AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Oxaliplatin

Chemical Name:

• [ SP -4-2-(1 R -trans)]-(1,2-cyclohexanediamine- N , N ')[ethanedioato(2-)- O , O ']platinum

Molecular Formula:

• C₈H₁₄N₂O₄Pt

Oxaliplatin is a platinum-containing antineoplastic agent.1,  2

Colorectal Cancer

Oxaliplatin, in combination with fluorouracil and leucovorin, is used as adjuvant therapy for stage III cancer of the colon in patients who have undergone complete resection of the primary tumor.1,  9,  10 Oxaliplatin also is used in combination with fluorouracil and leucovorin in the treatment of advanced cancer of the colon and rectum.1

Oxaliplatin also has been used in combination with capecitabine† (a prodrug of fluorouracil) as adjuvant therapy following the complete resection of the primary tumor in patients with stage III colon cancer.10001,  10002,  10003,  10008,  10011,  10012,  10013,  10014,  10015,  10016

Adjuvant Therapy for Stage III Colon Cancer

Oxaliplatin in Combination with Fluorouracil and Leucovorin

Oxaliplatin, in combination with fluorouracil and leucovorin, is used as adjuvant therapy for stage III cancer of the colon in patients who have undergone complete resection of the primary tumor.1,  9,  10 This indication is based on survival benefit observed with the combination of oxaliplatin, fluorouracil, and leucovorin compared with the combination of fluorouracil and leucovorin.1,  9,  10

Use of oxaliplatin, in combination with fluorouracil and leucovorin, as adjuvant therapy for stage III colon cancer is based principally on evidence of improved disease-free and overall survival from a multicenter, open-label, randomized study (Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer [MOSAIC]) in 2246 patients with stage II or III colon cancer who had undergone complete resection of the primary tumor.1,  9,  10 Eligible patients were randomized to receive a 2-day combination regimen of oxaliplatin, fluorouracil, and leucovorin (leucovorin 200 mg/m² administered by IV infusion over 2 hours, followed by fluorouracil 400 mg/m² administered by IV injection and fluorouracil 600 mg/m² administered by IV infusion over 22 hours, administered for 2 consecutive days; oxaliplatin 85 mg/m² was administered by IV infusion over 2 hours concurrently with leucovorin on the first day only) or a 2-day combination regimen of fluorouracil and leucovorin (leucovorin 200 mg/m² administered by IV infusion over 2 hours, followed by fluorouracil 400 mg/m² administered by IV injection and fluorouracil 600 mg/m² administered by IV infusion over 22 hours).1,  9 Treatment with both regimens was repeated at intervals of 2 weeks for a total of 12 cycles.1,  9

Among patients with stage III colon cancer, treatment with the oxaliplatin/fluorouracil/leucovorin regimen was associated with higher rates of disease-free survival at 5 years and overall survival at 6 years (66 and 73%, respectively) compared with the fluorouracil/leucovorin regimen (59 and 69%, respectively).1,  10 At a median follow-up of 9.5 years, the disease-free and overall survival benefit of oxaliplatin/fluorouracil/leucovorin in patients with stage III colon cancer was maintained (10-year disease-free and overall survival rates of 62 and 67%, respectively, with oxaliplatin/fluorouracil/leucovorin compared with 54 and 59%, respectively, with fluorouracil/leucovorin).23 Among patients with stage II disease, 5-year disease-free survival rates and 6-year overall survival rates with the 2 regimens were similar.1,  10 Likewise, 10-year disease-free and overall survival rates failed to show a benefit for oxaliplatin/fluorouracil/leucovorin compared with fluorouracil/leucovorin in patients with stage II disease.23 Grade 3 and 4 hematologic toxicity (neutropenia, thrombocytopenia, anemia) occurred more commonly with oxaliplatin/fluorouracil/leucovorin than with fluorouracil/leucovorin, although the incidence of febrile neutropenia was low with both regimens.1,  9 Grade 3 and 4 GI toxicity (nausea, vomiting, diarrhea) also occurred more commonly with oxaliplatin/fluorouracil/leucovorin.1,  9 Peripheral sensory neuropathy was reported in 92% of patients receiving oxaliplatin/fluorouracil/leucovorin compared with 16% of those receiving fluorouracil/leucovorin (see Neuropathy under Warnings/Precautions: Other Warnings and Precautions, in Cautions).1,  9

Oxaliplatin and Capecitabine

Efficacy and safety of oxaliplatin in combination with capecitabine† (CapeOx, CapOx, XELOX) as adjuvant therapy in patients with stage III colon cancer have been evaluated in an open-label, randomized phase 3 study (NO16968; XELOXA).10001 In this study, 1886 patients were randomized to receive either combination therapy with oxaliplatin (130 mg/m² administered by IV infusion over 2 hours on day 1) and capecitabine (1 g/m² administered orally twice daily on days 1-14) on a 3-week cycle for 8 cycles or combination therapy with IV fluorouracil and leucovorin (Mayo Clinic or Roswell Park regimen).10001 The Mayo Clinic regimen consisted of fluorouracil 425 mg/m² administered by rapid IV injection (“bolus”) and leucovorin 20 mg/m² administered by rapid IV infusion on days 1-5 of each 4-week cycle for a total of 6 cycles (24 weeks), and the Roswell Park regimen consisted of fluorouracil 500 mg/m² administered by rapid IV injection (“bolus”) and leucovorin 500 mg/m² administered as a 2-hour IV infusion on day 1 of weeks 1-6 of each 8-week cycle for a total of 4 cycles (32 weeks).10003 Patients were enrolled no more than 8 weeks following surgery with curative intent, by which time full recovery from surgery was required.10001 The median age of patients was 61-62 years.10001 Most patients (99%) enrolled in the study had a baseline ECOG performance status of 0 or 1.10001 The primary measure of efficacy was disease-free survival.10001

At a median follow-up of 74 months, patients who received oxaliplatin in combination with capecitabine had higher disease-free (66.1 versus 59.8%; hazard ratio: 0.8) and relapse-free (69.3 versus 62.2%; hazard ratio: 0.78) survival rates compared with patients who received fluorouracil and leucovorin.10002 At a median follow-up of 83 months, patients who received oxaliplatin in combination with capecitabine also had a higher overall survival rate (74.4 versus 69.6%; hazard ratio: 0.83) compared with those who received fluorouracil and leucovorin.10002 Subgroup analysis based on prognostic factors (e.g., age, regional lymph node involvement, baseline carcinoembryonic antigen [CEA] concentration) suggested that the effect of capecitabine in combination with oxaliplatin on disease-free and overall survival was consistent across the subgroups, including those 70 years of age or older; however, the effect size appeared to be reduced in patients 70 years of age or older compared with younger patients.10002 Neurosensory toxicity (any grade: 78 versus 8%; grade 3 or 4: 11 versus less than 1%), grade 3 or 4 hand-foot syndrome (5 versus less than 1%), and grade 3 or 4 thrombocytopenia (5% versus less than 1%) occurred more frequently in patients receiving oxaliplatin in combination with capecitabine, while grade 3 or 4 neutropenia (9 versus 16%), febrile neutropenia (less than 1 versus 4%), and stomatitis (less than 1 versus 9%) occurred more frequently in those receiving fluorouracil and leucovorin.10001,  10003

Use of combination therapy with oxaliplatin and capecitabine also was investigated in a randomized, multicenter, phase 3 study in patients with high-risk stage II or stage III colorectal cancer who had undergone complete resection of the primary tumor; however, interpretation of the results is limited by the failure to meet the planned accrual of 800 patients in the study to demonstrate superiority.10006 In this study, 408 patients were randomized to receive either combination therapy with oxaliplatin (130 mg/m² on day 1) and capecitabine (1 g/m² twice daily on days 1-14) on a 3-week cycle for 8 cycles or combination therapy with an oxaliplatin, fluorouracil, and leucovorin (modified FOLFOX6) regimen on a 2-week cycle for 12 cycles.10006 At a median follow-up of 74.7 months, median disease-free and overall survival had not been reached; however, 3-year disease-free and overall survival rates were similar between patients receiving capecitabine in combination with oxaliplatin (79.5 and 86.9%, respectively) compared with patients receiving modified FOLFOX6 (79.8 and 87.2%, respectively).10006

Because the duration and severity of peripheral neuropathy appear to increase with increasing cumulative dosage of oxaliplatin,10009 the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration pooled data from 6 similarly designed prospective, randomized controlled phase 3 studies (Cancer and Leukemia Group B/Southwest Oncology Group [CALGB/SWOG] study 80702, Short Course Oncology Treatment [SCOT], Adjuvant Chemotherapy for Colon Cancer with High Evidence [ACHIEVE], Three or Six Colon Adjuvant [TOSCA], Hellenic Oncology Research Group [HORG], IDEA France)10010,  10011,  10012,  10013,  10014,  10015 to evaluate noninferiority of a shortened duration (i.e., 3 months) of adjuvant fluoropyrimidine-oxaliplatin doublet therapy compared to the standard duration of 6 months in patients with stage II or III colon cancer.10008 In this pooled analysis, 12,834 patients with stage III colon cancer received fluoropyrimidine-oxaliplatin doublet therapy with FOLFOX (i.e., FOLFOX4, modified FOLFOX6) or capecitabine in combination with oxaliplatin for 3 or 6 months; however, trials conducted in the US and Canada allowed only the use of modified FOLFOX6.10008,  10016 Subgroup analysis of the IDEA collaboration demonstrated noninferiority of a shorter duration (i.e., 3 months) of capecitabine in combination with oxaliplatin (particularly in those with low-risk stage III disease [T1-T3 and N1]) and less toxicity compared with 6 months of therapy.10009,  10017 (See Duration of Adjuvant Therapy under Colorectal Cancer: Adjuvant Therapy for Stage III Colon Cancer, in Uses.)

Based on current evidence, combination therapy with oxaliplatin and capecitabine is a reasonable choice (accepted, treatment option) for use as adjuvant therapy in patients with stage III colon cancer who have undergone complete resection of the primary tumor.10007,  10018 Although the standard duration of adjuvant capecitabine in combination with oxaliplatin has been 6 months, subgroup analysis of the IDEA collaboration demonstrated noninferiority of a shorter duration (i.e., 3 months) of capecitabine in combination with oxaliplatin, particularly in those with low-risk stage III disease (T1-T3 and N1), and less toxicity compared with 6 months of therapy.10009,  10017 Some clinicians state that factors that should be considered when selecting the duration of adjuvant fluoropyrimidine-oxaliplatin doublet therapy, such as capecitabine in combination with oxaliplatin, include tolerability, patient preference, patient characteristics, preexisting conditions, and other factors.10009

Duration of Adjuvant Therapy

In a pooled analysis (IDEA collaboration) of 6 similarly designed prospective randomized controlled phase 3 studies evaluating noninferiority of a shortened duration (i.e., 3 months) of adjuvant fluoropyrimidine-oxaliplatin doublet therapy compared to the standard duration of 6 months in patients with stage II or III colon cancer,10008 12,834 patients with stage III colon cancer received fluoropyrimidine-oxaliplatin doublet therapy with FOLFOX (i.e., FOLFOX4, modified FOLFOX6) or capecitabine in combination with oxaliplatin for 3 or 6 months.10008,  10016 At the time of the initial analysis (median follow-up of 41.8 months), fluoropyrimidine-oxaliplatin doublet therapy for a duration of 3 months did not meet the noninferiority criterion for 3- or 5-year disease-free survival when compared to a duration of 6 months.10008,  10017 However, in patients treated with capecitabine in combination with oxaliplatin, 3 months of therapy appeared to be at least equivalent to a treatment duration of 6 months, particularly in patients with low-risk disease.10008 In patients treated with FOLFOX, 6 months of therapy appeared to be superior to the shorter treatment duration of 3 months.10008 (See Tables 1, 2, and 3.) Grade 3 or 4 neurosensory toxicity was substantially lower in patients receiving 3 months of fluoropyrimidine-oxaliplatin doublet therapy compared with those receiving 6 months of therapy (2.5-2.6 versus 8.9-15.9%, respectively).10008 Although the standard duration of adjuvant fluoropyrimidine-oxaliplatin doublet therapy has been 6 months, a shorter duration of therapy may be considered in certain patients based on these data.10008,  10009,  10017 Some clinicians state that factors that should be considered when selecting the duration of adjuvant fluoropyrimidine-oxaliplatin doublet therapy include tolerability, patient preference, patient characteristics, preexisting conditions, and other factors.10009

Treatment of Advanced Colorectal Cancer

Oxaliplatin, in combination with fluorouracil and leucovorin, is used in the treatment of advanced cancer of the colon and rectum.1 The combination regimen has been studied as first-line therapy for unresectable cancer of the colon or rectum1,  11 and also as second-line therapy in patients whose disease has recurred or progressed during or within 6 months following first-line therapy with the combination of fluorouracil, leucovorin, and irinotecan.1

Previously Untreated Advanced Colorectal Cancer

Use of oxaliplatin, in combination with fluorouracil and leucovorin, as first-line therapy for advanced colorectal cancer is based principally on evidence of improved response and survival from a multicenter, open-label, randomized study conducted by the North Central Cancer Treatment Group (NCCTG N9741) in patients with previously untreated unresectable colorectal cancer.1,  11 The oxaliplatin/fluorouracil/leucovorin regimen was compared with 2 other regimens (oxaliplatin plus irinotecan and the combination of irinotecan, fluorouracil, and leucovorin) in 795 concurrently randomized patients with previously untreated unresectable colorectal cancer.1,  11

In this study, the oxaliplatin/fluorouracil/leucovorin combination was administered as a 2-day regimen (leucovorin 200 mg/m² administered by IV infusion over 2 hours, followed by fluorouracil 400 mg/m² administered by IV injection and fluorouracil 600 mg/m² administered by IV infusion over 22 hours, administered for 2 consecutive days; oxaliplatin 85 mg/m² was administered by IV infusion over 2 hours concurrently with leucovorin on the first day only); therapy was repeated at intervals of 2 weeks.1,  11 The irinotecan/oxaliplatin regimen consisted of oxaliplatin 85 mg/m² and irinotecan 200 mg/m², both administered by IV infusion on day 1 and repeated at 3-week intervals.1,  11 The irinotecan/fluorouracil/leucovorin regimen consisted of irinotecan 125 mg/m² administered by IV infusion, fluorouracil 500 mg/m² administered by IV injection, and leucovorin 20 mg/m² administered by IV injection on days 1, 8, 15, and 22 and repeated at 6-week intervals.1,  11

Overall response rates were higher with oxaliplatin/fluorouracil/leucovorin therapy (45%) compared with irinotecan/fluorouracil/leucovorin (31%) or irinotecan/oxaliplatin (35%) therapy.11 The median time to disease progression was similar with the irinotecan/oxaliplatin (6.5 months) and irinotecan/fluorouracil/leucovorin (6.9 months) regimens, but was longer (8.7 months) with the oxaliplatin/fluorouracil/leucovorin regimen.11 Median overall survival of patients receiving oxaliplatin/fluorouracil/leucovorin therapy (19.5 months) was longer than that of patients receiving irinotecan/fluorouracil/leucovorin therapy (15 months) but did not differ from that of patients receiving irinotecan/oxaliplatin (17.4 months).11 Grade 3 and 4 GI toxicity (nausea, vomiting, diarrhea) and febrile neutropenia were more commonly associated with the irinotecan-containing regimens, whereas grade 3 and 4 paresthesias were more commonly associated with the oxaliplatin/fluorouracil/leucovorin regimen.1,  11

Previously Treated Advanced Colorectal Cancer

Use of oxaliplatin, in combination with fluorouracil and leucovorin, as second-line therapy for advanced colorectal cancer is based principally on response rate and an interim analysis showing improved time to radiographic progression of the disease in a multicenter, randomized, open-label, controlled study in over 450 patients (of more than 800 patients enrolled) with advanced colorectal cancer that had recurred or progressed during or within 6 months following first-line therapy with the combination of fluorouracil, leucovorin, and irinotecan.1 There currently are no data demonstrating a clinical benefit (e.g., improvement in disease-related symptoms, increased survival).1

In this study, eligible patients with unresectable, measurable, and histologically proven disease were randomized to receive oxaliplatin alone (85 mg/m² administered by IV infusion over 2 hours), a 2-day combination regimen of fluorouracil and leucovorin (leucovorin 200 mg/m² administered by IV infusion over 2 hours, followed by fluorouracil 400 mg/m² administered by IV injection and fluorouracil 600 mg/m² administered by IV infusion over 22 hours), or a 2-day combination regimen of oxaliplatin, fluorouracil, and leucovorin (leucovorin 200 mg/m² administered by IV infusion over 2 hours, followed by fluorouracil 400 mg/m² administered by IV injection and fluorouracil 600 mg/m² administered by IV infusion over 22 hours, administered for 2 consecutive days; oxaliplatin 85 mg/m² was administered by IV infusion over 2 hours concurrently with leucovorin on the first day only).1 Therapy was repeated at intervals of 2 weeks until radiographic progression, toxicity, or 13 months since the first dose had elapsed, whichever occurred first.1,  7 Patients randomized to receive oxaliplatin monotherapy or fluorouracil/leucovorin received a median of 3 cycles, while those randomized to receive oxaliplatin/fluorouracil/leucovorin received a median of 6 cycles.1

Partial response rates were higher in patients receiving oxaliplatin/fluorouracil/leucovorin (9%) than in those who received oxaliplatin monotherapy (1%) or fluorouracil/leucovorin (0%).1 There were no complete responses in any group.1,  7 In addition, the median time to radiographic disease progression was longer in patients receiving oxaliplatin/fluorouracil/leucovorin (4.6 months) than in those who received oxaliplatin alone (1.6 months) or fluorouracil/leucovorin (2.7 months).1,  7

Reconstitution and Administration

Oxaliplatin is administered by IV infusion over 2 hours.1,  24 Commercially available oxaliplatin powder for injection must be reconstituted and diluted prior to administration; the commercially available concentrate for injection must be diluted prior to administration.1,  24 Reconstitution or final dilution of the drug must never be performed with a sodium chloride solution or other chloride-containing solutions.1,  24 Because aluminum has been reported to cause degradation of platinum compounds (see Chemistry and Stability, in Cisplatin 10:00), the manufacturers state that needles or IV administration sets containing aluminum parts should not be used for the reconstitution or dilution of oxaliplatin.1,  24

Oxaliplatin sterile powder for injection is reconstituted by adding 10 mL (to the vial labeled as containing 50 mg of oxaliplatin) or 20 mL (to the vial labeled as containing 100 mg of oxaliplatin) of water for injection or 5% dextrose injection to provide a solution containing 5 mg/mL;7,  24 the reconstituted drug may be stored in the vial under refrigeration for up to 24 hours.24 Alternatively, the commercially available concentrate for injection containing oxaliplatin 5 mg/mL can be used.1 The appropriate dose should be withdrawn and diluted in 250-500 mL of 5% dextrose injection prior to administration; the diluted drug may be stored under refrigeration for up to 24 hours or at room temperature for up to 6 hours.1,  24 Oxaliplatin solutions should be inspected visually for particulate matter and/or discoloration prior to administration and should be discarded if either is present.1,  24 The commercially available concentrate for injection must be protected from light and freezing; following dilution, protection from light is not required.1 Oxaliplatin powder for injection is not sensitive to light.24

The manufacturers state that oxaliplatin solutions must not be mixed or administered simultaneously through the same IV line with alkaline drugs or media (e.g., basic solutions of fluorouracil).1,  24 The infusion line should be flushed with 5% dextrose injection prior to administration of oxaliplatin or any concomitant drug.1,  7,  24

Leucovorin is administered by IV infusion over 2 hours concurrently with oxaliplatin but in a separate container using a Y-type administration set.1,  24 The dose of fluorouracil then is administered by direct IV injection over 2-4 minutes, followed by the maintenance dose administered by IV infusion over 22 hours.1,  24 The respective manufacturer's prescribing information should be consulted for additional information on the reconstitution and administration of fluorouracil and leucovorin.1,  24

The manufacturers of oxaliplatin recommend that procedures for proper handling and disposal of antineoplastic drugs (e.g., use of gloves) be used to avoid exposure to oxaliplatin during preparation of IV solutions.1,  24 If oxaliplatin solution comes in contact with the skin or mucous membranes, the skin should be washed immediately and thoroughly with soap and water or the mucosa should be flushed with copious amounts of water.1,  24 Since oxaliplatin is an antineoplastic agent, the manufacturers state that consideration should be given to handling and disposal according to guidelines issued for cytotoxic drugs, although there is no general agreement that all of the procedures recommended in such guidelines are necessary or appropriate.1,  24 For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

General Dosage

For the treatment of colorectal cancer, an oxaliplatin dosage of 85 mg/m² is administered by IV infusion on day 1 as part of a 2-day combination regimen that includes fluorouracil and leucovorin.1 The 2-day regimen may be repeated at intervals of 2 weeks.1 Because this regimen may be associated with an increased incidence of grade 3 or 4 nausea and vomiting compared with the combination regimen containing only fluorouracil and leucovorin, the manufacturer of oxaliplatin states that premedication with antiemetics, including selective inhibitors of type 3 serotonergic (5-HT₃) receptors (e.g., dolasetron, granisetron, ondansetron) with or without dexamethasone, should be considered prior to each 2-day cycle.1 According to the manufacturer, hydration prior to administration of oxaliplatin is not necessary.1

The combination regimen of oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) is administered over 2 consecutive days.1,  9 On day 1, oxaliplatin 85 mg/m² and leucovorin 200 mg/m² (diluted with 5% dextrose injection) are administered concurrently (in separate containers using a Y-type administration set) by IV infusion over 2 hours.1 Fluorouracil 400 mg/m² then is administered by IV injection over 2-4 minutes followed by fluorouracil 600 mg/m² (diluted with 500 mL of 5% dextrose injection) administered as an IV infusion over 22 hours.1 On day 2, leucovorin 200 mg/m² is administered by IV infusion over 2 hours, followed by fluorouracil 400 mg/m² administered by IV injection over 2-4 minutes and fluorouracil 600 mg/m² administered as an IV infusion over 22 hours.1 When this regimen is used as adjuvant therapy for stage III colon cancer, a total of 12 cycles (6 months) of therapy is recommended.1,  9 In patients with advanced colorectal cancer, treatment with the regimen is recommended until evidence of disease progression or unacceptable toxicity occurs.1,  11

An alternative regimen of oxaliplatin, fluorouracil, and leucovorin (i.e., modified FOLFOX6) also has been used for treatment of advanced colorectal cancer and for adjuvant therapy of colon cancer.12 The modified FOLFOX6 regimen is administered over 2 consecutive days.12 Oxaliplatin 85 mg/m² and leucovorin 400 mg/m² (or, alternatively, leucovorin 350 mg) (diluted with 5% dextrose injection) are administered concurrently (in separate containers using a Y-type administration set) by IV infusion over 2 hours.12 Fluorouracil 400 mg/m² then is administered by IV injection over 5 minutes followed by fluorouracil 1200 mg/m² administered as an IV infusion daily for 2 days (i.e., 2400 mg/m² administered as an IV infusion over 46-48 hours [total fluorouracil dosage of 2800 mg/m² per cycle]).12 Clinicians should consult individual protocols for specific dosage information.12

When oxaliplatin has been used in combination with capecitabine† (CapeOx, CapOx, XELOX) as adjuvant therapy following the complete resection of the primary tumor in patients with stage III colon cancer, oxaliplatin 130 mg/m² has been administered by IV infusion over 2 hours on day 1 and capecitabine 1 g/m² has been administered orally twice daily on days 1-14 of each 3-week cycle.10001,  10006 Treatment has been continued for 4 or 8 cycles of therapy; however, 4 cycles (for a treatment duration of 3 months) of capecitabine in combination with oxaliplatin has been shown to have comparable efficacy and less toxicity than 8 cycles of therapy (for a treatment duration of 6 months).10001,  10006,  10008,  10016,  10017

Dose Modification for Toxicity

The management of certain adverse effects (e.g., neurosensory effects, GI or hematologic toxicity) may require modification of oxaliplatin dosage or duration of infusion.1 Increasing the duration of oxaliplatin infusion from 2 to 6 hours may minimize acute toxicities; adjustment of infusion duration for fluorouracil or leucovorin is not necessary.1

Oxaliplatin should be permanently discontinued in patients experiencing a hypersensitivity reaction, posterior reversible encephalopathy syndrome (PRES), interstitial lung disease, pulmonary fibrosis, or rhabdomyolysis.1

Adjuvant Therapy for Stage III Colon Cancer

If persistent grade 2 peripheral sensory neuropathy occurs in patients receiving oxaliplatin in the adjuvant setting for the treatment of stage III colon cancer, reduction of oxaliplatin dosage to 75 mg/m² should be considered; in those with persistent grade 3 peripheral sensory neuropathy, discontinuance of oxaliplatin should be considered.1 If grade 4 peripheral sensory neuropathy occurs, oxaliplatin should be discontinued.1

If grade 3 or 4 thrombocytopenia, grade 4 neutropenia, or febrile neutropenia occurs in patients receiving oxaliplatin in the adjuvant setting for the treatment of stage III colon cancer, administration of the next dose of oxaliplatin should be delayed until neutrophil count reaches or exceeds 1500/mm³ and platelet count reaches or exceeds 75,000/mm³; oxaliplatin may then be resumed at a reduced dosage of 75 mg/m².1

If grade 3 or 4 GI toxicity occurs in patients receiving oxaliplatin in the adjuvant setting for the treatment of stage III colon cancer, oxaliplatin therapy should be withheld.1 When GI toxicity resolves, oxaliplatin may be resumed at a reduced dosage of 75 mg/m²; the dosage of fluorouracil should be reduced to 300 mg/m² by IV injection over 2-4 minutes and 500 mg/m² by IV infusion over 22 hours.1

Therapy for Advanced Colorectal Cancer

If persistent grade 2 adverse neurosensory effects occur in patients with advanced colorectal cancer, reduction of oxaliplatin dosage to 65 mg/m² should be considered; in those with persistent grade 3 neurosensory effects, discontinuance of oxaliplatin should be considered.1 If grade 4 peripheral sensory neuropathy occurs, oxaliplatin should be discontinued.1

If grade 3 or 4 thrombocytopenia, grade 4 neutropenia, or febrile neutropenia occurs in patients with advanced colorectal cancer, administration of the next dose of oxaliplatin should be delayed until neutrophil count reaches or exceeds 1500/mm³ and platelet count reaches or exceeds 75,000/mm³; oxaliplatin may then be resumed at a reduced dosage of 65 mg/m².1

If grade 3 or 4 GI toxicity occurs in patients with advanced colorectal cancer, oxaliplatin therapy should be withheld.1 When GI toxicity resolves, oxaliplatin may be resumed at a reduced dosage of 65 mg/m²; the dosage of fluorouracil should be reduced to 300 mg/m² by IV injection over 2-4 minutes and 500 mg/m² by IV infusion over 22 hours.1

Special Populations

Renal Impairment

For patients with severe renal impairment (creatinine clearance less than 30 mL/minute), the oxaliplatin dosage should be reduced to 65 mg/m².1

No initial dosage adjustment is necessary in patients with mild (creatinine clearance 50-79 mL/minute) or moderate (creatinine clearance 30-49 mL/minute) renal impairment.1

Contraindications

History of hypersensitivity reactions to oxaliplatin, any ingredient in the formulation, or other platinum-containing compounds. 1,  7

Warnings/Precautions

Warnings

Hypersensitivity Reactions

Serious and fatal hypersensitivity reactions may occur within minutes of administration of oxaliplatin and during any cycle.1 Grade 3 or 4 hypersensitivity reactions, including anaphylaxis, have been reported in 2-3% of patients with colon cancer receiving oxaliplatin.1,  24 These hypersensitivity reactions (e.g., rash, urticaria, erythema, pruritus, bronchospasm, hypotension) are similar in nature and severity to those associated with other platinum-containing antineoplastic agents.1 If hypersensitivity reactions occur, the drug should be immediately and permanently discontinued and appropriate treatment should be initiated.1

Other Warnings and Precautions

Because the oxaliplatin therapeutic regimen includes the use of fluorouracil and leucovorin, the usual cautions, precautions, and contraindications of these drugs also should be considered.7

Neuropathy

Treatment with oxaliplatin is consistently associated with acute or delayed neuropathy, both of which are principally peripheral neuropathies.1,  2 The duration and severity of peripheral neuropathy appear to increase with increasing cumulative dosage of oxaliplatin.2,  7 Peripheral sensory neuropathy occurred in 92% of patients receiving the combination of oxaliplatin, fluorouracil, and leucovorin as adjuvant therapy for colon cancer; grade 3 events occurred in 12% of patients.1,  10 In patients with advanced colorectal cancer, peripheral sensory neuropathy occurred in 82 or 74% of patients receiving the oxaliplatin/fluorouracil/leucovorin regimen as first- or second-line therapy, respectively; grade 3 or 4 events occurred in 19% of those receiving the regimen as first-line therapy and 7% of those receiving the regimen as second-line therapy. 1,  11 The median onset of grade 3 peripheral sensory neuropathy was cycle 9 of adjuvant therapy and cycle 6 of second-line therapy.1

Acute , reversible sensory neuropathy that is principally peripheral has been reported in 56% of patients receiving oxaliplatin/fluorouracil/leucovorin therapy; acute neurotoxicity has been reported in approximately 30% of patients during an individual treatment cycle.1 Grade 3 or 4 acute neuropathy occurred in 2% of patients receiving the oxaliplatin/fluorouracil/leucovorin regimen as second-line therapy for advanced colorectal cancer.1 In the adjuvant setting, 12% of patients experienced grade 3 peripheral neuropathy during treatment.10 Differences among studies in the reporting of oxaliplatin-associated neuropathy reflect the use of different grading scales.1,  10,  11 In studies in patients with advanced colorectal cancer, neuropathy was graded using a study-specific scale (range of 1-4) for characterizing paresthesias and dysesthesias;1,  11 in the study of adjuvant therapy, the National Cancer Institute Common Toxicity Criteria (NCI-CTC Version 2.0) scale for grading neuropathy (applicable range of 0-3) was used.1,  10

Manifestations of acute peripheral neuropathy include transient paresthesia,1,  3 dysesthesia,1,  3 and hypoesthesia in the hands, feet, perioral area, or throat; jaw spasm, abnormal tongue sensation, dysarthria, ocular pain, and a feeling of chest pressure also have been observed.1 These symptoms may occur within hours1,  2 or 2 days following administration of oxaliplatin, resolve within 14 days, and frequently recur with further administration of the drug.1 Because symptoms of acute sensory neuropathy may be precipitated or exacerbated by exposure to cold temperature or cold objects,1,  2 patients should be advised to refrain from ingesting cold beverages or food, to avoid exposure to cold temperatures, and to use gloves when handling cold or frozen objects; the manufacturer states that ice (e.g., for mucositis prophylaxis) should be avoided during infusion of oxaliplatin.1 (See Advice to Patients.)

An acute syndrome of pharyngolaryngeal dysesthesia (grade 3 or 4),1,  3 characterized by subjective sensations of dysphagia or dyspnea without laryngospasm or bronchospasm (i.e., no stridor or wheezing), has been reported in 1-2% of patients with previously untreated advanced colorectal cancer receiving oxaliplatin in clinical studies;1 symptoms usually resolve within hours of onset.2,  7 Some evidence indicates that prolonging the duration of oxaliplatin infusion may reduce the incidence of laryngopharyngeal dysesthesia.2,  7

Delayed sensory neuropathy that is principally peripheral has been reported in 48% of patients receiving oxaliplatin/fluorouracil/leucovorin therapy.1 Symptoms of delayed neuropathy usually include paresthesias, dysesthesias, and hypoesthesias; however, impaired proprioception, which can interfere with daily activities (e.g., writing, buttoning clothing, swallowing, walking), also has been observed.1,  2 Delayed neuropathy can occur without any prior acute neuropathic event and typically persists for more than 14 days following administration of oxaliplatin.1 Approximately 80% of patients who developed grade 3 persistent neuropathy during clinical studies had progressed from prior grade 1 or 2 neuropathic events.1 Symptoms of persistent neuropathy may improve in some patients upon discontinuance of oxaliplatin.1 Long-term follow-up of patients receiving adjuvant therapy with the oxaliplatin/fluorouracil/leucovorin regimen indicated that the incidence of peripheral sensory neuropathy after completion of such therapy was 39% at 6 months with a decline to 21% at 18 months;1 the incidence of grade 3 neurotoxicity was 1% at 6 and 18 months and 0.7% at 48 months.1,  10 Grade 3 or 4 neuropathy occurred in 7% of patients receiving the oxaliplatin/fluorouracil/leucovorin regimen as second-line therapy for advanced colorectal cancer.1

Preventive strategies, including the use of intermittent oxaliplatin regimens (i.e., “stop and go” schedule) and other potential neuromodulatory regimens (e.g., amifostine, carbamazepine, gabapentin, glutathione), have been evaluated to reduce the incidence and severity of oxaliplatin-induced neurotoxicity; however, due to the lack of adequate data from well-conducted clinical trials, there is insufficient evidence to support the use of any preventive therapy.14 In a retrospective cohort study in patients with advanced colorectal cancer, the incidence of grade 3 distal paresthesias was lower in those who received IV infusions of calcium gluconate and magnesium sulfate (immediately before and after infusions of oxaliplatin) compared with those who did not receive such infusions (7 versus 26%).15 Calcium gluconate and magnesium sulfate infusions are being evaluated in randomized, double-blind, placebo-controlled studies in patients receiving oxaliplatin/fluorouracil/leucovorin-based regimens for colorectal cancer.16,  17,  18 Preliminary data from one of these studies suggest a reduction in neurotoxicity in patients receiving prophylactic calcium and magnesium therapy;16 however, data from another study suggested that addition of calcium and magnesium to the chemotherapy regimen had a negative effect on clinical response and antitumor activity.18 Additional data are needed to define the role of prophylactic calcium and magnesium therapy in reducing the severity and duration of acute and chronic oxaliplatin-induced neurotoxicity and to confirm the effects, if any, of such therapy on clinical response to oxaliplatin-based regimens used in the treatment of colorectal cancer.17,  19,  20

Hematologic Effects

Grade 3 or 4 neutropenia occurred in 41 or 44%, respectively, of patients receiving oxaliplatin/fluorouracil/leucovorin therapy for colorectal cancer.1 Febrile neutropenia or documented infection with severe neutropenia occurred in 1.8% of patients receiving this adjuvant regimen.1 Among patients with advanced colorectal cancer, febrile neutropenia occurred in 4 or 6% of those receiving oxaliplatin/fluorouracil/leucovorin as first- or second-line therapy, respectively, and neutropenia with infection occurred in 8% of those receiving first-line oxaliplatin/fluorouracil/leucovorin therapy.1 Sepsis, neutropenic sepsis, and septic shock, sometimes fatal, also have been reported in patients receiving oxaliplatin/fluorouracil/leucovorin therapy for colorectal cancer.1

Grade 3 or 4 thrombocytopenia occurred in 2-5% of patients receiving oxaliplatin/fluorouracil/leucovorin therapy for colorectal cancer.1

Complete blood cell counts (CBCs) should be monitored at baseline, prior to each cycle of oxaliplatin, and as clinically indicated.1 The manufacturer states that oxaliplatin should not be administered until neutrophil counts reach 1500/mm³ or more and platelet counts reach 75,000/mm³ or more.1 If sepsis or septic shock occurs, oxaliplatin therapy should be withheld.1 Temporary interruption followed by dosage reduction may be necessary if neutropenia or thrombocytopenia occurs.1

Posterior Reversible Encephalopathy Syndrome

Posterior reversible encephalopathy syndrome (PRES), with or without concomitant hypertension, occurred in less than 0.1% of patients receiving oxaliplatin in clinical trials.1 Manifestations of PRES include headache, altered mental status, seizure, and visual disturbance (e.g., vision loss, blurred vision).1 If PRES is suspected, an MRI should be performed for diagnostic evaluation.1 If PRES is confirmed. therapy with oxaliplatin should be permanently discontinued.1

Pulmonary Toxicity

Pulmonary fibrosis, which may be fatal, occurred in less than 1% of patients receiving oxaliplatin in clinical trials.1,  7 In patients receiving the oxaliplatin/fluorouracil/leucovorin regimen as adjuvant therapy, the combined incidence of grade 3 cough and dyspnea was less than 1% (with no reports of grade 4 pulmonary toxicity); grade 3 or 4 pulmonary toxicity (cough, dyspnea, hypoxia) was reported in 7% of patients receiving first-line oxaliplatin/fluorouracil/leucovorin therapy for advanced colorectal cancer.1 In the study of adjuvant oxaliplatin/fluorouracil/leucovorin therapy, one death secondary to eosinophilic pneumonia was reported.1 If unexplained respiratory manifestations (e.g., nonproductive cough, dyspnea, crackles, radiographic evidence of pulmonary infiltrates) develop, the manufacturer states that oxaliplatin should be discontinued temporarily until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.1 If interstitial lung disease or pulmonary fibrosis is confirmed, therapy with oxaliplatin should be permanently discontinued.1

Hepatic Effects

Increased concentrations of aminotransferases (ALT, AST) and alkaline phosphatase occurred in 57 and 42%, respectively, of patients receiving oxaliplatin/fluorouracil/leucovorin as adjuvant therapy compared with 34 and 20%, respectively, of patients receiving fluorouracil/leucovorin; the incidence of hyperbilirubinemia was similar in both treatment groups.1 Liver biopsy specimens from patients receiving oxaliplatin/fluorouracil/leucovorin therapy have revealed evidence of hepatic vascular conditions (e.g., peliosis hepatis, nodular regenerative hyperplasia or sinusoidal changes, perisinusoidal fibrosis, veno-occlusive lesions).1 In patients with abnormal liver function test results or portal hypertension that cannot be explained by metastases to the liver, hepatic vascular toxicity should be considered and, if appropriate, investigated.1

Liver function tests (e.g., aminotransferases, bilirubin) should be monitored at baseline, prior to each cycle of oxaliplatin, and as clinically indicated.1

Cardiac Effects

Prolongation of the QT interval and subsequent ventricular arrhythmia, including torsades de pointes with fatal outcome, have occurred in patients receiving oxaliplatin.1

Oxaliplatin should be avoided in patients with congenital long QT syndrome.1 Electrocardiograms (ECGs) should be monitored in patients with congestive heart failure, bradyarrhythmias, or electrolyte abnormalities and in those who are receiving drugs known to prolong the QT interval (i.e., class IA and III antiarrhythmics).1 Serum electrolyte abnormalities should be monitored and corrected prior to initiation of oxaliplatin and periodically during therapy.1

Rhabdomyolysis

Rhabdomyolysis, which may be fatal, has been reported in patients receiving oxaliplatin.1

If manifestations of rhabdomyolysis (e.g., hematuria, anuria) occur, therapy with oxaliplatin should be permanently discontinued.1

Hemorrhage

In clinical trials, hemorrhage occurred more frequently in patients receiving oxaliplatin/fluorouracil/leucovorin therapy than in those receiving fluorouracil/leucovorin.1 Grade 3 or 4 GI bleeding was reported in 0.2% of patients receiving adjuvant oxaliplatin/fluorouracil/leucovorin therapy.1 Epistaxis was reported in 10% of patients receiving oxaliplatin/fluorouracil/leucovorin compared with 2% of patients receiving irinotecan/fluorouracil/leucovorin and 1% of those receiving irinotecan/oxaliplatin as first-line therapy for advanced colorectal cancer.1

Prolongation of the prothrombin time and international normalized ratio (INR), occasionally associated with hemorrhage, has been reported in patients receiving oxaliplatin/fluorouracil/leucovorin therapy concomitantly with anticoagulant therapy.1 More frequent monitoring is required for patients receiving oxaliplatin/fluorouracil/leucovorin therapy concomitantly with oral anticoagulants (e.g., warfarin).1

Thrombocytopenia and immune-mediated thrombocytopenia have occurred in patients receiving oxaliplatin.1 Rapid onset of thrombocytopenia and increased risk of hemorrhage have been observed in patients experiencing immune-mediated thrombocytopenia; discontinuance of oxaliplatin therapy should be considered if immune-mediated thrombocytopenia occurs.1 (See Hematologic Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Fetal/Neonatal Morbidity and Mortality

Based on its mechanism of action and animal findings, oxaliplatin may cause fetal harm.1 Embryotoxicity (i.e., increased early resorption, decreased fetal weight, delayed ossification) was observed in pregnant rats receiving oxaliplatin at a dosage equivalent to less than one-tenth the recommended human dose based on body surface area.1

Pregnancy should be avoided during therapy.1 The manufacturer recommends confirmation of pregnancy status prior to initiation of therapy, and women of reproductive potential should be advised to use effective contraceptive methods during therapy and for at least 9 months after the last dose of the drug.1 In addition, men with female partners of reproductive potential should use effective methods of contraception during therapy and for 6 months after the last dose of the drug.1 If oxaliplatin is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.1

Impairment of Fertility

Results of animal studies suggest that oxaliplatin may cause impairment of male and female fertility.1 In these animal studies, degeneration of reproductive tissues (i.e., testicular degeneration, hypoplasia, atrophy) was observed in male dogs given oxaliplatin at doses approximately one-sixth the recommended human dose based on body surface area.1

Specific Populations

Pregnancy

Oxaliplatin may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1 (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Lactation

It is not known whether oxaliplatin or its metabolites are distributed into milk.1 Because of the potential for serious adverse reactions to oxaliplatin in nursing infants, women should be advised to discontinue nursing during therapy and for 3 months after the last dose of the drug.1 The effects of oxaliplatin on nursing infants or on milk production are unknown.1

Pediatric Use

Safety and efficacy of oxaliplatin have not been established in pediatric patients.1,  7 No substantial antitumor activity has been reported in clinical trials in 69 pediatric patients with solid tumors.1

Geriatric Use

Clearance of ultrafilterable platinum does not appear to be affected substantially by a however, the incidence of certain adverse effects (i.e., granulocytopenia, leukopenia, grade 3 or 4 neutropenia, diarrhea, dehydration, hypokalemia, fatigue, syncope) was higher in geriatric patients than in younger adults.1 In the study of adjuvant therapy for colon cancer, the effect on disease-free survival of the oxaliplatin/fluorouracil/leucovorin regimen compared with that of fluorouracil/leucovorin in patients 65 years of age or older was inconclusive.1 In patients receiving the oxaliplatin/fluorouracil/leucovorin regimen as first-line therapy for advanced colorectal cancer, no differences in efficacy were observed in patients 65 years of age or older compared with the overall study population. 1 In patients receiving the oxaliplatin/fluorouracil/leucovorin regimen for previously treated advanced colorectal cancer, no differences in efficacy were observed in patients 65 years of age or older compared with younger adults.1

Renal Impairment

Following administration of oxaliplatin 85 mg/m², mean dose-adjusted area under the plasma concentration-time curve (AUC) of unbound platinum increased by 40 or 95% in patients with mild (creatinine clearance of 50-80 mL/minute) or moderate (creatinine clearance of 30-49 mL/minute) renal impairment, respectively, compared with patients with normal renal function.1 Mean dose-adjusted peak plasma concentration of unbound platinum appeared to be similar in patients with mild or moderate renal impairment compared with those with normal renal function.1 Following administration of oxaliplatin 65 mg/m² in patients with severe renal impairment (creatinine clearance less than 30 mL/minute), mean dose-adjusted AUC and peak plasma concentration of unbound platinum increased by 342 or 38%, respectively, compared with patients with normal renal function receiving oxaliplatin 85 mg/m²; dosage adjustment is recommended in patients with severe renal impairment.1

Common Adverse Effects

Adverse effects reported in 20% or more of patients receiving the oxaliplatin/fluorouracil/leucovorin regimen as adjuvant therapy for colon cancer and at an incidence that is at least 5% higher than that reported with fluorouracil/leucovorin alone include peripheral sensory neuropathy, nausea, vomiting, diarrhea, fatigue, anorexia, and pyrexia.1 Laboratory abnormalities reported in 20% or more of patients receiving the oxaliplatin/fluorouracil/leucovorin regimen and at an incidence that is at least 5% higher than that reported with fluorouracil/leucovorin alone include neutropenia, thrombocytopenia, anemia, elevated aminotransferase concentrations, and elevated alkaline phosphatase concentrations.1

Adverse effects reported in 20% or more of patients receiving the oxaliplatin/fluorouracil/leucovorin regimen for previously untreated advanced colorectal cancer include adverse neurologic effects (i.e., neuropathy, including paresthesia, pharyngo-laryngeal dysesthesias), adverse GI effects (i.e., nausea, diarrhea, vomiting, stomatitis, anorexia, constipation, abdominal pain), fatigue, cough, and alopecia.1 Laboratory abnormalities reported in 20% or more of patients receiving the oxaliplatin/fluorouracil/leucovorin regimen include leukopenia, neutropenia, thrombocytopenia, and anemia.1

Adverse effects reported in 20% or more of patients receiving the oxaliplatin/fluorouracil/leucovorin regimen for previously treated advanced colorectal cancer include adverse neurologic effects (i.e., neuropathy, including acute or persistent neuropathy), adverse GI effects (nausea, vomiting, diarrhea, stomatitis, abdominal pain, anorexia), fatigue, pyrexia, dyspnea, and constipation.1 Laboratory abnormalities reported in 20% or more of patients receiving the oxaliplatin/fluorouracil/leucovorin regimen include anemia, leukopenia, neutropenia, thrombocytopenia, and elevated aminotransferase concentrations.1

Anticoagulants

Prolongation of prothrombin time and international normalized ratio (INR), occasionally associated with hemorrhage, has been reported in patients receiving oxaliplatin/fluorouracil/leucovorin therapy concomitantly with anticoagulant therapy.1 More frequent monitoring is required for patients receiving oxaliplatin/fluorouracil/leucovorin therapy concomitantly with oral anticoagulants (e.g., warfarin).1

Fluorouracil

Pharmacokinetic interaction unlikely when recommended dosages and administration schedule (see Dosage and Administration) are used.1,  2 Potential pharmacokinetic interaction (20% increase in plasma fluorouracil concentrations) during concomitant use of fluorouracil and 130 mg/m² of oxaliplatin at intervals of 3 weeks.1,  7

Other Antineoplastic Agents

Pharmacokinetic interaction with irinotecan or topotecan unlikely.2

Nephrotoxic Drugs

Potential pharmacokinetic interaction (decreased clearance of platinum-containing compounds); however, this interaction has not been specifically studied.1 The manufacturer states that concomitant use of oxaliplatin with other nephrotoxic drugs should be avoided.1

Protein-bound Drugs

In vitro data indicate that erythromycin, granisetron, paclitaxel, salicylates, and valproate sodium are unlikely to displace platinum from plasma proteins.1

Drugs Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interaction with drugs metabolized by cytochrome P-450 (CYP) isoenzymes or those that induce or inhibit these isoenzymes unlikely.1 However, no studies have been conducted.1

Drugs that Prolong the QT Interval

Because oxaliplatin has been associated with QT-interval prolongation and ventricular arrhythmias, the manufacturer states that concomitant use of oxaliplatin with other drugs known to prolong the QT interval should be avoided.1 (See Cardiac Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Pharmacokinetics

Undergoes rapid and extensive nonenzymatic biotransformation to numerous platinum-containing transient reactive intermediates.1,  2 Pharmacokinetic parameters generally expressed in terms of platinum-containing complexes rather than parent compound.2

Distribution

Extent

Following a 2-hour IV infusion, 85% of administered platinum is rapidly distributed into tissues or eliminated in urine; approximately 15% of administered platinum is present in systemic circulation.1

No evidence of accumulation in plasma following usual dosa 1,  2 possible progressive accumulation in erythrocytes.2

Not known whether oxaliplatin or its metabolites are distributed into milk.1

Plasma Protein Binding

>90% irreversibly bound to plasma proteins (principally albumin and γ-globulins).1

Elimination

Metabolism

Undergoes rapid and extensive nonenzymatic biotransformation; no evidence of CYP-mediated metabolism in vitro.1

Elimination Route

Eliminated principally by renal excretion;1,  2 renal clearance of ultrafilterable platinum appears to be directly proportional to GFR.1

Following 2-hour IV infusion, approximately 54 or 2% of platinum-containing derivatives is excreted in urine and feces, respectively, within 5 days.1

Half-life

Distribution and elimination of platinum-containing derivatives appears to be triphasic, with 2 relatively short distribution phases with half-lives of approximately 0.43 and 16.8 hours, respectively, and a long elimination phase with a half-life of approximately 392 hours.1

Description

Oxaliplatin is a platinum-containing antineoplastic agent.1,  2 The drug is an organoplatinum complex, consisting of a platinum atom complexed with 1,2-diaminocyclohexane (DACH) and a labile oxalate ligand.1 Oxaliplatin must undergo nonenzymatic activation before antineoplastic activity occurs.1,  7 In physiologic solutions, the labile oxalate ligand of oxaliplatin presumably is displaced, forming several transient reactive complexes (e.g., monoaquo DACH platinum, diaquo DACH platinum) that covalently bind to specific DNA base sequences, producing intrastrand and interstrand DNA cross-links.1,  2 Cross-links between specific DNA base sequences (i.e., adjacent guanine residues, adjacent adenine and guanine residues, guanine residues separated by an intervening nucleotide) produced by transient reactive intermediates of oxaliplatin are thought to inhibit DNA replication and transcription.1,  2 Some evidence indicates that the presence of the bulky DACH carrier ligand of oxaliplatin may contribute to a greater degree of inhibition of DNA synthesis and cytotoxicity compared with that observed with cisplatin and may result in the lack of cross-resistance between oxaliplatin and cisplatin.2 Oxaliplatin is cycle-phase nonspecific.1

Oxaliplatin has been shown to exhibit antitumor activity against colon carcinoma in vivo.1 Synergistic antiproliferative activity of oxaliplatin and fluorouracil has been demonstrated in vitro and in vivo in several tumor models (i.e., HT29 [colon], GR [mammary], L1210 [leukemia]).1,  2

Because oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation to numerous platinum-containing transient reactive intermediates,1,  2 pharmacokinetic parameters of the drug generally are expressed in terms of platinum-containing complexes rather than the parent compound.2 Following a 2-hour IV infusion of oxaliplatin, approximately 15% of the administered platinum is present in the systemic circulation while the remaining 85% is rapidly distributed into tissues or eliminated in urine.1 A fraction of the platinum-containing complexes distributed into peripheral tissues is irreversibly bound to and accumulates (approximately twofold) in erythrocytes, where the complexes appear to have no relevant activity.1 Approximately 90% of the platinum in the systemic circulation is irreversibly bound to plasma proteins, principally albumin and gamma globulins.1 It is thought that antineoplastic activity of oxaliplatin resides only in platinum-containing species present in the ultrafilterable plasma fraction (biotransformed, nonprotein-bound species); however, the pharmacodynamic relationship between platinum ultrafiltrate concentrations and safety or efficacy of oxaliplatin has not been established.1,  2,  7 There is no evidence that platinum accumulates in plasma following administration of 85 mg/m² dosages of oxaliplatin once every 2 weeks;1,  2 however, a progressive accumulation of platinum in erythrocytes has been reported.2

Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation; there is no evidence of cytochrome P-450 (CYP)-mediated metabolism in vitro.1 As many as 17 platinum-containing derivatives, including several cytotoxic species (e.g., monochloro DACH platinum, dichloro DACH platinum, monoaquo DACH platinum, diaquo DACH platinum) and various noncytotoxic species, have been isolated from plasma ultrafiltrate samples from patients receiving oxaliplatin.1 Distribution of platinum-containing derivatives appears to be triphasic, with the half-lives of the first, second, and third phases averaging approximately 0.43, 16.8, and 391 hours, respectively.1 Platinum-containing derivatives are eliminated principally by renal excretion;1,  2 renal clearance of ultrafilterable platinum appears to be directly proportional to glomerular filtration rate (GFR).1 Following administration of a single 2-hour IV infusion of oxaliplatin, approximately 54 or 2% of platinum-containing derivatives is excreted in urine and feces, respectively, within 5 days.1

Advice to Patients

Risk of hypersensitivity reactions.1 Importance of seeking immediate medical attention if signs of severe hypersensitivity reaction (e.g., chest tightness, shortness of breath, wheezing, dizziness, faintness, angioedema) occur.1

Risk of neuropathy.1 Importance of understanding that symptoms of acute sensory neuropathy may be precipitated or exacerbated by exposure to cold temperature or cold objects; importance of avoiding cold drinks or use of ice and of covering exposed skin prior to exposure to cold temperature or cold objects.1 Importance of reading manufacturer's patient information for further instructions to minimize exposure to cold temperature or cold objects.1

Risk of anemia, leukopenia, neutropenia, and thrombocytopenia; importance of informing a clinician immediately if bleeding, fever (particularly if associated with persistent diarrhea), or evidence of infection develops.1

Risk of posterior reversible encephalopathy syndrome and visual abnormalities (e.g., transient vision loss); such effects may affect ability to drive or operate machinery.1

Risk of pulmonary toxicity.1 Importance of promptly informing clinician of any persistent or recurrent respiratory symptoms (e.g., nonproductive cough, dyspnea).1

Risk of hepatotoxicity.1 Importance of informing clinician if symptoms of hepatotoxicity occur.1

Risk of QT-interval prolongation.1 Importance of informing clinician if symptoms of QT-interval prolongation (e.g., syncope) occur.1

Risk of rhabdomyolysis.1 Importance of promptly informing clinician if new or worsening signs or symptoms of rhabdomyolysis (e.g., dark urine, anuria, urinary retention) occur.1

Risk of persistent vomiting, diarrhea, or signs of dehydration.1

Risk of fetal harm.1 Necessity of advising women of reproductive potential that they should use effective contraceptive methods while receiving the drug and for 9 months after the last dose of the drug.1 Importance of advising men who are partners with women of reproductive potential to use effective methods of contraception while receiving the drug and for 6 months after the last dose of the drug.1 Importance of patients informing their clinicians if they are pregnant or think they may be pregnant.1 If pregnancy occurs, advise patient of potential risk to fetus.1

Importance of advising women to avoid breast-feeding while receiving oxaliplatin therapy and for 3 months after the last dose of the drug.1

Risk of impaired male and female fertility.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illness.1 (See Cautions.)

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

1. Sanofi-Aventis. Eloxatin^® (oxaliplatin) for injection prescribing information. Bridgewater, NJ; 2020 Apr.

2. Culy CR, Clemett D, Wiseman LR. Oxaliplatin: a review of its pharmacological properties and clinical efficacy in metastatic colorectal cancer and its potential in other malignancies. Drugs . 2000; 60:895-924. [PubMed 11085200]

3. de Gramont A, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol . 2000 Aug;18:2938-47.

4. Giacchetti S, Perpoint B, Zidani R et al. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol . 2000 Jan;18:136-47.

5. Tabah-Fisch I, Maindrault-Goebel F, Benavides M et al. Oxaliplatin/5FU/LV is feasible, safe and active in elderly colorectal cancer (CRC) patients. Proceedings of ASCO. 2002; Abstract No. 556.

6. Grothey A, Deschler B, Kroening H et al. Phase III study of bolus 5-fluorouracil (5-FU)/folinic acid (FA) (Mayo) vs weekly high-dose 24-h 5-FU infusion/FA + oxaliplatin (OXA) (FUFOX) in advanced colorectal cancer (ACRC). Proceedings of ASCO. 2002; Abstract No. 512.

7. Sanofi-Synthelabo, New York, NY: Personal communication.

8. Goldberg RM, Morton RF, Sargent DJ et al. Oxaliplatin or CPT-11 + 5FU/leucovorin or oxaliplatin + CPT-11 in advanced colorectal cancer (ACRC): efficacy and safety results from a North American Gastrointestinal Intergroup Study (N9741). Abstract #6 presented at Perspectives in Colorectal Cancer, a Consensus Meeting, Fourth International Conference, Barcelona, June 2002.

9. André T, Boni C, Mounedji-Boudiaf L et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med . 2004; 350:2343-51. [PubMed 15175436]

10. André T, Boni C, Navarro M et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol . 2009; 27:3109-16. [PubMed 19451431]

11. Goldberg RM, Sargent DJ, Morton RF et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol . 2004; 22:23-30. [PubMed 14665611]

12. Cheeseman SL, Joel SP, Chester JD et al. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer . 2002; 87:393-9. [PubMedCentral][PubMed 12177775]

14. Saif MW, Reardon J. Management of oxaliplatin-induced peripheral neuropathy. Ther Clin Risk Manag . 2005; 1:249-58. [PubMedCentral][PubMed 18360567]

15. Gamelin L, Boisdron-Celle M, Delva R et al. Prevention of oxaliplatin-related neurotoxicity by calcium and magnesium infusions: a retrospective study of 161 patients receiving oxaliplatin combined with 5-Fluorouracil and leucovorin for advanced colorectal cancer. Clin Cancer Res . 2004; 10:4055-61. [PubMed 15217938]

16. Nikcevich, DA, Grothey A, Sloan JA et al. Effect of intravenous calcium and magnesium (IV CaMg) on oxaliplatin-induced sensory neuropathy (sNT) in adjuvant colon cancer: results of the phase III placebo-controlled, double-blind NCCTG trial N0347. J Clin Oncol . 2008; 26: Abstract 4009 (presented at the 2008 ASCO Annual Meeting).

17. Gamelin L, Boisdron-Celle M, Morel A et al. Oxaliplatin-related neurotoxicity: interest of calcium-magnesium infusion and no impact on its efficacy. J Clin Oncol . 2008; 26:1188-9; author reply 1189-90. [PubMed 18309961]

18. Hochster HS, Grothey A, Shplisky A et al. Effect of intravenous (IV) calcium and magnesium (Ca/Mg) versus placebo on reponse to FOLFOX + bevacizumab (BEV) in the CONcePT trial. Presented at the ASCO 2008 Gastrointestinal Cancers Symposium. From ASCO website. Abstract 280. Accessed 2009 Jul 9. [Web]

19. A phase III randomized, placebo-controlled, double-blind study of intravenous calcium/magnesium to prevent oxaliplatin-induced sensory neuropathy. From ClinicalTrials.gov registry. Accessed 2009 Jul 13. [Web]

20. CONCEPT: Phase IV, randomized, prospective, multicenter comparison of intermittent schedule of oxaliplatin combined with FOLFOX/bevacizumab vs conventional mode of administration of FOLFOX/bevacizumab + neuroprophylaxis with calcium/magnesium for optimization of first-line therapy of metastatic colorectal cancer. From ClinicalTrials.gov registry. Accessed 2009 Jul 16. [Web]

21. O'Dea D, Handy CM, Wexler A. Ocular changes with oxaliplatin. Clin J Oncol Nurs . 2006; 10:227-9. [PubMed 16708705]

22. Leonard GD, Wright MA, Quinn MG et al. Survey of oxaliplatin-associated neurotoxicity using an interview-based questionnaire in patients with metastatic colorectal cancer. BMC Cancer . 2005; 5:116. [PubMedCentral][PubMed 16168057]

23. André T, de Gramont A, Vernerey D et al. Adjuvant Fluorouracil, Leucovorin, and Oxaliplatin in Stage II to III Colon Cancer: Updated 10-Year Survival and Outcomes According to BRAF Mutation and Mismatch Repair Status of the MOSAIC Study. J Clin Oncol . 2015; 33:4176-87. [PubMed 26527776]

24. Breckenridge Pharmaceutical, Inc. Oxaliplatin for injection prescribing information. Berlin, CT; 2019 May.

10001. Haller DG, Tabernero J, Maroun J et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol . 2011; 29:1465-71. [PubMed 21383294]

10002. Schmoll HJ, Tabernero J, Maroun J et al. Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer: Final Results of the NO16968 Randomized Controlled Phase III Trial. J Clin Oncol . 2015; 33:3733-40. [PubMed 26324362]

10003. Schmoll HJ, Cartwright T, Tabernero J et al. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol . 2007; 25:102-9. [PubMed 17194911]

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