The AUC_0-48hr of platinumin the plasma ultrafiltrate increases as renal function decreases. The AUC_0-48hr of platinumin patients with mild (creatinine clearance, CL_cr 50 to 80 mL/min), moderate (CL_cr 30 to < 50 mL/min) and severe renal (CL_cr < 30 mL/min) impairment is increased by about 60, 140 and 190%, respectively, compared to patients with normal renal function (CL_cr > 80 mL/min) [See ADVERSE REACTIONS, DRUG INTERACTIONS and Use In Specific Patient Populations].

Drug - Drug Interactions

No pharmacokinetic interaction between 85 mg/m² of ELOXATIN and infusional 5-FU has been observed in patients treated every 2 weeks, but increases of 5-FU plasma concentrations by approximately 20% have been observed with doses of 130 mg/mm² of ELOXATIN administered every 3 weeks. In vitro, platinumwas not displaced fromplasma proteins by the following medications: erythromycin, salicylate, sodiumvalproate, granisetron, and paclitaxel. In vitro, oxaliplatin is not metabolized by, nor does it inhibit, human cytochrome P450 isoenzymes. No P450-mediated drug-drug interactions are therefore anticipated in patients. Since platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by co-administration of potentially nephrotoxic compounds, although this has not been specifically studied.

Clinical Studies

Combination Adjuvant Therapy with ELOXATIN and Infusional 5-FU/LV in Patients with Colon Cancer

An international, multicenter, randomized study compared the efficacy and evaluated the safety of ELOXATIN in combination with an infusional schedule of 5-FU/LV to infusional 5-FU/LV 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 ELOXATIN and infusional 5-FU/LV to those receiving 5-FU/LV 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 N_1-2 M0; Dukes' C) colon carcinoma (with the inferior pole of the tumor above the peritoneal reflection, i.e., ≥ 15 cmfromthe 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 ≥ 100x10⁹/L, serumcreatinine ≤ 1.25 x ULN total bilirubin < 2 x ULN, AST/ALT < 2 x 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

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