Eloxatin injection

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Eloxatin


Generic Name: oxaliplatin
Dosage Form: Injection

WARNING

Eloxatin (oxaliplatin for 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.

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 (see WARNINGS and ADVERSE REACTIONS).

Eloxatin Description

Eloxatin (oxaliplatin for injection) is an antineoplastic agent with the molecular formula C8H14N2O4Pt and the chemical name of cis-[(1R,2R)-1,2-cyclohexanediamine-N,N"] [oxalato(2-)-O,O"] platinum. Oxaliplatin 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.

The molecular weight is 397.3. Oxaliplatin is slightly soluble in water at 6 mg/mL, very slightly soluble in methanol, and practically insoluble in ethanol and acetone. Eloxatin is supplied in vials containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free lyophilized powder for reconstitution. Lactose monohydrate is present as an inactive ingredient at 450 mg and 900 mg in the 50 mg and 100 mg dosage strengths, respectively.

Eloxatin - Clinical Pharmacology

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.

Pharmacology

In vivo studies have shown antitumor activity of oxaliplatin against colon carcinoma. In combination with 5-fluorouracil (5-FU), 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)].

Human 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 IV infusion of Eloxatin at a dose of 85 mg/m2 expressed as ultrafilterable platinum were Cmax of 0.814 µg/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.

Distribution

At the end of a 2-hour infusion of Eloxatin, approximately 15% of the administered platinum is present in the systemic circulation. The remaining 85% is rapidly distributed into tissues or eliminated in the urine. In patients, plasma protein binding of platinum is irreversible and is greater than 90%. The main binding proteins are albumin and gamma-globulins. Platinum also binds irreversibly and accumulates (approximately 2-fold) in erythrocytes, where it appears to have no relevant activity. No platinum accumulation was observed in plasma ultrafiltrate following 85 mg/m2 every two weeks.

Metabolism

Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation. There is no evidence of cytochrome P450-mediated metabolism in vitro.

Up to 17 platinum-containing derivatives have been observed in plasma ultrafiltrate samples from patients, including several cytotoxic species (monochloro DACH platinum, dichloro DACH platinum, and monoaquo and diaquo DACH platinum) and a number of noncytotoxic, conjugated species.

Elimination

The major route of platinum elimination is renal excretion. At five days after a single 2-hour infusion of Eloxatin, urinary elimination accounted for about 54% of the platinum eliminated, with fecal excretion accounting for only about 2%. Platinum was cleared from plasma at a rate (10 – 17 L/h) that was similar to or exceeded the average human glomerular filtration rate (GFR; 7.5 L/h). There was no significant effect of gender on the clearance of ultrafilterable platinum. The renal clearance of ultrafilterable platinum is significantly correlated with GFR (see ADVERSE REACTIONS).

Pharmacokinetics in Special Populations

Renal Impairment

The AUC0–48hr of platinum in the plasma ultrafiltrate increases as renal function decreases. The AUC0–48hr of platinum in patients with mild (creatinine clearance, CLcr 50 to 80 mL/min), moderate (CLcr 30 to <50 mL/min) and severe renal (CLcr<30 mL/min) impairment is increased by about 60, 140 and 190%, respectively, compared to patients with normal renal function (CLcr>80 mL/min) (see PRECAUTIONS and ADVERSE REACTIONS).

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/m2 of Eloxatin administered every 3 weeks. In vitro, platinum was not displaced from plasma proteins by the following medications: erythromycin, salicylate, sodium valproate, granisetron, and paclitaxel. In vitro, oxaliplatin is not metabolized by, nor does it inhibit, human cytochrome P450 isoenzymes. No P450-mediated drug-drug interactions are 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 Stage II or III 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 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) > 1.5×109/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.

Table 1 - Dosing Regimens in Adjuvant Therapy Study
Treatment
Arm Dose Regimen
Eloxatin + 5-FU/LV
FOLFOX4
(N =1123)
Day 1: Eloxatin: 85 mg/m2 (2-hour infusion) + LV: 200 mg/m2 (2-hour infusion), followed by
5-FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)

Day 2: LV: 200 mg/m2 (2-hour infusion), followed by
5-FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)
q2w
12 cycles
5-FU/LV
(N=1123)
Day 1: LV: 200 mg/m2 (2-hour infusion), followed by
5-FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)

Day 2: LV: 200 mg/m2 (2-hour infusion), followed by
5-FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)
q2w
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 2 - Patient Characteristics in Adjuvant Therapy Study
Eloxatin +
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) 61.0 60.0
<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 caecum 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 76.0 75.9
  T4 19.0 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 3 - Dosing in Adjuvant Therapy Study
Eloxatin +
infusional 5-FU/LV
N=1108
Infusional 5-FU/LV
N=1111
Median Relative Dose Intensity (%)
  5-FU 84.4 97.7
  Eloxatin 80.5 N/A
Median Number of Cycles 12 12
Median Number of cycles with Eloxatin 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.

Table 4 - Summary of DFS analysis [ITT analysis (minimum follow-up of 41 months)]
Parameter Eloxatin +
Infusional 5-FU/LV
Infusional 5-FU/LV
*
For patients alive or lost to follow-up
Overall
N 1123 1123
Median follow-up (months)* 47.7 47.4
Number of events – relapse or death (%) 267 (23.8) 332 (29.6)
4-year Disease-free survival % [95% CI] 75.9 [73.4, 78.5] 69.1 [66.3, 71.9]
Hazard ratio [95% CI] 0.76 [0.65, 0.90]
Stratified Logrank test p=0.0008
Stage III
N 672 675
Number of events –relapse or death (%) 200 (29.8) 252 (37.3)
4-year Disease-free survival % [95% CI] 69.7 [66.2, 73.3] 61.0 [57.1, 64.8]
Hazard ratio [95% CI] 0.75 [0.62, 0.90]
Logrank test p=0.002
Stage II
N 451 448
Number of events – relapse or death (%) 67 (14.9) 80 (17.9)
4-year Disease-free survival % [95% CI] 85.1 [81.7, 88.6] 81.3 [77.6, 85.1]
Hazard ratio [95% CI] 0.80 [0.58, 1.11]
Logrank test p=0.179

In the overall study population DFS was statistically significantly improved in the Eloxatin combination arm compared to infusional 5-FU/LV alone. A statistically significant improvement in DFS was noted in Stage III patients, but not in Stage II patients.

Figure 1 shows the Kaplan-Meier DFS curves for the comparison of Eloxatin and infusional 5-FU/LV combination and infusional 5-FU/LV alone for the overall population (ITT analysis). Figure 2 shows the Kaplan-Meier DFS curves for the comparison of Eloxatin and infusional 5-FU/LV combination and infusional 5-FU/LV alone for the Stage III Subgroup.

Figure 1 - Kaplan-Meier DFS curves by treatment arm for Overall Population

Figure 2 - Kaplan-Meier DFS curves by treatment arm for Stage III Subgroup

Survival data were not mature at the time of the analysis with a median follow-up of 47 months. No statistically significant difference in overall survival [Hazard Ratio 0.89 (95% CI 0.72, 1.09) p=0.236] was shown between the two treatment arms in the entire population or in the Stage II [Hazard Ratio 0.98 (95% CI 0.63, 1.53) p=0.94] or Stage III [Hazard Ratio 0.86 (95%CI 0.68, 1.08) p=0.196] subgroups.

A descriptive subgroup analysis demonstrated that the improvement in DFS for the Eloxatin combination arm compared to the infusional 5-FU/LV alone arm appeared to be maintained across genders. The effect of Eloxatin on disease free survival benefit in patients ≥65 years of age was not conclusive. Insufficient subgroup sizes prevented analysis by race.

Combination Therapy with Eloxatin and 5-FU/LV 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-FU/LV. The results reported below compared the efficacy and safety of two experimental regimens, Eloxatin in combination with infusional 5-FU/LV and a combination of Eloxatin plus irinotecan, to an approved control regimen of irinotecan plus 5-FU/LV in 795 concurrently randomized patients previously untreated for locally advanced or metastatic colorectal cancer. After completion of enrollment, the dose of irinotecan plus 5-FU/LV 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 Eloxatin plus 5-FU/LV arm received an irinotecan-containing regimen and 23% of patients on the irinotecan plus 5-FU/LV 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 5 – Dosing Regimens in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial
Treatment Dose Regimen
Arm
Eloxatin + 5-FUL/LV
FOLFOX4
(N=267)
Day 1: Eloxatin: 85 mg/m2 (2-hour infusion) + LV 200 mg/m2 (2-hour infusion), followed by
5-FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)

Day 2: LV 200 mg/m2 (2-hour infusion), followed by
5-FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)
q2w
Irinotecan +
5-FU/LV
IFL
(N=264)
Day 1: irinotecan 125 mg/m2 as a 90–min infusion +
LV 20 mg/m2 as a 15-min infusion or IV push, followed by
5-FU 500 mg/m2 IV bolus weekly x 4
q6w
Eloxatin + Irinotecan IROX
(N=264)
Day 1: Eloxatin: 85 mg/m2 IV (2-hour infusion) +
irinotecan 200 mg/m2 IV over 30 minutes
q3w

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

Table 6 – Patient Demographics and Dosing in Patients Previously Untreated for Advanced Colorectal Cancer Clinical Trial
Eloxatin +
5-FU/LV
N=267
Irinotecan +
5-FU/LV
N=264
Eloxatin +
irinotecan
N=264
Sex: Male (%) 58.8 65.2 61.0
  Female (%) 41.2 34.8 39.0
Median age (years) 61.0 61.0 61.0
>65 years of age (%) 61 62 63
≥65 years of age (%) 39 38 37
ECOG (%)
0.1 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 39.0
  Liver + other 41.2 38.6 40.9
  Lung only 6.4 3.8 5.3
  Other (including lymph nodes) 11.6 11.0 12.9
  Not reported 0.7 1.5 1.5
Prior radiation (%) 3.0 1.5 3.0
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 Eloxatin and 5-FU/LV regimen; 6 weeks for the irinotecan plus 5-FU/LV regimen; and 3 weeks for the Eloxatin plus irinotecan regimen. The median number of cycles administered per patient was 10 (23.9 weeks) for the Eloxatin and 5-FU/LV regimen, 4 (23.6 weeks) for the irinotecan plus 5-FU/LV regimen, and 7 (21.0 weeks) for the Eloxatin plus irinotecan regimen. Patients treated with the Eloxatin and 5-FU/LV 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-FU/LV. The following table summarizes the efficacy results.

Table 7 – Summary of Efficacy
Eloxatin +
5-FU/LV
N=267
irinotecan +
5-FU/LV
N=264
Eloxatin +
irinotecan
N=264
*
Compared to irinotecan plus 5-FU/LV (IFL) arm
Based on all patients with measurable disease at baseline
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 (0.53–0.80)*
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 (0.61–0.89)*
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 (39.0) 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 – 52.0) (26.2 – 38.9) (28.1 – 40.8)
P-value 0.0080*

The numbers in the response rate and TTP analysis are based on unblinded investigator assessment.

Figure 3 illustrates the Kaplan-Meier survival curves for the comparison of Eloxatin and 5-FU/LV combination and Eloxatin plus irinotecan to irinotecan plus 5-FU/LV.

Figure 3 – Kaplan-Meier Overall Survival by treatment arm

A descriptive subgroup analysis demonstrated that the improvement in survival for Eloxatin plus 5-FU/LV compared to irinotecan plus 5-FU/LV appeared to be maintained across age groups, prior adjuvant therapy, and number of organs involved. An estimated survival advantage in Eloxatin plus 5-FU/LV versus irinotecan plus 5-FU/LV was seen in both genders; however it was greater among women than men. Insufficient subgroup sizes prevented analysis by race.

Combination Therapy with Eloxatin and 5-FU/LV 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 Eloxatin in combination with an infusional schedule of 5-FU/LV to the same dose and schedule of 5-FU/LV 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-FU/LV 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 8 – Dosing Regimens in Refractory and Relapsed Colorectal Cancer Clinical Trial
Treatment
Arm Dose Regimen
Eloxatin + 5-FU/LV
(N =152)
Day 1: Eloxatin: 85 mg/m2 (2-hour infusion) +
LV 200 mg/m2 (2-hour infusion), followed by
5-FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)

Day 2: LV 200 mg/m2 (2-hour infusion), followed
by 5-FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)
q2w
5-FU/LV (N=151)
Day 1: LV 200 mg/m2 (2-hour infusion), followed by
5-FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)

Day 2: LV 200 mg/m2 (2-hour infusion), followed by
5-FU: 400 mg/m2 (bolus), 600 mg/m2 (22-hour infusion)
q2w
Eloxatin (N=156) Day 1: Eloxatin 85 mg/m2 (2-hour infusion) q2w

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 9 – Patient Demographics in Refractory and Relapsed Colorectal Cancer Clinical Trial
5-FU/LV
(N = 151)
Eloxatin
(N = 156)
Eloxatin + 5-FU/LV
(N = 152)
Sex: Male (%) 54.3 60.9 57.2
  Female (%) 45.7 39.1 42.8
Median age (years) 60.0 61.0 59.0
  Range 21–80 27–79 22–88
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 – 100 94.7 92.3 95.4
  50 – 60 2.6 4.5 2.0
  Not reported 2.6 3.2 2.6
Prior radiotherapy (%) 25.2 19.2 25.0
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 59.0 53.3

The median number of cycles administered per patient was 6 for the Eloxatin and 5-FU/LV combination and 3 each for 5-FU/LV alone and Eloxatin alone.

Patients treated with the combination of Eloxatin and 5-FU/LV had an increased response rate compared to patients given 5-FU/LV or oxaliplatin alone. The efficacy results are summarized in the tables below.

Table 10 - Response Rates (ITT Analysis)
Best Response 5-FU/LV
(N=151)
Eloxatin
(N=156)
Eloxatin + 5-FU/LV
(N=152)
CR 0 0 0
PR 0 2 (1%) 13 (9%)
p-value 0.0002 for 5-FU/LV vs. Eloxatin + 5 FU/LV
95%CI 0–2.4% 0.2–4.6% 4.6–14.2%
Table 11 - Summary of Radiographic Time to Progression*
Arm 5-FU/LV
(N=151)
Eloxatin
(N=156)
Eloxatin + 5-FU/LV
(N=152)
*
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.
No. of Progressors 74 101 50
No. of patients with no radiological 22 16 17
evaluation beyond baseline (15%) (10%) (11%)
Median TTP (months) 2.7 1.6 4.6
95% CI 1.8–3.0 1.4–2.7 4.2–6.1

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-FU/LV alone.

Of the 13 patients who had tumor response to the combination of Eloxatin and 5-FU/LV, 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.

Indications and Usage for Eloxatin

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.

Eloxatin, used in combination with infusional 5-FU/LV, is indicated for the treatment of advanced carcinoma of the colon or rectum.

Contraindications

Eloxatin should not be administered to patients with a history of known allergy to Eloxatin or other platinum compounds.

Warnings

As in the case for other platinum compounds, hypersensitivity and anaphylactic/anaphylactoid reactions to Eloxatin have been reported (see ADVERSE REACTIONS). These allergic reactions were similar in nature and severity to those reported with other platinum-containing compounds, i.e., 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 associated with platinum compounds from this reaction have been reported.

Pregnancy Category D

Eloxatin may cause fetal harm when administered to a pregnant woman. Pregnant rats were administered 1 mg/kg/day oxaliplatin (less than one-tenth the recommended human dose based on body surface area) during gestation days 1–5 (pre-implantation), 6–10, or 11–16 (during organogenesis). Oxaliplatin caused developmental mortality (increased early resorptions) when administered on days 6–10 and 11–16 and adversely affected fetal growth (decreased fetal weight, delayed ossification) when administered on days 6–10. 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 while receiving treatment with Eloxatin.

Precautions

General

Eloxatin 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.

Neuropathy

Patients with Stage II or III Colon Cancer

Neuropathy was graded using a prelisted module derived from the Neuro-Sensory section of the NCI CTC scale version 1, as follows:

Table 12 - NCI CTC Grading for Neuropathy in Adjuvant Patients
NCI 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 Eloxatin 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=39.6%, Grade 2=15.7%, Grade 3=5.0%) peripheral sensory neuropathy decreasing to 39% at 6 months follow-up (Grade 1=30.5%, Grade 2=7.4%, Grade 3=1.3%) and 21% at 18 months of follow-up (Grade 1=17.2%, Grade 2=3.0%, Grade 3=0.5%).

Previously Untreated and Previously Treated Patients with Advanced Colorectal Cancer

Neuropathy was graded using a study-specific neurotoxicity scale, which was different than the National Cancer Institute Common Toxicity Criteria, Version 2.0 (NCI CTC) (see below).

In the previously treated study, neuropathy information was collected to establish that Eloxatin 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 Eloxatin with 5-FU/LV. In any individual cycle acute neurotoxicity was observed in approximately 30% of patients. Ice (mucositis prophylaxis) should be avoided during the infusion of Eloxatin because cold temperature can exacerbate acute neurological symptoms (see DOSAGE AND ADMINISTRATION: Dose Modifications).

    An acute syndrome of pharyngolaryngeal dysesthesia seen in 1–2% (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).

  • 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 Eloxatin with 5-FU/LV. 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 Eloxatin.

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.

Neurotoxicity scale

The grading scale for paresthesias/dysesthesias was: 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.

Pulmonary Toxicity

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% (any grade) and <1% (grade 3) with no grade 4 events in the Eloxatin plus infusional 5-FU/LV arm compared to 4.5% (any grade) and no grade 3 and 0.1% grade 4 events in the infusional 5-FU/LV alone arm in adjuvant colon cancer patients. In this study, one patient died from eosinophilic pneumonia in the Eloxatin combination arm. The combined incidence of cough, dyspnea and hypoxia was 43% (any grade) and 7% (grade 3 and 4) in the Eloxatin plus 5-FU/LV arm compared to 32% (any grade) and 5% (grade 3 and 4) in the irinotecan plus 5-FU/LV 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, Eloxatin should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.

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 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, should be investigated in case of abnormal liver function test results or portal hypertension, which cannot be explained by liver metastases.

Information for Patients

Patients and patients" caregivers should be informed of the expected side effects of Eloxatin, 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. Patients should be instructed to avoid cold drinks, use of ice, and should cover exposed skin prior to exposure to cold temperature or cold objects.

Patients must be adequately informed of the risk of low blood cell counts and instructed to contact their physician immediately should fever, particularly if associated with persistent diarrhea, or evidence of infection develop.

Patients should be instructed to contact their physician if persistent vomiting, diarrhea, signs of dehydration, cough or breathing difficulties occur, or signs of allergic reaction appear.

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 Eloxatin cycle (see DOSAGE AND ADMINISTRATION).

Laboratory Test Interactions

None known.

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 x 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.

Pregnancy Category D - See WARNINGS

Nursing Mothers

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

Pediatric Use

The safety and effectiveness of Eloxatin in pediatric patients have not been established.

Patients with Renal Impairment

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 (see CLINICAL PHARMACOLOGY and ADVERSE REACTIONS).

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) 723 patients treated with Eloxatin and infusional 5-FU/LV were < 65 years and 400 patients were ≥ 65 years. In the previously untreated for advanced colorectal cancer randomized clinical trial (see CLINICAL STUDIES) of Eloxatin, 160 patients treated with Eloxatin and 5-FU/LV 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 randomized clinical trial (see CLINICAL STUDIES) of Eloxatin, 95 patients treated with Eloxatin and 5-FU/LV were < 65 years and 55 patients were ≥65 years. The rates of overall adverse events, 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.

Drug Interactions

No specific cytochrome P-450-based drug interaction studies have been conducted. No pharmacokinetic interaction between 85 mg/m2 Eloxatin and 5-FU/LV has been observed in patients treated every 2 weeks. Increases of 5-FU plasma concentrations by approximately 20% have been observed with doses of 130 mg/m2 Eloxatin dosed every 3 weeks. Since 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).

Adverse Reactions

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 Eloxatin either as a single agent or in combination with other medications. 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 PRECAUTIONS).

Combination Adjuvant Therapy with Eloxatin and infusional 5-FU/LV in Patients with Stage II or III Colon Cancer

One thousand one hundred and eight patients with stage II or III colon cancer, who had undergone complete resection of the primary tumor, have been treated in a clinical study with Eloxatin in combination with infusional 5-FU/LV (See CLINICAL STUDIES). The incidence of grade 3 or 4 adverse events was 70% on the Eloxatin combination arm, and 31% on the infusional 5-FU/LV arm. The adverse reactions in this trial are shown in the tables below. Discontinuation of treatment due to adverse events occurred in 15% of the patients receiving Eloxatin and infusional 5-FU/LV. Both 5-FU/LV and Eloxatin are associated with gastrointestinal or hematologic adverse events. When Eloxatin is administered in combination with infusional 5-FU/LV, the incidence of these events is increased.

The incidence of death within 28 days of last treatment, regardless of causality, was 0.5% (n=6) in both the Eloxatin combination and infusional 5-FU/LV arms, respectively. Deaths within 60 days from initiation of therapy were 0.3% (n=3) in both the Eloxatin combination and infusional 5-FU/LV arms, respectively. On the Eloxatin combination arm, 3 deaths were due to sepsis/neutropenic sepsis, 2 from intracerebral bleeding and one from eosinophilic pneumonia. On the 5-FU/LV arm, one death was due to suicide, 2 from Steven-Johnson Syndrome (1 patient also had sepsis), 1 unknown cause, 1 anoxic cerebral infarction and 1 probable abdominal aorta rupture.

The following table provides adverse events reported in the adjuvant therapy colon cancer clinical trial (see CLINICAL STUDIES) by body system and decreasing order of frequency in the Eloxatin and infusional 5-FU/LV arm for events with overall incidences ≥ 5% and for NCI grade 3/4 events with incidences ≥ 1%. This table does not include hematologic and blood chemistry abnormalities; these are shown separately below.

Table 13 - Adverse Experiences Reported in Patients with Stage II or III Colon Cancer receiving Adjuvant Treatment (≥5% of all patients and with ≥1% NCI Grade 3/4 events)
Eloxatin + 5-FU/LV
N=1108
5-FU/LV
N=1111
Adverse Event (WHO/Pref) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%)
*
Includes thrombosis related to the catheter
Any Event 100 70 99 31
Allergy/Immunology
Allergic Reaction 10 3 2 <1
Constitutional Symptoms/Pain
Fatigue 44 4 38 1
Abdominal Pain 18 1 17 2
Dermatology/Skin
Skin Disorder 32 2 36 2
Injection Site Reaction* 11 3 10 3
Gastrointestinal
Nausea


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