2.1 Dosage

Administer Oxaliplatin Injection, USP in combination with 5-fluorouracil/leucovorin every 2 weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles):

Day 1: Oxaliplatin Injection, USP 85 mg/m 2 intravenous infusion in 250 to 500 mL 5% Dextrose injection, USP and leucovorin 200 mg/m 2 intravenous infusion in 5% Dextrose Injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5- fluorouracil 400 mg/m 2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m 2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.

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

2.2 Dose Modification Recommendations

Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory tests . Prolongation of infusion time for Oxaliplatin Injection, USP from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5-fluorouracil and leucovorin do not need to be changed. Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory tests [see Warnings and Precautions (5.9)]. Prolongation of infusion time for Oxaliplatin Injection, USP from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5-fluorouracil and leucovorin do not need to be changed.

Adjuvant Therapy in Patients with Stage III Colon Cancer

Neuropathy and other toxicities were graded using the NCI CTC scale version 1 Neuropathy and other toxicities were graded using the NCI CTC scale version 1 [see Warnings and Precautions (5.2)].

For patients who experience persistent Grade 2 neurosensory events that do not resolve, a doseFor patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose

reduction of Oxaliplatin Injection, USP to 75 mg/m should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The infusional 5-fluorouracil/leucovorin regimen need not be altered. reduction of Oxaliplatin Injection, USP to 75 mg/m 2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The infusional 5-fluorouracil/leucovorin regimen need not be altered.

dose reduction of Oxaliplatin Injection, USP to 75 mg/m and infusional 5-fluorouracil to 300 mg/m bolus and 500 mg/m 22 hour infusion is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment), or grade 4 neutropenia, or febrile neutropenia, or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 × 10 /L and platelets ≥75 × 10 /L. A dose reduction of Oxaliplatin Injection, USP to 75 mg/m 2 and infusional 5-fluorouracil to 300 mg/m 2 bolus and 500 mg/m 2 22 hour infusion is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment), or grade 4 neutropenia, or febrile neutropenia, or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 × 10 9/L and platelets ≥75 × 10 9/L.

Dose Modifications in Therapy in Previously Untreated and Previously Treated Patients with Advanced Colorectal Cancer

Neuropathy was graded using a study-specific neurotoxicity scale . 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.Other toxicities were graded by the NCI CTC, Version 2.0.

For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of Oxaliplatin Injection, USP to 65 mg/m should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The 5- fluorouracil/leucovorin regimen need not be altered. For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of Oxaliplatin Injection, USP to 65 mg/m 2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The 5- fluorouracil/leucovorin regimen need not be altered.

dose reduction of Oxaliplatin Injection, USP to 65 mg/m and 5-fluorouracil by 20% (300 mg/m bolus and 500 mg/m 22-hour infusion) is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment), or grade 4 neutropenia, or febrile neutropenia, or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 × 10 /L and platelets ≥75 × 10 /L. A dose reduction of Oxaliplatin Injection, USP to 65 mg/m 2 and 5-fluorouracil by 20% (300 mg/m 2 bolus and 500 mg/m 2 22-hour infusion) is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment), or grade 4 neutropenia, or febrile neutropenia, or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 × 10 9/L and platelets ≥75 × 10 9/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, USP is 85 mg/m . In patients with severe renal impairment, the initial recommended Oxaliplatin Injection, USP dose should be reduced to 65 mg/m . In patients with normal renal function or mild to moderate renal impairment, the recommended dose of Oxaliplatin Injection, USP is 85 mg/m 2. In patients with severe renal impairment, the initial recommended Oxaliplatin Injection, USP dose should be reduced to 65 mg/m 2 [see Use in Specific Populations (8.6) and Clinical Pharmacology(12.3)].

2.3 Preparation of Infusion Solution

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, USP.

After dilution with 250 to 500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20 to 25°C (68 to 77°F)] or up to 24 hours under refrigeration [2 to 8°C (36 to 46°F)].

After final dilution, protection from light is not required.

Oxaliplatin Injection, USP is incompatible in solution with alkaline medications or media (such as basic solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection, USP prior toadministration 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, USP should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.

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 withplatinum 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

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

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

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 Delay Oxaliplatin Injection, USP until neutrophils are ≥ 1.5 x 10 /L. Withhold Oxaliplatin Injection, USP for sepsis or septic shock. Dose reduce Oxaliplatin Injection, USP after recovery from Grade 4 neutropenia or febrile 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 x 10 9/L. Withhold Oxaliplatin Injection, USP for sepsis or septic shock. Dose reduce Oxaliplatin Injection, USP after recovery from Grade 4 neutropenia or febrile neutropenia [s ee D o s age and A d m i n i s t r a ti on ( 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 [s ee C li n i c al T r i a ls E x p e r i e n ce ( 6. 1 ) ].

5.6 Cardiovascular Toxicity

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 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

, 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 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. [s ee U se in Sp ec ific P opu l a ti ons ( 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 [s ee D o s age and A d m i n i s t r a ti on ( 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.

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 [s ee W a r n i ngs and P r ec au ti ons ( 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 [s ee C li n i c al S t ud i es ( 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 [s ee C li n i c al S t ud i es ( 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%.

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)

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/m 2 with escalation to 110 mg/m 2. The dose limiting toxicity (DLT) was sensory neuropathy at the 110 mg/m 2 dose. Fifteen patients received oxaliplatin at a dose of 90 mg/m 2 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/m 2 with escalation to 160 mg/m 2, for a maximum of 6 cycles. In a separate cohort, oxaliplatin 85 mg/m 2 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/m 2 dose. Based on these studies, oxaliplatin 130 mg/m 2 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/m 2 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/m 2 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/m 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 C max of 0.75 ± 0.24 mcg/mL, AUC 0-48 of 7.52 ± 5.07 mcg·h/mL and AUC inf of 8.83 ± 1.57 mcg·h/mL at 85 mg/m 2 of oxaliplatin and C max of 1.10 ± 0.43 mcg/mL, AUC 0-48 of 9.74 ± 2.52 mcg·h/mL and AUC inf of 17.3 ± 5.34 mcg·h/mL at 130 mg/m 2 of oxaliplatin.

8.5 Geriatric Use

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)].

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-g uanines (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 5-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 (t 1/2α; 0.43 hours and t 1/2β; 16.8 hours) and a long terminal elimination phase (t 1/2γ; 391 hours). Pharmacokinetic parameters obtained after a single 2-hour intravenous infusion of Oxaliplatin Injection, USP at a dose of 85 mg/m 2 expressed as ultrafilterable platinum were C max of 0.814 mcg/mL and volume of distribution of 440 L.



Interpatient and intrapatient variability in ultrafilterable platinum exposure (AUC 0–48hr) 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 Injection, USP, 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/m 2 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 Injection, USP, 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). T here 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

Pediatric

[See Use In Specific Patient Populations (8.4)].

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/m 2 Oxaliplatin Injection, USP and those in the severe (CrCL < 30 mL/min, N=4) group were treated with 65 mg/m 2 Oxaliplatin Injection, USP. 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 C max of unbound platinum appeared to be similar among the normal, mild and moderate renal function groups, but was 38 % higher in the severe group than in the normal group. Caution should be exercised in renally impaired patients [see Use in Specific Populations (8.6)]. The starting dose of Oxaliplatin Injection, USP should be reduced in patients with severe renal impairment [see Dosage and Administration (2.2)]. The starting dose of Oxaliplatin Injection, USP should be reduced in patients with severe renal impairment [see Dosage and Administration (2.2)].

Drug - Drug Interactions

No pharmacokinetic interaction between 85 mg/m 2 of Oxaliplatin Injection, USP and infusional 5-fluorouracil has been observed in patients treated every 2 weeks, but increases of 5-fluorouracil plasma concentrations by approximately 20 % have been observed with doses of 130 mg/m 2 of Oxaliplatin Injection, USP 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 therefo re 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 caused developmental mortality (increased early resorptions, decreased live fetuses, decreased live births) and delayed growth (decreased fetal weight).

Testicular damage, characterized by degeneration, hypoplasia, and atrophy, was observed in dogs administered oxaliplatin at 0.75 mg/kg/day × 5 days every 28 days for three cycles. A no effect level was not identified. This daily dose is approximately one-sixth of the recommended human dose on a body surface area basis.

14.1 Combination Adjuvant Therapy with Oxaliplatin Injection, USP and Infusional 5-fluorouracil/leucovorin in Patients with Colon Cancer

An international, multicenter, randomized study compared the efficacy and evaluated the safety of Oxaliplatin Injection, USP in combination with an infusional schedule of 5-fluorouracil/leucovorin to infusional 5-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 Injection, USP and infusional 5-fluorouracil/leucovorin to those receiving 5-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 (T 3 to T 4 N0 M0 ; Dukes' B2) or III (any T N 1–2 M0 ; Dukes' C) colon carcinoma (with the inferior pole of the tumor above the peritoneal reflection, i.e., ≥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) > 1.5x10 9/L, platelets ≥100×10 9/L, serum creatinine ≤ 1.25 × ULN total bilirubin < 2 × ULN, AST/ALT < 2 × ULN and carcino-embyrogenic 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.

Table 15 - Dosing Regimens in Adjuvant Therapy 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.

Table 16 - Patient Characteristics in Adjuvant Therapy Study

Table 17 - Dosing in Adjuvant Therapy Study

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.

Table 18 - Summary of DFS analysis – ITT analysis

Data cut off for disease free survival 1 June 2006

* Disease-free survival at 5 years

**A hazard ratio of less than 1.00 favors Oxaliplatin Injection, USP + Infusional 5-fluorouracil/leucovorin

In the overall and stage III colon cancer populations DFS was statistically significantly improved in the Oxaliplatin Injection, USP combination arm compared to infusional 5-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 Injection, USP and infusional 5-fluorouracil/leucovorin combination and infusional 5-fluorouracil/leucovorin alone for the overall population (ITT analysis).Figure 3 shows the DFS Kaplan-Meier curves for the comparison of Oxaliplatin Injection, USP and infusional 5-fluorouracil/leucovorin combination and infusional 5-fluorouracil/leucovorin alone in Stage III patients.

F ig u re 2 - D FS Ka p la n- M e i er c u r v es by t r ea t m e nt a rm ( c u to ff: 1 J une 2006) - I TT po pu la t ion

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.

Table 19 - Summary of OS analysis - ITT analysis

*A hazard ratio of less than 1.00 favors Oxaliplatin Injection, USP + infusional 5-fluorouracil/leucovorin

Data cut off for overall survival 16 January 2007

14.2 Combination Therapy with Oxaliplatin Injection, USP and 5-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 5-fluorouracil/leucovorin. The results reported below compared the efficacy and safety of two experimental regimens, Oxaliplatin Injection, USP in combination with infusional 5-fluorouracil/leucovorin and a combination of Oxaliplatin Injection, USP plus irinotecan, to an approved control regimen of irinotecan plus 5-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 5-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 × 10 9/L, platelets ≥ 100 × 10 9/L, hemoglobin ≥9.0 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 Injection, USP plus 5-fluorouracil/leucovorin arm received an irinotecan-containing regimen and 23% of patients on the irinotecan plus 5-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.

Table 20 – Dosing Regimens in Patients Previously Untreated for

Advanced Colorectal Cancer Clinical Trial

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

Table 21 – Patient Demographics in Patients Previously Untreated for

Advanced Colorectal Cancer Clinical Trial

The length of a treatment cycle was 2 weeks for the Oxaliplatin Injection, USP and 5-fluorouracil/leucovorin regimen; 6 weeks for the irinotecan plus 5-fluorouracil/leucovorin regimen; and 3 weeks for the Oxaliplatin Injection, USP plus irinotecan regimen. The median number of cycles administered per patient was 10 (23.9 weeks) for the Oxaliplatin Injection, USP and 5 fluorouracil/leucovorin regimen, 4 (23.6 weeks) for the irinotecan plus 5-fluorouracil/leucovorin regimen, and 7 (21.0 weeks) for the Oxaliplatin Injection, USP plus irinotecan regimen. Patients treated with the Oxaliplatin Injection, USP and 5-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 5-fluorouracil/leucovorin. The following table summarizes the efficacy results.

Table 22 – Summary of Efficacy

*Compared to irinotecan plus 5-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 1.00 favors Oxaliplatin Injection, USP + Infusional 5- fluorouracil/leucovorin

Figure 4 illustrates the Kaplan-Meier survival curves for the comparison of Oxaliplatin Injection, USP and 5-fluorouracil/leucovorin combination and Oxaliplatin Injection, USP plus irinotecan to irinotecan plus 5-fluorouracil/leucovorin.

Figure 4 – Kaplan-Meier Overall Survival by treatment arm

A descriptive subgroup analysis demonstrated that the improvement in survival for Oxaliplatin Injection, USP plus 5-fluorouracil/leucovorin compared to irinotecan plus 5-fluorouracil/leucovorin appeared to be maintained across age groups, prior adjuvant therapy, and number of organs involved. An estimated survival advantage in Oxaliplatin Injection, USP plus 5-fluorouracil/leucovorin versus irinotecan plus 5-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 Injection, USP and 5-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 Injection, USP in combination with an infusional schedule of 5-fluorouracil/leucovorin to the same dose and schedule of 5-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 5-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.

Table 23 – Dosing Regimens in Refractory and Relapsed Colorectal

Cancer Clinical Trial

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.

Table 24 – Patient Demographics in Refractory and Relapsed Colorectal

Cancer Clinical Trial

The median number of cycles administered per patient was 6 for the Oxaliplatin Injection, USP and 5-fluorouracil/leucovorin combination and 3 each for 5-fluorouracil/leucovorin alone and Oxaliplatin Injection, USP alone.

Patients treated with the combination of Oxaliplatin Injection, USP and 5-fluorouracil/leucovorin had an increased response rate compared to patients given 5-fluorouracil/leucovorin or oxaliplatin alone. The efficacy results are summarized in the tables below.

Table 25 - Response Rates (ITT Analysis)

Table 26 - Summary of Radiographic Time to Progression *

*This is not an ITT analysis. Events were limited to radiographic disease progression documented by independent review of radiographs. Clinical progression was notincluded 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 5-fluorouracil/leucovorin alone.







Of the 13 patients who had tumor response to the combination of Oxaliplatin Injection, USP and 5- 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.

16.1 How Supplied

Oxaliplatin Injection is supplied in clear, glass, single-dose, moulded vials with dark grey colored bromobutyl omni flex plus coated rubber stoppers and aluminum flip-off seals containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL. Water for Injection, USP is present as an inactive ingredient.

,

16.2 Storage

Store at 20° to 25°C (68° to 77°F);excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature]. Do not freeze. Protect from light (keep in outer carton).

16.3 Handling and Disposal

As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions prepared from Oxaliplatin Injection. The use of gloves is recommended. If a solution of Oxaliplatin Injection contacts the skin, wash the skin immediately and thoroughly with soap and water. If Oxaliplatin Injection contacts the mucous membranes, flush thoroughly with water.







Procedures for the handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.