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Dosage and Administration

Recommended Dose Schedule for Eloxatin in Combination With Infusional
5-FU/LV (FOLFOX4)* Regimen

The recommended dose schedule given every 2 weeks is as follows:

Day 1:	Eloxatin 85-mg/m² IV infusion in 250-500 mL D5W and leucovorin 200-mg/m² IV infusion in D5W, both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-FU 400-mg/m² IV bolus given over 2-4 minutes, followed by 5-FU 600-mg/m² IV infusion in 500 mL D5W (recommended) as a 22-hour continuous infusion.
Day 2:	Leucovorin 200-mg/m² IV infusion over 120 minutes, followed by 5-FU 400-mg/m² IV bolus given over 2-4 minutes, followed by 5-FU 600-mg/m² IV infusion in 500 mL D5W (recommended) as a 22-hour continuous infusion.
	Eloxatin is not administered on day 2.

Adjuvant treatment in patients with stage III colon cancer is recommended for a total of 6 months (ie, 12 cycles, every 2 weeks) according to the same regimen used for patients with advanced colorectal cancer.

Repeat cycle every 2 weeks.

No prehydration required
Premedication with antiemetics, including 5-HT₃ blockers with or without dexamethasone, is recommended

*FOLFOX = Folinic Acid, 5-Fluorouracil, Oxaliplatin.

Dose Modification Recommendations

Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and laboratory tests

Toxicity^*	Dose Modification Recommendations
Acute, reversible, primarily peripheral sensory neuropathy	Prolong Eloxatin infusion from 2 to 6 h^†
	Adjuvant stage III colon cancer	Advanced CRC
Persistent grade 2 neurosensory events that do not resolve	Reduce Eloxatin dose to 75 mg/m^2†	Reduce Eloxatin dose to 65 mg/m^2†
Persistent grade 3 neurosensory events	Consider discontinuing therapy
After recovery from grade 3/4 gastrointestinal toxicity (despite prophylactic treatment) Grade 4 neutropenia Grade 3/4 thrombocytopenia	Reduce Eloxatin dose to 75 mg/m² and reduce 5-FU by 20% (300-mg/m² bolus and 500-mg/m² 22-h infusion)^‡	Reduce Eloxatin dose to 65 mg/m² and reduce 5-FU by 20% (300-mg/m² bolus and 500-mg/m² 22-h infusion)^‡

^*For patients receiving adjuvant therapy for stage III colon cancer, neuropathy and other toxicities were graded using the NCI CTC scale, version 1; for patients receiving therapy for advanced CRC, neuropathy was graded using a study-specific neurotoxicity scale, and other toxicities were graded by the NCI CTC, version 2.0.
^†The 5-FU/LV doses need not be altered.
^‡The next dose should be delayed until neutrophils >1.5 x 10⁹/L, and platelets >75 x 10⁹/L.

National Comprehensive Cancer Network (NCCN) Recommends mFOLFOX6 for Patients with MCRC ¹

Eloxatin Day 1 with 5-FU/LV bolus and a 46-hour 5-FU infusion given on Day 1 (mFOLFOX6)

Day 1:

Eloxatin 85-mg/m² IV infusion in 250-500 mL D5W and leucovorin
400-mg/m² IV infusion in D5W, both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-FU 400-mg/m² IV bolus given over 2-4 minutes, followed by 5-FU 1200-mg/m²/day x 2 days (total 2,400 mg/m² over 46 hours) IV infusion in 500 mL D5W (recommended) as a 46-hour continuous infusion.

mFOLFOX6 is a convenient option that reduces the patient and nurse time in the office by eliminating the Day 2 visit
Pharmacokinetic analysis shows that fluoruracil exposure is similar for patients with MCRC receiving mFOLFOX6 compared with a standard de Gramont regimen
Based on these results, mFOLFOX6 was the Eloxatin-containing regimen chosen for the phase III FOCUS trial involving 2,135 patients with MCRC

Prescribing Considerations

The safety and effectiveness of the combination of Eloxatin and 5-FU/LV in patients with renal impairment have not been evaluated
The combination of Eloxatin and 5-FU/LV should be used with caution in patients with preexisting renal impairment since the primary route of platinum elimination is renal
Clearance of ultrafilterable platinum is decreased in patients with mild, moderate, and severe renal impairment
A pharmacodynamic relationship between platinum ultrafiltrate levels and clinical safety and effectiveness has not been established
The administration of Eloxatin does not require prehydration
Premedication with antiemetics, including 5-HT₃ blockers with or without dexamethasone, is recommended
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 Eloxatin cycle
For information on 5-fluorouracil and leucovorin, see the respective package inserts

References:

Eloxatin® (oxaliplatin injection) prescribing information, sanofi-aventis.

Eloxatin.com Registration | Colorectal Cancer Symptoms | Colorectal Cancer Treatment | Colorectal Cancer Side Effects

ELOXATIN, used in combination with infusional 5-FU/LV, is indicated for

Adjuvant treatment of stage III colon cancer patients who have undergone complete resection of the primary tumor. The indication is based on an improvement in disease-free survival, with no demonstrated benefit in overall survival after a median follow-up of 4 years
Treatment of advanced carcinoma of the colon or rectum

Clinical Safety Considerations

ELOXATIN should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.

Anaphylactic-like reactions to ELOXATIN have been reported and may occur within minutes of ELOXATIN administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms, and discontinuation of ELOXATIN therapy may be required.

ELOXATIN should not be administered to patients with a history of known allergy to ELOXATIN or other platinum compounds. Hypersensitivity and anaphylactic/anaphylactoid reactions to ELOXATIN have been reported and were similar in nature and severity to those reported with other platinum compounds (ie, rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension). These reactions occur within minutes of administration and should be managed with appropriate supportive therapy. Drug-related deaths from this reaction have been reported
ELOXATIN may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant while receiving ELOXATIN. It is not known whether ELOXATIN or its derivatives are excreted in human milk
ELOXATIN has been associated with pulmonary fibrosis (<1% of study patients), which may be fatal. The combined incidence of cough and dyspnea was 7.4% (<1% grade 3, no grade 4) in the ELOXATIN plus 5-FU/LV arm compared to 4.5% (no grade 3, 0.1% grade 4) in the 5-FU/LV alone arm in the adjuvant colon cancer study. In this study, one patient died from eosinophilic pneumonia in the ELOXATIN combination arm. The combined incidence of cough, dyspnea, and hypoxia was 43% (7% grade 3 and 4) in the ELOXATIN plus 5-FU/LV arm compared to 32% (5% grade 3 and 4) in the irinotecan plus 5-FU/LV arm in patients with previously untreated colorectal cancer. In case of unexplained respiratory symptoms, ELOXATIN should be discontinued until pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis
ELOXATIN is associated with two types of primarily peripheral sensory neuropathy: an acute, reversible type of early onset and a persistent type (>14 days). In patients with advanced colorectal cancer, paresthesias occurred in 77% (all grades) and 18% (grade 3/4) of previously untreated patients. In previously treated patients, acute neuropathy occurred in 56% (all grades) and 2% (grade 3/4) of patients; persistent neuropathy occurred in 48% (all grades) and 6% (grade 3/4) of patients. In patients with stage II and III colon cancer, paresthesia was seen in 92% (all grades) and 13% (grade 3/4) of patients; 21% (all grades) and 0.5% (grade 3/4) of patients had residual paresthesia at 18-month follow-up
Hepatotoxicity, as evidenced in the adjuvant study by increase in transaminases and alkaline phosphatase, was observed more commonly in the ELOXATIN combination 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, investigated in case of abnormal liver function test results or portal hypertension not explained by liver metastases
Monitoring of white blood cell count with differential, hemoglobin, platelet count, and blood chemistries (including ALT, AST, bilirubin, and creatinine) is recommended before each ELOXATIN cycle
The safety and effectiveness of ELOXATIN plus 5-FU/LV in patients with renal impairment have not been evaluated. Since the primary route of platinum elimination is renal, this combination should be used with caution in patients with preexisting renal impairment. Clearance of these products may be decreased by coadministration of potentially nephrotoxic compounds, although this has not been specifically studied
The incidence of diarrhea, dehydration, hypokalemia, leukopenia, fatigue, and syncope was higher in patients 65 years old
Extravasation may result in local pain and inflammation that may be severe and lead to complications, including necrosis. Injection site reaction, including redness, swelling, and pain, has been reported
There have been reports of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients receiving ELOXATIN plus 5-FU/LV while on anticoagulants. Patients receiving ELOXATIN plus 5-FU/LV and requiring oral anticoagulants may require closer monitoring
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 patients with advanced colorectal cancer were peripheral sensory neuropathy, fatigue, neutropenia, nausea, emesis, and diarrhea

Dosage and Administration

National Comprehensive Cancer Network (NCCN) Recommends mFOLFOX6 for Patients with MCRC 1

Prescribing Considerations

National Comprehensive Cancer Network (NCCN) Recommends mFOLFOX6 for Patients with MCRC ¹