2.1 Dosage

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

Day 1: Oxaliplatin Injection 85 mg/m2 intravenous infusion in 250–500 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 5-fluorouracil 400 mg/m2 intravenous bolus given over 2–4 minutes, followed by 5-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 5-fluorouracil 400 mg/m2 intravenous bolus given over 2–4 minutes, followed by 5-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 5-fluorouracil and leucovorin, see the respective package inserts.

2.2 Dose Modification Recommendations

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

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

5.1 Allergic Reactions

See boxed warning

Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to Oxaliplatin Injection has been observed in 2–3% 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

5.3 Severe Neutropenia

Grade 3 or 4 neutropenia occurred in 41–44% of patients with colorectal cancer treated with Oxaliplatin Injection 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 , including fatal outcomes [see Adverse Reactions (6.1)].

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

5.4 Pulmonary Toxicity

Oxaliplatin Injection 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 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 combination arm. The combined incidence of cough, dyspnea and hypoxia was 43% (any grade) and 7% (grade 3 and 4) in the Oxaliplatin Injection 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 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 combination arm than in the control arm. The incidence of increased bilirubin was similar on both arms. Changes noted on liver biopsies include: peliosis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive lesions. Hepatic vascular disorders should be considered, and if appropriate, should be investigated in case of abnormal liver function test results or portal hypertension, which cannot be explained by liver metastases [see Clinical Trials Experience (6.1)].

5.6 Cardiovascular Toxicity

QT prolongation and ventricular arrhythmias including fatal Torsade de Pointes have been reported in postmarketing experiences following Oxaliplatin Injection 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 Injection. Discontinue Oxaliplatin Injection if any signs or symptoms of rhabdomyolysis occur. [see Adverse Reactions (6.2)].

5.8 Use in Pregnancy

Pregnancy Category D

Oxaliplatin Injection may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Oxaliplatin Injection in pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Oxaliplatin Injection. [see Use in Specific Populations (8.1)].

5.9 Recommended Laboratory Tests

Standard monitoring of the white blood cell count with differential, hemoglobin, platelet count, and blood chemistries (including ALT, AST, bilirubin and creatinine) is recommended before each Oxaliplatin Injection cycle [see Dosage and Administration (2)].

There have been reports while on study and from post-marketing surveillance of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received Oxaliplatin Injection plus 5-fluorouracil/leucovorin while on anticoagulants. Patients receiving Oxaliplatin Injection 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. 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)].

6.2 Postmarketing Experience

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

Body as a whole:
angioedema, anaphylactic shock

Cardiovascular disorders:
QT prolongation leading to ventricular arrhythmias including fatal Torsade de Pointes

Central and peripheral nervous system disorders:
loss of deep tendon reflexes, dysarthria, Lhermitte's sign, cranial nerve palsies, fasciculations, convulsion, Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES).

Hearing and vestibular system disorders:
deafness

Infections:
septic shock, including fatal outcomes

Infusion reactions/hypersensitivity:
laryngospasm

Liver and Gastrointestinal system disorders:
severe diarrhea/vomiting resulting in hypokalemia, colitis (including Clostridium difficile diarrhea), metabolic acidosis; ileus; intestinal obstruction, pancreatitis; veno-occlusive disease of liver also known as sinusoidal obstruction syndrome, and perisinusoidal fibrosis which rarely may progress.

Musculoskeletal and connective tissue disorders
rhabdomyolysis, including fatal outcomes.

Platelet, bleeding, and clotting disorders:
immuno-allergic thrombocytopenia
prolongation of prothrombin time and of INR in patients receiving anticoagulants

Red Blood Cell disorders:
hemolytic uremic syndrome, immuno-allergic hemolytic anemia

Renal disorders:
Acute tubular necrosis, acute interstitial nephritis and acute renal failure.

Respiratory system disorders:
pulmonary fibrosis, and other interstitial lung diseases (sometimes fatal)

Vision disorders:
decrease of visual acuity, visual field disturbance, optic neuritis and transient vision loss (reversible following therapy discontinuation)

8.1 Pregnancy

8.3 Nursing Mothers

It is not known whether Oxaliplatin Injection 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, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The effectiveness of oxaliplatin in children has not been established. Oxaliplatin has been tested in 2 Phase 1 and 2 Phase 2 trials in 235 patients ages 7 months to 22 years with solid tumors (see below) and no significant activity observed.

In a Phase 1/2 study, oxaliplatin was administered as a 2-hour intravenous infusion on Days 1, 8 and 15 every 4 weeks (1 cycle), for a maximum of 6 cycles, to 43 patients with refractory or relapsed malignant solid tumors, mainly neuroblastoma and osteosarcoma. Twenty eight pediatric patients in the Phase 1 study received oxaliplatin at 6 dose levels starting at 40 mg/m2 with escalation to 110 mg/m2. The dose limiting toxicity (DLT) was sensory neuropathy at the 110 mg/m2 dose. Fifteen patients received oxaliplatin at a dose of 90 mg/m2 intravenous in the Phase 2 portion of the study. At this dose, paresthesia (60%, G3/4: 7%), fever (40%, G3/4: 7%) and thrombocytopenia (40%, G3/4: 27%) were the main adverse reactions. No responses were observed.

In a second Phase 1 study, oxaliplatin was administered to 26 pediatric patients as a 2-hour intravenous infusion on day 1 every 3 weeks (1 cycle) at 5 dose levels starting at 100 mg/m2 with escalation to 160 mg/m2, for a maximum of 6 cycles. In a separate cohort, oxaliplatin 85 mg/m2 was administered on day 1 every 2 weeks, for a maximum of 9 doses. Patients had metastatic or unresectable solid tumors mainly neuroblastoma and ganglioneuroblastoma. No responses were observed. The DLT was sensory neuropathy at the 160 mg/m2 dose. Based on these studies, oxaliplatin 130 mg/m2 as a 2-hour intravenous infusion on day 1 every 3 weeks (1 cycle) was used in subsequent Phase II studies. A dose of 85 mg/m2 on day 1 every 2 weeks was also found to be tolerable.

In one Phase 2 study, 43 pediatric patients with recurrent or refractory embryonal CNS tumors received oxaliplatin 130 mg/m2 every 3 weeks for a maximum of 12 months in absence of progressive disease or unacceptable toxicity. In patients < 10 kg the oxaliplatin dose used was 4.3 mg/kg. The most common adverse reactions reported were leukopenia (67%, G3/4: 12%), anemia (65%, G3/4: 5%), thrombocytopenia (65%, G3/4: 26%), vomiting (65%, G3/4: 7%), neutropenia (58%, G3/4: 16%) and sensory neuropathy (40%, G3/4: 5%). One partial response was observed.

In a second Phase 2 study, 123 pediatric patients with recurrent solid tumors, including neuroblastoma, osteosarcoma, Ewing sarcoma or peripheral PNET, ependymoma, rhabdomyosarcoma, hepatoblastoma, high grade astrocytoma, Brain stem glioma, low grade astrocytoma, malignant germ cell tumor and other tumors of interest received oxaliplatin 130 mg/m2 every 3 weeks for a maximum of 12 months or 17 cycles. In patients ≤ 12 months old the oxaliplatin dose used was 4.3 mg/kg. The most common adverse reactions reported were sensory neuropathy (52%, G3/4: 12%), thrombocytopenia (37%, G3/4: 17%), anemia (37%, G3/4: 9%), vomiting (26%, G3/4:4%), ALT increased (24%, G3/4: 6%), AST increased (24%, G3/4: 2%), and nausea (23%, G3/:4 3%). Two partial responses were observed.

The pharmacokinetic parameters of ultrafiltrable platinum have been evaluated in 105 pediatric patients during the first cycle. The mean clearance in pediatric patients estimated by the population pharmacokinetic analysis was 4.7 L/h. The inter-patient variability of platinum clearance in pediatric cancer patients was 41%. Mean platinum pharmacokinetic parameters in ultrafiltrate were Cmax of 0.75 ± 0.24 mcg/mL, AUC0–48 of 7.52 ± 5.07 mcg∙h/mL and AUCinf of 8.83 ± 1.57 mcg∙h/mL at 85 mg/m2 of oxaliplatin and Cmax of 1.10 ± 0.43 mcg/mL, AUC0–48 of 9.74 ± 2.52 mcg∙h/mL and AUCinf of 17.3 ± 5.34 mcg∙h/mL at 130 mg/m2 of oxaliplatin.

8.5 Geriatric Use

No significant effect of age on the clearance of ultrafilterable platinum has been observed.

In the adjuvant therapy colon cancer randomized clinical trial, [see Clinical Studies (14)] 723 patients treated with Oxaliplatin Injection 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 combination arm compared to the infusional 5-fluorouracil/leucovorin alone arm appeared to be maintained across genders. The effect of Oxaliplatin Injection 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 combination therapy experienced more grade 3–4 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, 160 patients treated with Oxaliplatin Injection 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, 95 patients treated with Oxaliplatin Injection 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 is administered to patients with renal impairment. The starting Oxaliplatin Injection dose does not need to be reduced in patients with mild (creatinine clearance=50-80 mL/min) or moderate (creatinine clearance=30-49 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)].

There is no known antidote for Oxaliplatin Injection overdose. In addition to thrombocytopenia, the anticipated complications of an Oxaliplatin Injection overdose include hypersensitivity reaction, myelosuppression, nausea, vomiting, diarrhea and neurotoxicity.

Several cases of overdoses have been reported with Oxaliplatin Injection. Adverse reactions observed were Grade 4 thrombocytopenia (<25,000/mm3) without any bleeding, anemia, sensory neuropathy such as paresthesia, dysesthesia, laryngospasm and facial muscle spasms, gastrointestinal disorders such as nausea, vomiting, stomatitis, flatulence, abdomen enlarged and Grade 4 intestinal obstruction, Grade 4 dehydration, dyspnea, wheezing, chest pain, respiratory failure, severe bradycardia and death.

Patients suspected of receiving an overdose should be monitored, and supportive treatment should be administered. The maximum dose of oxaliplatin that has been administered in a single infusion is 825 mg.

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 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 (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 Injection 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.

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 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 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 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 (T3–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) > 1.5x109/L, platelets ≥100×109/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.

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.

In the overall and stage III colon cancer populations DFS was statistically significantly improved in the Oxaliplatin Injection 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 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 and infusional 5-fluorouracil/leucovorin combination and infusional 5-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.

14.2 Combination Therapy with Oxaliplatin Injection 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 in combination with infusional 5-fluorouracil/leucovorin and a combination of Oxaliplatin Injection 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 × 109/L, platelets ≥ 100 × 109/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 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.

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 Injection and 5-fluorouracil/leucovorin regimen; 6 weeks for the irinotecan plus 5-fluorouracil/leucovorin regimen; and 3 weeks for the Oxaliplatin Injection plus irinotecan regimen. The median number of cycles administered per patient was 10 (23.9 weeks) for the Oxaliplatin Injection 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 plus irinotecan regimen. Patients treated with the Oxaliplatin Injection 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.

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

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 Injection and 5-fluorouracil/leucovorin combination and 3 each for 5-fluorouracil/leucovorin alone and Oxaliplatin Injection alone.

Patients treated with the combination of Oxaliplatin Injection 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.

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 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 USP is supplied in clear, glass, single-use vials with gray elastomeric 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.

NDC 60505-6132-6: 50 mg/10 mL single-use vial with flip-off seal individually packaged in a carton.

NDC 60505-6132-7: 100 mg/20 mL single-use vial with flip-off seal individually packaged in a carton.

16.2 Storage

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Do not freeze and protect from light (keep in original 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 USP. The use of gloves is recommended. If a solution of Oxaliplatin Injection USP contacts the skin, wash the skin immediately and thoroughly with soap and water. If Oxaliplatin Injection USP 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.