oxaliplatin 50 MG in 10 ML Injection
DRUG INTERACTIONS
7 No specific cytochrome P-450-based drug interaction studies have been conducted.
No pharmacokinetic interaction between 85 mg/m 2 oxaliplatin and 5-fluorouracil/leucovorin has been observed in patients treated every 2 weeks.
Increases of 5-fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m 2 oxaliplatin dosed every 3 weeks.
Because platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by coadministration of potentially nephrotoxic compounds; although, this has not been specifically studied [see Clinical Pharmacology ( 12.3 )].
OVERDOSAGE
10 There is no known antidote for oxaliplatin overdose.
In addition to thrombocytopenia, the anticipated complications of an oxaliplatin overdose include hypersensitivity reaction, myelosuppression, nausea, vomiting, diarrhea and neurotoxicity.
Several cases of overdoses have been reported with oxaliplatin.
Adverse reactions observed were Grade 4 thrombocytopenia (< 25,000/mm 3 ) 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.
DESCRIPTION
11 Oxaliplatin Injection is an antineoplastic agent with the chemical name of cis -[(1 R ,2 R )-1,2-cyclohexanediamine- N , N ‘] [oxalato(2-)- O , O ‘] platinum.
Oxaliplatin, USP is an organoplatinum complex in which the platinum atom is complexed with 1,2-diaminocyclohexane(DACH) and with an oxalate ligand as a leaving group.
C 8 H 14 N 2 O 4 Pt M.W.
397.3 C 8 H 14 N 2 O 4 Pt M.W.
397.3 Oxaliplatin, USP is slightly soluble in water at 6 mg/mL, very slightly soluble in methanol, and practically insoluble in ethanol and acetone.
Oxaliplatin Injection is supplied in vials containing 50 mg or 100 mg of oxaliplatin, USP as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL.
Lactose monohydrate is present as an inactive ingredient at 450 mg and 900 mg in the 50 mg and 100 mg dosage strengths, respectively.
Water for injection is also present as an inactive ingredient.
Structure
CLINICAL STUDIES
14 14.1 Combination Adjuvant Therapy with Oxaliplatin and Infusional 5-fluorouracil/leucovorin in Patients with Colon Cancer An international, multicenter, randomized study compared the efficacy and evaluated the safety of oxaliplatin in combination with an infusional schedule of 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 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) > 1.5 × 10 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 Treatment Arm Dose Regimen Oxaliplatin + 5-FU/LV (FOLFOX4) (N = 1123) Day 1: Oxaliplatin: 85 mg/m 2 (2-hour infusion) + LV: 200 mg/m 2 (2-hour infusion), followed by 5-FU: 400 mg/m 2 (bolus), 600 mg/m 2 (22-hour infusion) Day 2: LV: 200 mg/m 2 (2-hour infusion), followed by 5-FU: 400 mg/m 2 (bolus), 600 mg/m 2 (22-hour infusion) every 2 weeks 12 cycles 5-FU/LV (N = 1123) Day 1: LV: 200 mg/m 2 (2-hour infusion), followed by 5-FU: 400 mg/m 2 (bolus), 600 mg/m 2 (22-hour infusion) Day 2: LV: 200 mg/m 2 (2-hour infusion), followed by 5-FU: 400 mg/m 2 (bolus), 600 mg/m 2 (22-hour infusion) every 2 weeks 12 cycles 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 Oxaliplatin + infusional 5-FU/LV N = 1123 Infusional 5-FU/LV N = 1123 Sex: Male (%) 56.1 52.4 Female (%) 43.9 47.6 Median age (years) 61 60 < 65 years of age (%) 64.4 66.2 ≥ 65 years of age (%) 35.6 33.8 Karnofsky Performance Status (KPS) (%) 100 29.7 30.5 90 52.2 53.9 80 4.4 3.3 70 13.2 11.9 ≤ 60 0.6 0.4 Primary site (%) Colon including cecum 54.6 54.4 Sigmoid 31.9 33.8 Recto sigmoid 12.9 10.9 Other including rectum 0.6 0.9 Bowel obstruction (%) Yes 17.9 19.3 Perforation (%) Yes 6.9 6.9 Stage at Randomization (%) II (T = 3,4 N = 0, M = 0) 40.1 39.9 III (T = any, N = 1,2, M = 0) 59.6 59.3 IV (T = any, N = any, M = 1) 0.4 0.8 Staging – T (%) T1 0.5 0.7 T2 4.5 4.8 T3 76 75.9 T4 19 18.5 Staging – N (%) N0 40.2 39.9 N1 39.4 39.4 N2 20.4 20.7 Staging – M (%) M1 0.4 0.8 Table 17 – Dosing in Adjuvant Therapy Study Oxaliplatin + infusional 5-FU/LV N = 1108 Infusional 5-FU/LV N = 1111 Median Relative Dose Intensity (%) 5-FU 84.4 97.7 Oxaliplatin 80.5 N/A Median Number of Cycles 12 12 Median Number of cycles With Oxaliplatin 11 N/A 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 Oxaliplatin + Infusional 5-FU/LV Infusional 5-FU/LV Parameter Overall N 1123 1123 Number of events – relapse or death (%) 304 (27.1) 360 (32.1) Disease-free survival % [95% CI] * 73.3 [70.7, 76] 67.4 [64.6, 70.2] Hazard ratio [95% CI] ** 0.80 [0.68, 0.93] Stratified Logrank test p = 0.003 Stage III (Dukes’ C) N 672 675 Number of events – relapse or death (%) 226 (33.6) 271 (40.1) Disease-free survival % [95% CI] * 66.4 [62.7, 70] 58.9 [55.2, 62.7] Hazard ratio [95% CI] ** 0.78 [0.65, 0.93] Logrank test p = 0.005 Stage II (Dukes’ B2) N 451 448 Number of events – relapse or death (%) 78 (17.3) 89 (19.9) Disease-free survival % [95% CI] * 83.7 [80.2, 87.1] 79.9 [76.2, 83.7] Hazard ratio [95% CI] ** 0.84 [0.62, 1.14] Logrank test p = 0.258 Data cut off for disease free survival 1 June 2006 *Disease-free survival at 5 years **A hazard ratio of less than 1 favors Oxaliplatin + Infusional 5-fluorouracil/leucovorin In the overall and stage III colon cancer populations DFS was statistically significantly improved in the oxaliplatin 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 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 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 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.
Table 19 – Summary of OS analysis – ITT analysis Parameter Oxaliplatin + Infusional 5-FU/LV Infusional 5-FU/LV Overall N 1123 1123 Number of death events (%) 245 (21.8) 283 (25.2) Hazard ratio* [95% CI] 0.84 [0.71, 1] Stage III (Dukes’ C) N 672 675 Number of death events (%) 182 (27.1) 220 (32.6) Hazard ratio* [95% CI] 0.80 [0.65, 0.97] Stage II (Dukes’ B2) N 451 448 Number of death events (%) 63 (14) 63 (14.1) Hazard ratio* [95% CI] 1 [0.70, 1.41] Data cut off for overall survival 16 January 2007 *A hazard ratio of less than 1 favors Oxaliplatin + Infusional 5-fluorouracil/leucovorin Figure 2 Figure 3 14.2 Combination Therapy with Oxaliplatin 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 in combination with infusional 5-fluorouracil/leucovorin and a combination of oxaliplatin 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 gm/dL, creatinine ≤ 1.5 × ULN, total bilirubin ≤ 1.5 mg/dL, AST ≤ 5 × ULN, and alkaline phosphatase ≤ 5 × ULN.
Patients may have received adjuvant therapy for resected Stage II or III disease without recurrence within 12 months.
The patients were stratified for ECOG performance status (0, 1 vs.
2), prior adjuvant chemotherapy (yes vs.
no), prior immunotherapy (yes vs.
no), and age (< 65 vs.
≥ 65 years).
Although no post study treatment was specified in the protocol, 65% to 72% of patients received additional post study chemotherapy after study treatment discontinuation on all arms.
Fifty-eight percent of patients on the oxaliplatin plus 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 Treatment Arm Dose Regimen Oxaliplatin + 5-FU/LV (FOLFOX4) (N = 267) Day 1: Oxaliplatin: 85 mg/m 2 (2-hour infusion) + LV 200 mg/m 2 (2-hour infusion), followed by 5-FU: 400 mg/m 2 (bolus), 600 mg/m 2 (22-hour infusion) Day 2: LV 200 mg/m 2 (2-hour infusion), followed by 5-FU: 400 mg/m 2 (bolus), 600 mg/m 2 (22-hour infusion) every 2 weeks Irinotecan + 5-FU/LV (IFL) (N = 264) Day 1: irinotecan 125 mg/m 2 as a 90-min infusion + LV 20 mg/m 2 as a 15 minute infusion or intravenous push, followed by 5-FU 500 mg/m 2 intravenous bolus weekly × 4 every 6 weeks Oxaliplatin + Irinotecan (IROX) (N = 264) Day 1: Oxaliplatin: 85 mg/m 2 intravenous (2- hour infusion) + irinotecan 200 mg/m 2 intravenous over 30 minutes every 3 weeks 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 Oxaliplatin + 5-FU/LV N = 267 Irinotecan + 5-FU/LV N = 264 Oxaliplatin + irinotecan N = 264 Sex: Male (%) 58.8 65.2 61 Female (%) 41.2 34.8 39 Median age (years) 61 61 61 < 65 years of age (%) 61 62 63 ≥ 65 years of age (%) 39 38 37 ECOG (%) 0 to 1 94.4 95.5 94.7 2 5.6 4.5 5.3 Involved organs (%) Colon only 0.7 0.8 0.4 Liver only 39.3 44.3 39 Liver + other 41.2 38.6 40.9 Lung only 6.4 3.8 5.3 Other (including lymph nodes) 11.6 11 12.9 Not reported 0.7 1.5 1.5 Prior radiation (%) 3 1.5 3 Prior surgery (%) 74.5 79.2 81.8 Prior adjuvant (%) 15.7 14.8 15.2 The length of a treatment cycle was 2 weeks for the oxaliplatin and 5-fluorouracil/leucovorin regimen; 6 weeks for the irinotecan plus 5-fluorouracil/leucovorin regimen; and 3 weeks for the oxaliplatin plus irinotecan regimen.
The median number of cycles administered per patient was 10 (23.9 weeks) for the oxaliplatin and 5-fluorouracil/leucovorin regimen, 4 (23.6 weeks) for the irinotecan plus 5-fluorouracil/leucovorin regimen, and 7 (21 weeks) for the oxaliplatin plus irinotecan regimen.
Patients treated with the oxaliplatin 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 Oxaliplatin + 5-FU/LV N = 267 irinotecan + 5-FU/LV N = 264 Oxaliplatin + irinotecan N = 264 Survival (ITT) Number of deaths N (%) 155 (58.1) 192 (72.7) 175 (66.3) Median survival (months) 19.4 14.6 17.6 Hazard Ratio and (95% confidence interval) 0.65 (0.53 to 0.80)* P-value < 0.0001* – – TTP (ITT, investigator assessment) Percentage of progressors 82.8 81.8 89.4 Median TTP (months) 8.7 6.9 6.5 Hazard Ratio and (95% confidence interval) *** 0.74 (0.61 to 0.89)* P-value 0.0014* – – Response Rate (investigator assessment)** Patients with measurable disease 210 212 215 Complete response N (%) 13 (6.2) 5 (2.4) 7 (3.3) Partial response N (%) 82 (39) 64 (30.2) 67 (31.2) Complete and partial response N (%) 95 (45.2) 69 (32.5) 74 (34.4) 95% confidence interval (38.5 to 52) (26.2 to 38.9) (28.1 to 40.8) P-value 0.0080* – – *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 favors Oxaliplatin + Infusional 5-fluorouracil/leucovorin Figure 4 illustrates the Kaplan-Meier survival curves for the comparison of oxaliplatin and 5-fluorouracil/leucovorin combination and oxaliplatin plus irinotecan to irinotecan plus 5-fluorouracil/leucovorin.
* Log rank test comparing oxaliplatin plus 5-FU/LV to irinotecan plus 5-FU/LV.
Figure 4 – Kaplan-Meier Overall Survival by treatment arm A descriptive subgroup analysis demonstrated that the improvement in survival for oxaliplatin 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 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.
Figure 4 14.3 Combination Therapy with Oxaliplatin 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 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 Treatment Arm Dose Regimen Oxaliplatin + 5-FU/LV (N = 152) Day 1: Oxaliplatin: 85 mg/m 2 (2-hour infusion) + LV 200 mg/m 2 (2-hour infusion), followed by 5-FU: 400 mg/m 2 (bolus), 600 mg/m 2 (22-hour infusion) Day 2: LV 200 mg/m 2 (2-hour infusion), followed by 5-FU: 400 mg/m 2 (bolus), 600 mg/m 2 (22-hour infusion) every 2 weeks 5-FU/LV (N = 151) Day 1: LV 200 mg/m 2 (2-hour infusion), followed by 5-FU: 400 mg/m 2 (bolus), 600 mg/m 2 (22-hour infusion) Day 2: LV 200 mg/m 2 (2-hour infusion), followed by 5-FU: 400 mg/m 2 (bolus), 600 mg/m 2 (22-hour infusion) every 2 weeks Oxaliplatin (N = 156) Day 1: Oxaliplatin 85 mg/m 2 (2-hour infusion) every 2 weeks 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 5-FU/LV (N = 151) Oxaliplatin (N = 156) Oxaliplatin + 5-FU/LV (N = 152) Sex: Male (%) 54.3 60.9 57.2 Female (%) 45.7 39.1 42.8 Median age (years) 60 61 59 Range 21 to 80 27 to 79 22 to 88 Race (%) Caucasian 87.4 84.6 88.8 Black 7.9 7.1 5.9 Asian 1.3 2.6 2.6 Other 3.3 5.8 2.6 KPS (%) 70 to 100 94.7 92.3 95.4 50 to 60 2.6 4.5 2 Not reported 2.6 3.2 2.6 Prior radiotherapy (%) 25.2 19.2 25 Prior pelvic radiation (%) 18.5 13.5 21.1 Number of metastatic sites (%) 1 27.2 31.4 25.7 ≥ 2 72.2 67.9 74.3 Liver involvement (%) Liver only 22.5 25.6 18.4 Liver + other 60.3 59 53.3 The median number of cycles administered per patient was 6 for the oxaliplatin and 5-fluorouracil/leucovorin combination and 3 each for 5-fluorouracil/leucovorin alone and oxaliplatin alone.
Patients treated with the combination of oxaliplatin 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) Best Response 5-FU/LV (N = 151) Oxaliplatin (N = 156) Oxaliplatin + 5-FU/LV (N = 152) CR 0 0 0 PR 0 2 (1%) 13 (9%) p-value 0.0002 for 5-FU/LV vs.
Oxaliplatin + 5-FU/LV 95% CI 0 to 2.4% 0.2 to 4.6% 4.6 to 14.2% Table 26 – Summary of Radiographic Time to Progression* Arm 5-FU/LV (N = 151) Oxaliplatin (N = 156) Oxaliplatin + 5-FU/LV (N = 152) No.
of Progressors 74 101 50 No.
of patients with no radiological evaluation beyond baseline 22 (15%) 16 (10%) 17 (11%) Median TTP (months) 2.7 1.6 4.6 95% CI 1.8 to 3 1.4 to 2.7 4.2 to 6.1 *This is not an ITT analysis.
Events were limited to radiographic disease progression documented by independent review of radiographs.
Clinical progression was not included in this analysis, and 18% of patients were excluded from the analysis based on unavailability of the radiographs for independent review.
At the time of the interim analysis 49% of the radiographic progression events had occurred.
In this interim analysis an estimated 2-month increase in median time to radiographic progression was observed compared to 5-fluorouracil/leucovorin alone.
Of the 13 patients who had tumor response to the combination of oxaliplatin 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.
HOW SUPPLIED
16 /STORAGE AND HANDLING 16.1 How Supplied Oxaliplatin Injection 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 and lactose monohydrate are present as inactive ingredients.
NDC No.
63323-211-10 Product No.
721210 50 mg single-use vial with flip-off seal individually packaged in a carton NDC No.
63323-212-20 Product No.
721220 100 mg single-use vial with flip-off seal individually packaged in a carton.
16.2 Storage Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
DO NOT FREEZE.
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.
The use of gloves is recommended.
If a solution of oxaliplatin contacts the skin, wash the skin immediately and thoroughly with soap and water.
If oxaliplatin 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.
RECENT MAJOR CHANGES
Dosage and Administration ( 2.2 ) 10/2015 Warnings and Precautions ( 5.3 , 5.4 , 5.7 , 5.8 , 5.9 ) 10/2015
GERIATRIC USE
8.5 Geriatric Use No significant effect of age on the clearance of ultrafilterable platinum has been observed.
In the adjuvant therapy colon cancer randomized clinical trial, [see Clinical Studies ( 14 )] 723 patients treated with oxaliplatin and infusional 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 combination arm compared to the infusional 5-fluorouracil/leucovorin alone arm appeared to be maintained across genders.
The effect of oxaliplatin in patients ≥ 65 years of age was not conclusive.
Insufficient subgroup sizes prevented analysis by race.
Patients ≥ 65 years of age receiving the oxaliplatin combination therapy experienced more grade 3 to 4 granulocytopenia than patients < 65 years of age (45% versus 39%).
In the previously untreated for advanced colorectal cancer randomized clinical trial [see Clinical Studies ( 14 )] of oxaliplatin, 160 patients treated with oxaliplatin and 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, 95 patients treated with oxaliplatin 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.
DOSAGE FORMS AND STRENGTHS
3 Oxaliplatin is a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL for dilution and supplied in single-use vials containing 50 mg or 100 mg of oxaliplatin.
Single-use vials of 50 mg or 100 mg oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/mL.
( 3 )
MECHANISM OF ACTION
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)].
INDICATIONS AND USAGE
1 Oxaliplatin, used in combination with infusional 5-fluorouracil/leucovorin, is indicated for: • adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor.
• treatment of advanced colorectal cancer.
Oxaliplatin injection is a platinum-based drug used in combination with infusional 5-fluorouracil/leucovorin, which is indicated for: • adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor.
( 1 ) • treatment of advanced colorectal cancer.
( 1 )
PEDIATRIC USE
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/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 2 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/m² 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.
PREGNANCY
8.1 Pregnancy Pregnancy Category D Based on direct interaction with DNA, oxaliplatin may cause fetal harm when administered to a pregnant woman.
There are no adequate and well-controlled studies of oxaliplatin 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.
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.
NUSRING MOTHERS
8.3 Nursing Mothers It is not known whether oxaliplatin 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, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
BOXED WARNING
WARNING: ANAPHYLACTIC REACTIONS Anaphylactic reactions to oxaliplatin have been reported, and may occur within minutes of oxaliplatin administration.
Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms of anaphylaxis [see Warnings and Precautions ( 5.1 )].
WARNING: ANAPHYLACTIC REACTIONS See full prescribing information for complete boxed warning .
Anaphylactic reactions to oxaliplatin have been reported, and may occur within minutes of oxaliplatin administration.
Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms.
( 5.1 )
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS • Allergic Reactions: Monitor for development of rash, urticaria, erythema, pruritis, bronchospasm, and hypotension.
( 5.1 ) • Neuropathy: Reduce the dose or discontinue oxaliplatin if necessary.
( 5.2 ) • Severe Neutropenia: Delay oxaliplatin until neutrophils are ≥1.5 x 10 9 /L.
Withhold oxaliplatin for sepsis.
( 5.3 ) • Pulmonary Toxicity: May need to discontinue oxaliplatin until interstitial lung disease or pulmonary fibrosis are excluded.
( 5.4 ) • Hepatotoxicity: Monitor liver function tests.
( 5.5 ) • Cardiovascular Toxicity: Correct hypokalemia or hypomagnesemia prior to initiating oxaliplatin.
( 5.6 ) • Rhabdomyolysis: Discontinue oxaliplatin if rhabdomyolysis occurs.
( 5.7 ) • Pregnancy.
Fetal harm can occur when administered to a pregnant woman.
Women should be apprised of the potential harm to the fetus.
( 5.8 , 8.1 ) 5.1 Allergic Reactions See boxed warning .
Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to oxaliplatin has been observed in 2% to 3% of colon cancer patients.
These allergic reactions which can be fatal, can occur within minutes of administration and at any cycle, and were similar in nature and severity to those reported with other platinum-containing compounds, such as rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension.
The symptoms associated with hypersensitivity reactions reported in the previously untreated patients were urticaria, pruritus, flushing of the face, diarrhea associated with oxaliplatin infusion, shortness of breath, bronchospasm, diaphoresis, chest pains, hypotension, disorientation and syncope.
These reactions are usually managed with standard epinephrine, corticosteroid, antihistamine therapy, and require discontinuation of therapy.
Rechallenge is contraindicated in these patients [see Contraindications ( 4 ) ] .
Drug-related deaths associated with platinum compounds from anaphylaxis have been reported.
5.2 Neurologic Toxicity Neuropathy Oxaliplatin is associated with two types of neuropathy An acute, reversible, primarily peripheral, sensory neuropathy that is of early onset, occurring within hours or one to two days of dosing, that resolves within 14 days, and that frequently recurs with further dosing.
The symptoms may be precipitated or exacerbated by exposure to cold temperature or cold objects and they usually present as transient paresthesia, dysesthesia and hypoesthesia in the hands, feet, perioral area, or throat.
Jaw spasm, abnormal tongue sensation, dysarthria, eye pain, and a feeling of chest pressure have also been observed.
The acute, reversible pattern of sensory neuropathy was observed in about 56% of study patients who received oxaliplatin with 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 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 because cold temperature can exacerbate acute neurological symptoms .
A persistent (> 14 days), primarily peripheral, sensory neuropathy that is usually characterized by paresthesias, dysesthesias, hypoesthesias, but may also include deficits in proprioception that can interfere with daily activities (e.g., writing, buttoning, swallowing, and difficulty walking from impaired proprioception).
These forms of neuropathy occurred in 48% of the study patients receiving oxaliplatin with 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.
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 Grade Definition Grade 0 No change or none Grade 1 Mild paresthesias, loss of deep tendon reflexes Grade 2 Mild or moderate objective sensory loss, moderate paresthesias Grade 3 Severe objective sensory loss or paresthesias that interfere with function Grade 4 Not applicable Peripheral sensory neuropathy was reported in adjuvant patients treated with the oxaliplatin combination with a frequency of 92% (all grades) and 13% (grade 3).
At the 28-day follow-up after the last treatment cycle, 60% of all patients had any grade (Grade 1=40%, Grade 2=16%, Grade 3=5%) peripheral sensory neuropathy decreasing to 39% at 6 months follow-up (Grade 1=31%, Grade 2=7%, Grade 3=1%) and 21% at 18 months of follow-up (Grade 1=17%, Grade 2=3%, Grade 3=1%).
In the advanced colorectal cancer studies, neuropathy was graded using a study-specific neurotoxicity scale, which was different from the NCI CTC scale, Version 2.0 (see below).
Table 2 – Grading Scale for Paresthesias/Dysesthesias in Advanced Colorectal Cancer Patients Grade Definition Grade 1 Resolved and did not interfere with functioning Grade 2 Interfered with function but not daily activities Grade 3 Pain or functional impairment that interfered with daily activities Grade 4 Persistent impairment that is disabling or life-threatening Overall, neuropathy was reported in patients previously untreated for advanced colorectal cancer in 82% (all grades) and 19% (grade 3/4), and in the previously treated patients in 74% (all grades) and 7% (grade 3/4) events.
Information regarding reversibility of neuropathy was not available from the trial for patients who had not been previously treated for colorectal cancer.
Reversible Posterior Leukoencephalopathy Syndrome Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES, Posterior Reversible Encephalopathy Syndrome) has been observed in clinical trials (< 0.1%) and postmarketing experience.
Signs and symptoms of RPLS could be headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension [see Adverse Reactions ( 6.2 ) ] .
Diagnosis of RPLS is based upon confirmation by brain imaging.
5.3 Severe Neutropenia Grade 3 or 4 neutropenia occurred in 41 to 44% of patients with colorectal cancer treated with oxaliplatin in combination with 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, including fatal outcomes [see Adverse Reactions ( 6.1 )] .
Delay oxaliplatin until neutrophils are ≥ 1.5 x 10 9 /L.
Withhold oxaliplatin for sepsis or septic shock.
Dose reduce oxaliplatin after recovery from Grade 4 neutropenia or febrile neutropenia [see Dosage and Administration (2.2)] .
5.4 Pulmonary Toxicity Oxaliplatin has been associated with pulmonary fibrosis (< 1% of study patients), which may be fatal.
The combined incidence of cough and dyspnea was 7.4% (any grade) and < 1% (grade 3) with no grade 4 events in the oxaliplatin plus infusional 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 combination arm.
The combined incidence of cough, dyspnea and hypoxia was 43% (any grade) and 7% (grade 3 and 4) in the oxaliplatin 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 should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.
5.5 Hepatotoxicity Hepatotoxicity as evidenced in the adjuvant study, by increase in transaminases (57% vs.
34%) and alkaline phosphatase (42% vs.
20%) was observed more commonly in the oxaliplatin combination arm than in the control arm.
The incidence of increased bilirubin was similar 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 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 and monitor these electrolytes periodically during therapy.
Avoid oxaliplatin in patients with congenital long QT syndrome [see Adverse Reactions ( 6.2 )] .
5.7 Rhabdomyolysis Rhabdomyolysis, including fatal cases, has been reported in patients treated with oxaliplatin.
Discontinue oxaliplatin if any signs or symptoms of rhabdomyolysis occur [see Adverse Reactions ( 6.2 )] .
5.8 Use in Pregnancy Pregnancy Category D Oxaliplatin may cause fetal harm when administered to a pregnant woman.
There are no adequate and well-controlled studies of oxaliplatin in pregnant women.
Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with oxaliplatin [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 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 plus 5-fluorouracil/leucovorin while on anticoagulants.
Patients receiving oxaliplatin plus 5-fluorouracil/leucovorin and requiring oral anticoagulants may require closer monitoring.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise patients: • To expect side effects of oxaliplatin, particularly its neurologic effects, both the acute, reversible effects and the persistent neurosensory toxicity.
Patients should be informed that the acute neurosensory toxicity may be precipitated or exacerbated by exposure to cold or cold objects.
• To avoid cold drinks, use of ice, and should cover exposed skin prior to exposure to cold temperature or cold objects.
• Of the risk of low blood cell counts and to contact their physician immediately should fever, particularly if associated with persistent diarrhea, or evidence of infection develop.
• To contact their physician if persistent vomiting, diarrhea, signs of dehydration, cough or breathing difficulties occur, or signs of allergic reaction appear.
• To exercise caution when driving and using machines.
No studies on the effects of the ability to operate cars and machines have been performed; however, oxaliplatin treatment resulting in an increase risk of dizziness, nausea and vomiting, and other neurologic symptoms that affect gait and balance may lead to a minor or moderate influence on the ability to drive and use machines.
• Of the potential effects of vision abnormalities, in particular transient vision loss (reversible following therapy discontinuation), which may affect patients’ ability to drive and use machines.
FDA-Approved Patient Labeling
DOSAGE AND ADMINISTRATION
2 Oxaliplatin injection should be administered under the supervision of a qualified 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.
• Administer oxaliplatin injection in combination with 5-fluorouracil/leucovorin every 2 weeks.
( 2.1 ): • Day 1: Oxaliplatin injection 85 mg/m 2 intravenous infusion in 250 to 500 mL 5% Dextrose Injection and leucovorin 200 mg/m 2 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/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 (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 (recommended) as a 22-hour continuous infusion.
• Reduce the dose of oxaliplatin injection to 75 mg/m 2 (adjuvant setting) or 65 mg/m 2 (advanced colorectal cancer) ( 2.2 ): • if there are persistent grade 2 neurosensory events that do not resolve.
• after recovery from grade 3/4 gastrointestinal toxicities (despite prophylactic treatment) or grade 4 neutropenia or febrile neutropenia or grade 3/4 thrombocytopenia.
Delay next dose until neutrophils ≥ 1.5 × 10 9 /L and platelets ≥ 75 × 10 9 /L.
• For patients with severe renal impairment (creatinine clearance < 30 mL/min), the initial recommended dose is 65 mg/m².
(2.2) • Discontinue oxaliplatin injection if there are persistent Grade 3 neurosensory events.
( 2.2 ) • Never prepare a final dilution with a sodium chloride solution or other chloride-containing solutions.
( 2.3 ) 2.1 Dosage Administer oxaliplatin 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 85 mg/m 2 intravenous infusion in 250 to 500 mL 5% Dextrose Injection and leucovorin 200 mg/m 2 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/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 (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 (recommended) as a 22-hour continuous infusion.
Figure 1 The administration of oxaliplatin does not require prehydration.
Premedication with antiemetics, including 5-HT 3 blockers with or without dexamethasone, is recommended.
For information on 5-fluorouracil and leucovorin, see the respective package inserts.
Figure 1 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 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 [see Warnings and Precautions ( 5.2 )].
For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of oxaliplatin 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.
A dose reduction of oxaliplatin 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 [see Warnings and Precautions ( 5.2 )] .
Other toxicities were graded by the NCI CTC, Version 2.0.
For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of oxaliplatin 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.
A dose reduction of oxaliplatin 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 is 85 mg/m 2 .
In patients with severe renal impairment, the initial recommended oxaliplatin 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.
After dilution with 250 to 500 mL of 5% Dextrose Injection, 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 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 should not be used for the preparation or mixing of the drug.
Aluminum has been reported to cause degradation of platinum compounds.