of the patient population entered into this study. The baseline characteristics were well balanced between arms.

The following table and figures summarize the disease-free survival (DFS) results in the overall randomized population and in patients with Stage II and III disease based on an ITT analysis. The median duration of follow-up was approximately 77 months.

*Disease-free survival at 5 years

**A hazard ratio of less than 1 favors Oxaliplatin + Infusional fluorouracil/leucovorin

In the overall and Stage III colon cancer populations DFS was statistically significantly improved in the oxaliplatin combination arm compared to infusional fluorouracil/leucovorin alone. However, a statistically significant improvement in DFS was not noted in Stage II patients.

Figure 2 shows the DFS Kaplan-Meier curves for the comparison of oxaliplatin and infusional fluorouracil/leucovorin combination and infusional fluorouracil/leucovorin alone for the overall population (ITT analysis).

Figure 3 shows the DFS Kaplan-Meier curves for the comparison of oxaliplatin and infusional fluorouracil/leucovorin combination and infusional fluorouracil/leucovorin alone in Stage III patients.

Figure 2:  DFS Kaplan-Meier Curves by Treatment Arm (cutoff: 1 June 2006) – ITT Population

Figure 3: DFS Kaplan-Meier Curves by Treatment Arm in Stage III Patients (cutoff: 1 June 2006) - ITT Population

The following table summarizes the overall survival (OS) results in the overall randomized population and in patients with stage II and III disease, based on the ITT analysis.

*A hazard ratio of less than 1 favors oxaliplatin + infusional fluorouracil/leucovorin

14.2 Combination Therapy with Oxaliplatin and Fluorouracil/Leucovorin in Patients Previously Untreated for Advanced Colorectal Cancer

A North American, multicenter, open-label, randomized controlled study was sponsored by the National Cancer Institute (NCI) as an intergroup study led by the North Central Cancer Treatment Group (NCCTG). The study had 7 arms at different times during its conduct, four of which were closed due to either changes in the standard of care, toxicity, or simplification. During the study, the control arm was changed to irinotecan plus fluorouracil/leucovorin. The results reported below compared the efficacy and safety of two experimental regimens, oxaliplatin in combination with infusional fluorouracil/leucovorin and a combination of oxaliplatin plus irinotecan, to an approved control regimen of irinotecan plus fluorouracil/leucovorin in 795 concurrently randomized patients previously untreated for locally advanced or metastatic colorectal cancer. After completion of enrollment, the dose of irinotecan plus fluorouracil/leucovorin was decreased due to toxicity. Patients had to be at least 18 years of age, have known locally advanced, locally recurrent, or metastatic colorectal adenocarcinoma not curable by surgery or amenable to radiation therapy with curative intent, histologically proven colorectal adenocarcinoma, measurable or evaluable disease, with an ECOG performance status 0, 1, or 2. Patients had to have granulocyte count ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L, hemoglobin ≥ 9 gm/dL, creatinine ≤ 1.5 × ULN, total bilirubin ≤ 1.5 mg/dL, AST ≤ 5 × ULN, and alkaline phosphatase ≤ 5 × ULN. Patients may have received adjuvant therapy for resected Stage II or III disease without recurrence within 12 months. The patients were stratified for ECOG performance status (0, 1 vs. 2), prior adjuvant chemotherapy (yes vs. no), prior immunotherapy (yes vs. no), and age (< 65 vs. ≥ 65 years). Although no post study treatment was specified in the protocol, 65% to 72% of patients received additional post study chemotherapy after study treatment discontinuation on all arms. Fifty-eight percent of patients on the oxaliplatin plus fluorouracil/leucovorin arm received an irinotecan-containing regimen and 23% of patients on the irinotecan plus fluorouracil/leucovorin arm received oxaliplatin-containing regimens. Oxaliplatin was not commercially available during the trial.

The following table presents the dosing regimens of the three arms of the study.

The following table presents the demographics of the patient population entered into this study.

The length of a treatment cycle was 2 weeks for the oxaliplatin and fluorouracil/leucovorin regimen; 6 weeks for the irinotecan plus fluorouracil/leucovorin regimen; and 3 weeks for the oxaliplatin plus irinotecan regimen. The median number of cycles administered per patient was 10 (23.9 weeks) for the oxaliplatin and fluorouracil/leucovorin regimen, 4 (23.6 weeks) for the irinotecan plus fluorouracil/leucovorin regimen, and 7 (21 weeks) for the oxaliplatin plus irinotecan regimen. Patients treated with the oxaliplatin and fluorouracil/leucovorin combination had a significantly longer time to tumor progression based on investigator assessment, longer overall survival, and a significantly higher confirmed response rate based on investigator assessment compared to patients given irinotecan plus fluorouracil/leucovorin. The following table summarizes the efficacy results.

*Compared to irinotecan plus fluorouracil/leucovorin (IFL) arm

**Based on all patients with measurable disease at baseline

The numbers in the response rate and TTP analysis are based on unblinded investigator assessment.

***A hazard ratio of less than 1 favors Oxaliplatin + Infusional fluorouracil/leucovorin

Figure 4 illustrates the Kaplan-Meier survival curves for the comparison of oxaliplatin and fluorouracil/leucovorin combination and oxaliplatin plus irinotecan to irinotecan plus fluorouracil/leucovorin.

* Log rank test comparing oxaliplatin plus FU/LV to irinotecan plus FU/LV.

Figure 4:  Kaplan-Meier Overall Survival by Treatment Arm

A descriptive subgroup analysis demonstrated that the improvement in survival for oxaliplatin plus fluorouracil/leucovorin compared to irinotecan plus fluorouracil/leucovorin appeared to be maintained across age groups, prior adjuvant therapy, and number of organs involved. An estimated survival advantage in oxaliplatin plus fluorouracil/leucovorin versus irinotecan plus fluorouracil/leucovorin was seen in both genders; however it was greater among women than men. Insufficient subgroup sizes prevented analysis by race.

14.3 Combination Therapy with Oxaliplatin and Fluorouracil/Leucovorin in Previously Treated Patients with Advanced Colorectal Cancer

A multicenter, open-label, randomized, three-arm controlled study was conducted in the US and Canada comparing the efficacy and safety of oxaliplatin in combination with an infusional schedule of fluorouracil/leucovorin to the same dose and schedule of fluorouracil/leucovorin alone and to single agent oxaliplatin in patients with advanced colorectal cancer who had relapsed/progressed during or within 6 months of first-line therapy with bolus fluorouracil/leucovorin and irinotecan. The study was intended to be analyzed for response rate after 450 patients were enrolled. Survival will be subsequently assessed in all patients enrolled in the completed study. Accrual to this study is complete, with 821 patients enrolled. Patients in the study had to be at least 18 years of age, have unresectable, measurable, histologically proven colorectal adenocarcinoma, with a Karnofsky performance status > 50%. Patients had to have SGOT(AST) and SGPT(ALT) ≤ 2× the institution's upper limit of normal (ULN), unless liver metastases were present and documented at baseline by CT or MRI scan, in which case ≤ 5× ULN was permitted. Patients had to have alkaline phosphatase ≤ 2× the institution's ULN, unless liver metastases were present and documented at baseline by CT or MRI scan, in which cases ≤ 5× ULN was permitted. Prior radiotherapy was permitted if it had been completed at least 3 weeks before randomization.

The dosing regimens of the three arms of the study are presented in the table below.

Patients entered into the study for evaluation of response must have had at least one unidimensional lesion measuring ≥ 20mm using conventional CT or MRI scans, or ≥ 10mm using a spiral CT scan. Tumor response and progression were assessed every 3 cycles (6 weeks) using the Response Evaluation Criteria in Solid Tumors (RECIST) until radiological documentation of progression or for 13 months following the first dose of study drug(s), whichever came first. Confirmed responses were based on two tumor assessments separated by at least 4 weeks.

The demographics of the patient population entered into this study are shown in the table below.

The median number of cycles administered per patient was 6 for the oxaliplatin and fluorouracil/leucovorin combination and 3 each for fluorouracil/leucovorin alone and oxaliplatin alone.

Patients treated with the combination of oxaliplatin and fluorouracil/leucovorin had an increased response rate compared to patients given fluorouracil/leucovorin or oxaliplatin alone. The efficacy results are summarized in the tables below.

*This is not an ITT analysis. Events were limited to radiographic disease progression documented by independent review of radiographs. Clinical progression was not included in this analysis, and 18% of patients were excluded from the analysis based on unavailability of the radiographs for independent review.

At the time of the interim analysis 49% of the radiographic progression events had occurred. In this interim analysis an estimated 2-month increase in median time to radiographic progression was observed compared to fluorouracil/leucovorin alone.

Of the 13 patients who had tumor response to the combination of oxaliplatin and fluorouracil/leucovorin, 5 were female and 8 were male, and responders included patients < 65 years old and ≥ 65 years old. The small number of non-Caucasian participants made efficacy analyses in these populations uninterpretable.