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Oxaliplatin
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85 mg/m2 IV concurrently via Y-site with leucovorin (500 mg/m2 IV) over 2 hours, followed 1 hour later by fluorouracil (500 mg/m2 IV bolus) on days 1, 15, and 29. On days 8, 22, and 36, administer leucovorin (500 mg/m2 IV over 2 hours) without oxaliplatin, followed 1 hour later by fluorouracil (500 mg/m2 IV bolus). Repeat every 8 weeks (56 days) for a total of 3 cycles (24 weeks). After a median 8 years of follow-up, patients with stage 2 or 3 colon cancer treated with FLOX (n = 1,247) had significantly improved disease-free survival (DFS) compared with those who received fluorouracil/leucovorin alone (FULV; n = 1,245) in a randomized, phase 3 clinical trial. Overall survival was similar between treatment groups; however, in an unplanned subgroup analysis, age less than 70 years may be associated with improved survival.[59877] [59899]
85 mg/m2 IV on day 1, administered concurrently over 2 hours in separate bags via Y-site with leucovorin (200 mg/m2 IV), followed by fluorouracil (400 mg/m2 IV bolus over 2 to 4 minutes, then fluorouracil 600 mg/m2 continuous IV infusion (CIV) over 22 hours). On day 2, give leucovorin (200 mg/m2 IV over 2 hours) followed by fluorouracil (400 mg/m2 IV bolus, then fluorouracil 600 mg/m2 CIV over 22 hours). This 2-day regimen (FOLFOX4) is repeated every 2 weeks for 12 cycles (6 months). Prolongation of the oxaliplatin infusion to 6 hours may mitigate acute toxicities; the infusion time for fluorouracil and leucovorin need not be changed. In a multicenter trial, patients with stage II or III completely resected colon cancer were randomized to either FOLFOX 4 or infusional fluorouracil/leucovorin (De Gramont regimen). At a median follow-up of 81.9 months in the patients with stage 3 disease, there was a significant improvement in 5-year disease-free survival (DFS) in patients receiving FOLFOX4 compared with those receiving infusional fluorouracil/leucovorin (73.3% vs. 67.4%). In a subgroup analysis of patients with stage 3 disease, the 6-year OS rates were also significantly improved with FOLFOX4 (72.9% vs. 68.7%). There was no significant difference observed in DFS or OS in patients with stage 2 disease.[41958] [40864] [20577]
85 mg/m2 IV administered concurrently but in separate bags via Y-site over 2 hours with leucovorin (400 mg/m2 IV), followed by fluorouracil (400 mg/m2 IV bolus) on day 1, followed by fluorouracil (1,200 mg/m2 per day on days 1 and 2 by continuous IV infusion (CIV) [total infusional dose, 2,400 mg/m2 over 46 to 48 hours]). This 2-day regimen (mFOLFOX6) is repeated every 2 weeks for 12 cycles (6 months). Prolongation of the oxaliplatin infusion to 6 hours may mitigate acute toxicities; the infusion time for fluorouracil and leucovorin need not be changed. Administering fluorouracil 2,400 mg/m2 over 46 to 48 hours (FOLFOX6) provides similar exposure to the daily bolus plus 22-hour fluorouracil infusion in FOLFOX4, with increased patient convenience and is preferred.[59867] In a multicenter trial, patients with stage II or III completely resected colon cancer were randomized to either FOLFOX4 or infusional fluorouracil/leucovorin (De Gramont regimen). At a median follow-up of 81.9 months in the patients with stage 3 disease, there was a significant improvement in 5-year disease-free survival (DFS) in patients receiving FOLFOX4 compared with infusional fluorouracil/leucovorin (73.3% vs. 67.4%). In a subgroup analysis of patients with stage 3 disease, the 6-year OS rates were also significantly improved with FOLFOX4 (72.9% vs. 68.7%). There was no significant difference observed in DFS or OS in patients with stage 2 disease.[40864] [20587]
130 mg/m2 IV on day 1 in combination with capecitabine (1,000 mg/m2 PO twice daily on days 1 to 14), repeated every 21 days for a maximum of 8 cycles. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[44458] Treatment with capecitabine/oxaliplatin (XELOX) improved 7-year disease-free survival compared with fluorouracil/leucovorin in patients with stage III colon cancer in a multicenter, randomized, phase 3 clinical trial (63% vs. 56%; p = 0.004); 7-year overall survival rates were 73% and 67% respectively (p = 0.04). Because alpha levels were not prespecified for testing treatment differences in the final analysis, p values provide only a descriptive statistical measure of a possible difference. In a biomarker analysis, low tumor expression of dihydropyridine dehydrogenase (DPD) may be predictive for XELOX efficacy; no significant associations were observed in the fluorouracil group.[45258] [69445]
130 mg/m2 IV on day 1 in combination with capecitabine (1,000 mg/m2 PO twice daily on days 1 to 14), every 21 days until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[44458] In a multicenter, randomized, phase 3 clinical trial, patients with metastatic colorectal cancer were randomized to treatment with XELOX or fluorouracil/leucovorin/oxaliplatin (FOLFOX4); the protocol was later amended to a 2 x 2 factorial design to allow further randomization to bevacizumab or placebo. Treatment with XELOX was noninferior to FOLFOX4 with regard to the primary outcome of progression-free survival (8 months vs. 8.5 months).[41607] In an exploratory overall survival analysis, the median overall survival was 19 months in the pooled capecitabine/capecitabine-placebo arms compared with 18.9 months in the pooled FOFOX4/FOLFOX4-placebo arms; the study was not powered for formal noninferiority testing for overall survival.[68390]
130 mg/m2 IV on day 1 in combination with capecitabine (1,000 mg/m2 PO twice daily on days 1 to 14) and bevacizumab (7.5 mg/kg IV on day 1), every 21 days until disease progression or unacceptable toxicity. Bevacizumab was administered prior to oxaliplatin on day 1 in the randomized clinical trial. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, randomized, phase 3 clinical trial, patients with metastatic colorectal cancer were randomized to treatment with XELOX or fluorouracil/leucovorin/oxaliplatin (FOLFOX4); the protocol was later amended to a 2 x 2 factorial design to allow further randomization to bevacizumab or placebo. The primary endpoint of median progression-free survival was significantly improved in patients treated with either XELOX or FOLFOX4 plus bevacizumab compared with those who received XELOX or FOLFOX4 alone (9.4 months vs. 8 months), with a median duration of response of 8.45 months versus 7.4 months, respectively. Overall survival, a secondary endpoint, was improved in the bevacizumab arms but did not reach statistical significance (21.3 vs. 19.9 months).[41609] [44458]
85 mg/m2 IV, given concurrently via Y-site with levo-leucovorin (200 mg/m2 IV) over 2 hours, preceded by irinotecan (165 mg/m2 IV over 1 hour), on day 1; follow the levo-leucovorin infusion on day 1 with fluorouracil (1,600 mg/m2 per day on days 1 and 2 as a continuous IV infusion (CIV) over 48 hours (total dose 3,200 mg/m2)) (FOLFOXIRI). Repeat every 2 weeks for up to 12 cycles. The order of administration is irinotecan, followed by oxaliplatin plus leucovorin, followed by fluorouracil. Treatment with FOLFOXIRI significantly improved the primary endpoint of overall response rate (ORR) compared with FOLFIRI (60% vs. 34%) in a multicenter, randomized, phase 3 study of patients with unresectable metastatic colorectal cancer (n = 244). In addition, progression-free survival (PFS) (9.8 months vs. 6.9 months) and overall survival (22.6 months vs. 16.7 months) were significantly improved in patients who received FOLFOXIRI. Grade 3 and 4 neutropenia (50% vs. 28%) and grade 2 and 3 peripheral neurotoxicity (19% vs. 0%) were significantly worse in the FOLFOXIRI arm.[46110]
85 mg/m2 IV concurrently via Y-site with leucovorin (400 mg/m2 IV) over 2 hours on day 1, followed by fluorouracil (400 mg/m2 IV bolus and then 1,200 mg/m2 per day on days 1 and 2 by continuous IV infusion (CIV) [total infusional dose 2,400 mg/m2 given over 46 to 48 hours]), repeated every 14 days (mFOLFOX6). Additionally, give cetuximab 400 mg/m2 IV over 120 minutes (maximum infusion rate, 10 mg/minute) on cycle 1, day 1 followed by weekly infusions of cetuximab 250 mg/m2 IV over 60 minutes (maximum infusion rate, 10 mg/minute); on day 1 of each 2-week cycle, begin oxaliplatin and leucovorin administration 1 hour after completion of cetuximab (order of administration on day 1 is cetuximab, followed by mFOLFOX6). First-line treatment with cetuximab plus modified FOLFOX (mFOLFOX) 4 or 6 significantly improved objective response rates (ORR) in patients with KRAS WT mCRC in two randomized clinical trials. The benefit to progression-free survival (PFS) was small to nonsignificant, and a benefit to overall survival (OS) was not demonstrated. Skin and gastrointestinal toxicities were increased in patients treated with cetuximab.[60036] [60037] [60038] Total exposure (AUC) to fluorouracil was similar when administered as two 22-hour infusions of 600 mg/m2, as in FOLFOX4, or as a single 46-hour infusion of 2,400 mg/m2, as in mFOLFOX6 in a pharmacokinetic study.[59867]
130 mg/m2 IV on day 1 in combination with capecitabine 1,000 mg/m2 PO twice daily on days 1 through 14, repeated every 3 weeks for 8 cycles. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a phase 3 clinical trial, 1,035 patients with stage II to IIIB gastric cancer were randomized to receive adjuvant capecitabine and oxaliplatin or observation after surgical (D2) resection. The primary end point, 3-year disease free survival, was significantly improved with XELOX (74% vs. 60%). At a median follow-up of 34.4 months, the difference in overall survival was not significantly different between the 2 treatment arms.[45379]
Oxaliplatin 85 mg/m2 IV over 2 hours on day 1 concurrently with leucovorin (200 mg/m2 IV over 2 hours on day 1) in combination with 5-FU (2600 mg/m2 continuous IV infusion over 24 hours on day 1). Repeat treatment every 2 weeks until disease progression or unacceptable toxicity. In a phase III trial, 220 patients with previously untreated advanced adenocarcinoma of the stomach or gastroesophageal junction were randomized to receive treatment with fluorouracil, leucovorin, and either oxaliplatin or cisplatin (FLO or FLP, respectively). The primary end point, PFS, was not significantly different between the 2 treatment arms (5.8 months vs. 3.9 months, p = 0.077). In a subgroup of 94 patients older than 65 years, FLO had a significantly better overall response rate, and PFS compared to FLP. Leukopenia, anemia, nausea/vomiting, fatigue, nephrotoxicity, hepatotoxicity, and alopecia occurred significantly more often in the FLP arm; neurosensory toxicity occurred significantly more often in the FLO arm.[36339]
85 mg/m2 IV on day 1, every 2 weeks until disease progression or unacceptable toxicity. Administer in combination with nivolumab (240 mg IV every 2 weeks until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression), leucovorin (400 mg/m2 IV on day 1 infused concurrently with oxaliplatin but in separate bags via Y-site), fluorouracil (400 mg/m2 IV bolus on day 1 following leucovorin, followed by 1,200 mg/m2 per day on days 1 and 2 by continuous IV infusion), every 2 weeks until disease progression or unacceptable toxicity.[40864] [20587] [58668] Administer nivolumab prior to chemotherapy when given on the same day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Patients with previously untreated advanced or metastatic gastric cancer, GEJ cancer, and esophageal cancer were randomized to treatment with nivolumab 240 mg IV in combination with mFOLFOX6 every 2 weeks, nivolumab 360 mg IV in combination with CapeOx every 3 weeks, or the same chemotherapy without nivolumab in a multicenter, open-label trial (CHECKMATE-649; n = 1,581). Overall survival was significantly improved with the addition of nivolumab to chemotherapy in the overall patient population (13.8 months vs. 11.6 months); results were consistent in patients with PD-L1 Combined Positive Score (CPS) of 1 or higher and PD-L1 CPS of 5 or higher. The median progression free survival was 7.7 months in patients who received nivolumab compared with 6.9 months in those who did not. The overall response rate was 47% versus 37% respectively (complete response, 10% vs. 7%), for a median duration of 8.5 months versus 6.9 months.[58668] [66712]
130 mg/m2 IV on day 1 every 3 weeks until disease progression or unacceptable toxicity. Administer in combination with nivolumab (360 mg IV every 3 weeks until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression) and capecitabine (1,000 mg/m2 PO twice daily on days 1 to 14 of each 21 day cycle until disease progression or unacceptable toxicity).[45258] [43412] [58668] Administer nivolumab prior to chemotherapy when given on the same day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Patients with previously untreated advanced or metastatic gastric cancer, GEJ cancer, and esophageal cancer were randomized to treatment with nivolumab 240 mg IV in combination with mFOLFOX6 every 2 weeks, nivolumab 360 mg IV in combination with CapeOx every 3 weeks, or the same chemotherapy without nivolumab in a multicenter, open-label trial (CHECKMATE-649; n = 1,581). Overall survival was significantly improved with the addition of nivolumab to chemotherapy in the overall patient population (13.8 months vs. 11.6 months); results were consistent in patients with PD-L1 Combined Positive Score (CPS) of 1 or higher and PD-L1 CPS of 5 or higher. The median progression free survival was 7.7 months in patients who received nivolumab compared with 6.9 months in those who did not. The overall response rate was 47% versus 37% respectively (complete response, 10% vs. 7%), for a median duration of 8.5 months versus 6.9 months.[58668] [66712]
As a single agent in previously treated patients (platinum with or without taxane), oxaliplatin 130 mg/m2 IV every 3 weeks demonstrated an overall response rate of 26% (11 of 42 evaluable patients, 2 complete responses), with 10 of 24 (42%) in platinum-sensitive and 1 of 18 (5.6%) in platinum-resistant patients.[27034] This lack of benefit in platinum-resistant patients was confirmed in another phase II study of single-agent oxaliplatin in 25 patients; a 4.3% ORR was observed.[45784] In a phase II-III trial of chemotherapy naive, advanced ovarian cancer patients, the safety and efficacy of oxaliplatin 130 mg/m2 IV plus cyclophosphamide (1000 mg/m2 IV) every 3 weeks were compared to a standard regimen of cisplatin and cyclophosphamide. Response rates, median progression-free survival, and overall survival were similar between the 2 groups. Myelosuppression and vomiting were significantly less in the oxaliplatin arm.[27035] Additional combination regimens studied in phase II trials include gemcitabine/oxaliplatin, paclitaxel/oxaliplatin, docetaxel/oxaliplatin, and pegylated liposomal doxorubicin/oxaliplatin. Overall response rates up to 81% and 37% were observed in platinum-sensitive and platinum-refractory patients, respectively.[45785][45786][45787][45788]
In a phase II trial, the safety and efficacy of oxaliplatin 130 mg/m2 IV on day 1 plus 5-fluorouracil (1000 mg/m2/day IV continuous infusion days 1—4) every 3 weeks were evaluated in taxane- and anthracycline-pretreated advanced and metastatic breast cancer patients. Of the 60 evaluable patients, 17 had a partial response, 26 had stable disease, and 17 had disease progression resulting in an overall response rate (ORR) of 26% and 36% in taxane- and anthracycline -resistant populations, respectively. All responders had metastatic liver disease. Median time to progression was 4.8 months, and median survival was 11.9 months.[27036] In another phase II clinical trial, 62 patients with pretreated (3 or more prior regimens) stage IV breast cancer were administered oxaliplatin 85 mg/m2 IV on day 1 in combination with leucovorin 200 mg/m2 IV on day 1, 5-fluorouracil 400 mg/m2 IV bolus on day 1, and 5-FU 1200 mg/m2 IV over 44 hours starting on day 1, repeated every 2 weeks. The overall response rate was 18.3%, with no patients achieving a complete response.[45789] A numerically higher ORR of 34% was observed in another phase II trial of 50 patients treated with the 3-drug regimen who had received at least 2 prior regimens (including a taxane and an anthracycline).[45790]
130 mg/m2 IV on day 1 with dexamethasone 40 mg PO days 1, 2, 3 and 4 and cytarabine 2 g/m2 IV every 12 hours for 2 doses on day 2, repeated every 21 days (DHAOx regimen) has been studied.[27037][27038] Rituximab 375 mg/m2 IV on day 1 in addition to DHAOx has also been studied.[44312] Two small trials (n = 15 and n = 24) examined substituting oxaliplatin for cisplatin in the DHAP regimen (cisplatin, dexamethasone, and cytarabine). The response rate for the DHAOx regimen was 50%—73% in these trials.[27037][27038] In a subsequent study, rituximab was given in combination with DHAOx. All 22 patients achieved a response, including a complete response rate of 95%.[44312]
85 mg/m2 IV on days 1 and 15 with leucovorin (200 mg/m2 IV on days 1, 8, 15, and 22) and 5-FU (2000 mg/m2 IV over 24 hours on days 1, 8, 15, and 22), repeated every 6 weeks (OFF regimen) has been studied. In a phase II trial of 36 patients with recurrent squamous cell carcinoma of the head and neck, OFF produced an overall response rate of 60.6% and an overall survival of 10.8 months.[45686]
85 mg/m2 IV over 2 hours on day 1, immediately followed by leucovorin 400 mg/m2 IV over 2 hours; begin irinotecan 150 mg/m2 IV over 90 minutes 30 minutes after the leucovorin infusion is started, followed by fluorouracil 2,400 mg/m2 IV continuously over 46 hours. Repeat every 14 days for 12 cycles. In a randomized phase 3 trial, adjuvant treatment with mFOLFIRINOX significantly increased both progression-free survival (PFS) and overall survival (OS) compared with gemcitabine monotherapy in patients with pancreatic cancer. In this trial, patients were carefully selected for treatment based on age (younger than 80 years of age), R0 or R1 resection, and a CA 19-9 level of 180 units/mL or less.[64744]
85 mg/m2 IV over 2 hours on day 1, immediately followed by leucovorin 400 mg/m2 IV over 2 hours; begin irinotecan 180 mg/m2 IV over 90 minutes through a Y-site connector 30 minutes after the leucovorin is started, followed immediately by fluorouracil 400 mg/m2 IV bolus then fluorouracil 2,400 mg/m2 IV over 46 hours. Repeat every 2 weeks for 6 months.[51161]
100 mg/m2 IV on day 2, after administration of gemcitabine (1,000 mg/m2 IV over 100 minutes) on day 1, every 2 weeks until disease progression or unacceptable toxicity. In a phase 3 study (n = 313), the primary endpoint of overall survival was not significantly different between patients treated with oxaliplatin and gemcitabine (GemOx) compared with gemcitabine alone (given over 30 minutes); however, 74% of patients in the gemcitabine arm crossed over to receive gemcitabine and platinum combinations at disease progression, possibly limiting this variable. Response rate (26.8% vs. 17.3%) and progression-free survival (5.8 months vs. 3.7 months) were each significantly better with GemOx. Also, clinical benefit response was significantly greater in patients who received GemOx (38.2% vs. 26.9%).[33970] In another phase 3 trial, 833 patients were randomized to receive GemOx, fixed dose-rate gemcitabine (1,500 mg/m2 IV at a rate of 10 mg/m2/minute on days 1, 8, and 15 of a 28-day cycle), or a 30-minute infusion of gemcitabine (1,000 mg/m2 IV weekly for 7 weeks, followed by 1 week off, and then 1,000 mg/m2 IV on days 2, 8, and 15 every 28 days). Neither GemOx or fixed dose-rate gemcitabine produced a statistically significant difference in overall survival compared with gemcitabine as a 30-minute infusion (5.7 months vs. 6.2 months vs. 4.9 months). Grade 3 or 4 neutropenia and thrombocytopenia occurred more frequently in the gemcitabine fixed dose-rate arm; grade 3 or 4 sensory neuropathy occurred more frequently with GemOx.[35046] [36044]
85 mg/m2 IV on days 8 and 22 in combination with fluorouracil (2,000 mg/m2 IV over 24 hours on days 1, 8, 15, and 22) and leucovorin (200 mg/m2 IV over 30 minutes on days 1, 8, 15, and 22), every 42 days until disease progression or unacceptable toxicity. In a phase 3 trial, the primary endpoint of overall survival was significantly longer in patients with pancreatic cancer that progressed on gemcitabine (n = 160) which received fluorouracil, leucovorin, and oxaliplatin (OFF) compared with fluorouracil and leucovorin alone (FF) (26 weeks vs. 13 weeks). Neurologic toxicity and leukopenia occurred more frequently in the oxaliplatin arm.[35050] Initially, this trial randomized patients to receive OFF plus best supportive care (BSC) or BSC alone. Because of the rejection of BSC as an acceptable second-line treatment modality and subsequent poor accrual, the study was amended after the recruitment of 6 patients to OFF versus FF. Final analysis of OFF vs. BSC revealed a significant improvement in overall survival (4.83 months vs. 2.3 months).[45671]
Multiple dosage regimens have been studied in phase II trials. Oxaliplatin 100 mg/m2 IV on days 1 and 15 in combination with gemcitabine (1000 mg/m2 IV on days 1, 8, and 15), repeated every 28 days;[36010] oxaliplatin 100 mg/m2 IV on day 2 in combination with gemcitabine (1000 mg/m2 IV at a fixed dose rate of 10 mg/m2/min on day 1), repeated every 14 days.[36011] All regimens should be given until disease progression or unacceptable toxicity. Response rates of 26%—36% have been achieved.
130 mg/m2 on days 1 and 15 every 4 weeks has been studied. The efficacy and toxicity of oxaliplatin 130 mg/m2 IV on days 1 and 15 every 4 weeks or oxaliplatin 60 mg/m2 IV on days 1, 8, and 15 every 4 weeks were evaluated in 32 patients (16 patients in each dose group) with nonseminomatous cisplatin-refractory germ cell cancer or relapsed disease following high-dose chemotherapy plus autologous stem cell support. Treatment was continued for 2 cycles after achievement of the best response, unless severe toxicity occurred. The response rate in the 130 mg/m2 group was 19%, providing the better dosage option for consideration. Overall, 4 patients achieved a partial response (13%) and 2 additional patients had disease stabilization.[27041]
80 mg/m2 IV on days 1 and 8 has been given in combination with gemcitabine 1000 mg/m2 IV on days 1 and 8, every 3 weeks for a maximum of 6 cycles. In a clinical trial of 25 patients with previously untreated mesothelioma, an ORR of 40% (0 CR, 10 PR) was observed.[46125] In a clinical trial of 29 patients (25 patients oxaliplatin/gemcitabine, 4 patients oxaliplatin monotherapy) with previously treated mesothelioma, a partial response was seen in only 2 patients (ORR 6.9%); both patients received combination chemotherapy.[46126]
85 mg/m2 IV on day 1, every 2 weeks until disease progression or unacceptable toxicity. Administer in combination with nivolumab (240 mg IV every 2 weeks until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression), leucovorin (400 mg/m2 IV on day 1 infused concurrently with oxaliplatin but in separate bags via Y-site), fluorouracil (400 mg/m2 IV bolus on day 1 following leucovorin, followed by 1,200 mg/m2 per day on days 1 and 2 by continuous IV infusion), every 2 weeks until disease progression or unacceptable toxicity.[40864] [20587] [58668] Administer nivolumab prior to chemotherapy when given on the same day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Patients with previously untreated advanced or metastatic gastric cancer, GEJ cancer, and esophageal cancer were randomized to treatment with nivolumab 240 mg IV in combination with mFOLFOX6 every 2 weeks, nivolumab 360 mg IV in combination with CapeOx every 3 weeks, or the same chemotherapy without nivolumab in a multicenter, open-label trial (CHECKMATE-649; n = 1,581). Overall survival was significantly improved with the addition of nivolumab to chemotherapy in the overall patient population (13.8 months vs. 11.6 months); results were consistent in patients with PD-L1 Combined Positive Score (CPS) of 1 or higher and PD-L1 CPS of 5 or higher. The median progression free survival was 7.7 months in patients who received nivolumab compared with 6.9 months in those who did not. The overall response rate was 47% versus 37% respectively (complete response, 10% vs. 7%), for a median duration of 8.5 months versus 6.9 months.[58668] [66712]
130 mg/m2 IV on day 1, in combination with capecitabine (850 mg/m2 or 1,000 mg/m2 PO twice daily on days 1 to 14), every 21 days until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[44458] In a randomized phase 2 trial, patients with advanced gastric cancer treated with XELOX had similar median times to progression (7.2 months vs. 6.2 months) and overall survival (13.3 months vs. 12.4 months) compared with those who received treatment with S-1 and oxaliplatin.[69456] In a noncomparative phase 2 trial, treatment of advanced esophageal cancer with XELOX resulted in an overall response rate of 39% for a median duration of 5.3 months; median survival time was 8 months.[69457]
130 mg/m2 IV on day 1, in combination with epirubicin (50 mg/m2 IV on day 1) and capecitabine (625 mg/m2 PO twice daily on days 1 to 21 [continuously]), repeated every 3 weeks for a maximum of 8 cycles; round the calculated capecitabine dose to the nearest 150 mg in order to administer whole tablets. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.[44458] Chemotherapy regimens epirubicin/oxaliplatin/capecitabine, epirubicin/cisplatin/capecitabine, epirubicin/oxaliplatin/fluorouracil, and epirubicin/cisplatin/fluorouracil were noninferior to each other with regard to overall survival (11.2 months vs. 9.9 months vs. 9.3 months vs. 9.9 months) in a multicenter, randomized phase 3 trial with a 2 x 2 design (REAL-2), patients with advanced esophagogastric cancer.[40571]
130 mg/m2 IV on day 1 every 3 weeks until disease progression or unacceptable toxicity. Administer in combination with nivolumab (360 mg IV every 3 weeks until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression) and capecitabine (1,000 mg/m2 PO twice daily on days 1 to 14 of each 21 day cycle until disease progression or unacceptable toxicity).[45258] [43412] [58668] Administer nivolumab prior to chemotherapy when given on the same day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Patients with previously untreated advanced or metastatic gastric cancer, GEJ cancer, and esophageal cancer were randomized to treatment with nivolumab 240 mg IV in combination with mFOLFOX6 every 2 weeks, nivolumab 360 mg IV in combination with CapeOx every 3 weeks, or the same chemotherapy without nivolumab in a multicenter, open-label trial (CHECKMATE-649; n = 1,581). Overall survival was significantly improved with the addition of nivolumab to chemotherapy in the overall patient population (13.8 months vs. 11.6 months); results were consistent in patients with PD-L1 Combined Positive Score (CPS) of 1 or higher and PD-L1 CPS of 5 or higher. The median progression free survival was 7.7 months in patients who received nivolumab compared with 6.9 months in those who did not. The overall response rate was 47% versus 37% respectively (complete response, 10% vs. 7%), for a median duration of 8.5 months versus 6.9 months.[58668] [66712]
Dosage adjustments for Treatment-Related Toxicities:
Gastrointestinal toxicity
Hematologic toxicity: Do not administer the next cycle of chemotherapy until the ANC is greater than or equal to 1,500/mm3 and platelets are greater than or equal to 75,000/mm3.
Hypersensitivity Reactions
Neurosensory toxicity
Posterior Reversible Encephalopathy Syndrome (PRES)
Pulmonary toxicity
Rhabdomyolysis
130 mg/m2 IV.
130 mg/m2 IV.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Oxaliplatin is an intravenous, non cell-cycle specific, platinum-based alkylating agent. Unlike cisplatin or carboplatin, it is not associated with significant renal or auditory toxicity. It contains a bulky carrier ligand (1,2-diaminocyclohexane [DACH] which is not present in either cisplatin or carboplatin, contributing to a lack of cross-resistance with these compounds.[41958][27029] Oxaliplatin is indicated for the treatment of colorectal cancer in combination with fluorouracil and leucovorin. Acute or delayed neuropathy can occur; avoid the topical application of ice, as cold temperatures may exacerbate acute neuropathy.[41958]
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
Emetic Risk
Extravasation Risk
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Reconstitution (lyophilized powder):
Dilution (aqueous solution and reconstituted lyophilized powder):
Administration:
Sensory peripheral neuropathy occurred in 92% (grade 3 or 4, 12%) of patients receiving adjuvant oxaliplatin with fluorouracil/leucovorin compared with 12% of those receiving fluorouracil/leucovorin alone in a randomized clinical trial; sensory disturbances also occurred in 8% (grade 3 or 4, 1%) of oxaliplatin-treated patients in this study. Neuropathy occurred in 69% to 82% (grade 3 or 4, 7% to 19%) of patients with advanced colorectal cancer. In previously untreated patients with advanced disease, that included paresthesias (62% to 77%; grade 3 or 4, 6% to 18%), pharyngolaryngeal dysesthesias (28% to 38%; grade 3 or 4, 1% to 2%), other neurosensory deficits (9% to 12%; grade 3 or 4, 1%), and neurologic symptoms not otherwise specified (1%); neuralgia was separately reported in 2% to 5% of these patients (grade 3 or 4, 1% or less). Oxaliplatin-related neuropathy can occur in two different timeframes: acute neuropathy, which usually occurs within hours or up to 2 days after a dose and resolves within 14 days of onset, and delayed neuropathy, which is typically persistent and lasting beyond 14 days. Acute neuropathy is often reversible and frequently recurs with subsequent dosing. Common symptoms include transient paresthesias, dysesthesia, and hypoesthesia in the hands, feet, perioral area, or throat and can be precipitated or exacerbated by exposure to cold temperature or cold objects. Jaw spasm, abnormal tongue sensation, dysarthria, ocular pain, chest pressure, and dysphagia or dyspnea without any laryngospasm or bronchospasm have also been observed. Acute neuropathy occurred in 56% to 65% (grade 3 or 4, 2% to 5%) of patients with advanced colorectal cancer receiving oxaliplatin therapy. Delayed neuropathy occurred in 43% to 48% (grade 3 or 4, 3% to 6%) of patients with advanced colorectal cancer receiving oxaliplatin therapy and can occur without any prior acute neuropathy; symptoms may improve upon discontinuation of oxaliplatin. While symptoms are also typically consistent with a peripheral sensory neuropathy, deficits in proprioception interfering with daily activities (e.g., writing, buttoning, swallowing, and walking) can also occur.[41958] The risk of developing function impairment was estimated to occur in 10% of patients receiving a cumulative oxaliplatin dose of 780 mg/m2 and 50% at a cumulative dose of 1,170 mg/m2.[27029]
Elevated serum creatinine occurred in 4% to 5% of patients with previously untreated advanced colorectal cancer treated with oxaliplatin in combination with chemotherapy (fluorouracil/leucovorin or irinotecan) in a randomized clinical trial. Acute renal tubular necrosis, acute interstitial nephritis, and acute renal failure (unspecified) have also been reported in postmarketing experience with oxaliplatin.[41958]
Diarrhea occurred in 46% to 67% (grade 3 or 4, 4% to 12%) of patients with colorectal cancer receiving oxaliplatin as monotherapy or in combination with fluorouracil/leucovorin; the incidence was higher in those receiving oxaliplatin plus irinotecan (76%; grade 3 or 4, 25%). Colostomy diarrhea was separately reported in patients with previously untreated advanced colorectal cancer receiving oxaliplatin with fluorouracil/leucovorin (13%; grade 3 or 4, 2%) or irinotecan (16%; grade 3 or 4, 3%). Tenesmus occurred in 2% to 5% of patients with previously-treated advanced colorectal cancer treated with oxaliplatin plus fluorouracil/leucovorin. The incidence of severe (grade 3 or 4) diarrhea was more common in females than in males, and in patients 65 years or older compared to younger patients. Severe diarrhea resulting in hypokalemia and colitis (including Clostridium difficile diarrhea) have been reported in postmarketing experience with oxaliplatin.[41958]
Thromboembolism occurred in 2% (grade 3 or 4, 1%) of patients with previously-treated advanced colorectal cancer receiving oxaliplatin monotherapy and in 9% (grade 3 or 4, 8%) of those receiving oxaliplatin plus fluorouracil/leucovorin in a randomized clinical trial. Thrombosis occurred in 3% to 6% (grade 3 or 4, 3% to 5%) of patients with previously untreated advanced colorectal cancer receiving oxaliplatin in combination with either fluorouracil/leucovorin or irinotecan in another clinical trial. Thromboembolic events occurred in 6% (grade 3 or 4, 1.2%) of patients receiving adjuvant therapy for colorectal cancer with oxaliplatin and fluorouracil/leucovorin.[41958]
An injection site reaction including redness, swelling, pain, and thrombosis related to the catheter was reported in 4% to 11% (grade 3 or 4, 3% or less) of patients receiving oxaliplatin as monotherapy or in combination with chemotherapy (fluorouracil/leucovorin or irinotecan) in clinical trials. Extravasation of oxaliplatin may result in local pain and inflammation that may be severe and lead to complications including tissue necrosis.[41958]
Unspecified skin disorders were reported in 32% (grade 3 or 4, 2%) of patients with colorectal cancer receiving adjuvant therapy with oxaliplatin plus fluorouracil/leucovorin compared with 36% (grade 3 or 4, 2%) of those receiving fluorouracil/leucovorin alone in a randomized clinical trial. Rash was reported in 5% to 11% (grade 3 or 4, less than 1%) of patients with advanced colorectal cancer receiving oxaliplatin as monotherapy or in combination with chemotherapy (fluorouracil/leucovorin or irinotecan). Palmar-plantar erythrodysesthesia (hand and foot syndrome) occurred in 1% of patients with advanced disease receiving oxaliplatin monotherapy, in 1% of patients receiving oxaliplatin plus irinotecan, and in 7% to 11% (grade 3 or 4, 1% or less) of those treated with oxaliplatin in combination with fluorouracil/leucovorin. Additional dermatologic adverse reactions that occurred in patients treated with oxaliplatin plus fluorouracil/leucovorin include pruritus (2% to 6%), xerosis (2% to 6%), nail changes (2% to 5%), pigmentation changes (2% to 5%), urticaria (2% to 5%), and erythematous rash (2% to 5%).[41958]
Serious hypersensitivity reactions or anaphylaxis can occur within minutes of oxaliplatin administration and during any cycle. Symptoms were similar in nature and severity to those reported with other platinum-containing compounds, and may include rash, urticaria, erythema, pruritus, and rarely, bronchospasm and hypotension. Allergic reactions were reported in 10% (grade 3 or 4, 3% or less) of colon cancer patients treated with oxaliplatin in combination with fluorouracil and leucovorin in clinical trials. Grade 3 or 4 hypersensitivity reactions, including anaphylaxis or anaphylactoid reactions, occurred in 2% to 3% of patients with colon cancer who received oxaliplatin. Angioedema, anaphylactic shock, and laryngospasm have been reported in postmarketing experience with oxaliplatin. Immediately and permanently discontinue oxaliplatin for hypersensitivity reactions and administer appropriate treatment for the management of hypersensitivity reactions.[41958]
Elevated hepatic enzymes (ALT/AST) (57% vs. 34%; grade 3 or 4, 2% vs. 1%) and alkaline phosphatase (42% vs. 20%; grade 3 or 4, less than 1% vs. less than 1%) occurred more often in patients receiving adjuvant therapy for colorectal cancer with oxaliplatin plus fluorouracil/leucovorin compared with fluorouracil/leucovorin alone in a randomized clinical trial; hyperbilirubinemia occurred with a similar frequency in each arm (20% vs. 20%; grade 3 or 4, 4% vs. 5%). On liver biopsies, peliosis hepatis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive disease (VOD) were observed. Increased AST (47% to 54%; grade 3 or 4, 4% or less), increased ALT (31% to 36%; grade 3 or 4, 1% or less), and increased bilirubin (13%; grade 3 or 4, 1% to 5%) were also reported in patients with previously-treated advanced colorectal cancer receiving oxaliplatin as monotherapy or in combination with fluorouracil/leucovorin, with enlarged abdomen and ascites each reported in 2% to 5% of patients in the combination therapy arm. In another randomized trial of patients with previously untreated advanced colorectal cancer receiving oxaliplatin with either fluorouracil/leucovorin or irinotecan, elevated liver function tests occurred less frequently including increased alkaline phosphatase (14% to 16%; grade 3 or 4, 2% or less), increased AST (11% to 17%; grade 3 or 4, 1%), increased ALT (5% to 6%; grade 3 or 4, 1% vs. 2%), and hyperbilirubinemia (3% to 6%; grade 3 or 4, 1% to 2%). Sinusoidal obstruction syndrome (SOS), perisinusoidal fibrosis (which rarely may progress), and focal nodular hyperplasia have also been reported in postmarketing experience with oxaliplatin.[41958]
Ataxia and involuntary muscle contractions were each reported in 2% to 5% of patients with previously-treated advanced colorectal cancer treated with oxaliplatin plus fluorouracil/leucovorin. Additionally, loss of deep tendon reflexes, Lhermitte's sign, cranial nerve palsies, fasciculations, and seizures have been reported in postmarketing experience with oxaliplatin.[41958]
Pulmonary fibrosis, which may be fatal, occurred in less than 1% of patients treated with oxaliplatin in clinical trials. The combined incidence of cough and dyspnea was 7.4% (grade 3, less than 1%) in patients receiving adjuvant therapy for colorectal cancer with oxaliplatin plus fluorouracil/leucovorin; dyspnea alone occurred in 5% (grade 3 or 4, less than 1%) of patients. In patients with previously untreated advanced colorectal cancer, the combined incidence of cough, dyspnea, and hypoxia was 43% (grade 3 or 4, 7%) in those who received oxaliplatin plus fluorouracil/leucovorin. Cough occurred in 11% to 35% (grade 3 or 4, 1% or less), dyspnea in 11% to 20% (grade 3 or 4, 2% to 7%), hypoxia in less than 5%, and pneumonitis in less than 5% of patients with advanced colorectal cancer receiving oxaliplatin as monotherapy or in combination with fluorouracil/leucovorin or irinotecan. Interstitial lung disease, sometimes fatal, was reported in postmarketing experience with oxaliplatin.[41958]
Abnormal lacrimation occurred in 1% to 9% of patients treated with oxaliplatin across clinical trials. Conjunctivitis was also reported in 2% to 9% of patients who received oxaliplatin in combination with fluorouracil/leucovorin. Visual impairment occurred in 5% to 6% (grade 3 or 4, 1% or less) of patients with previously untreated advanced colorectal cancer treated with oxaliplatin in combination with chemotherapy (fluorouracil/leucovorin or irinotecan) in one randomized clinical trial. Additional visual adverse reactions reported in postmarketing experience with oxaliplatin include decreased visual acuity, visual field disturbance, optic neuritis, and transient vision loss that was reversible following discontinuation of therapy.[41958]
Fatigue occurred in 44% (grade 3 or 4, 4%) of patients with colorectal cancer receiving adjuvant therapy with oxaliplatin plus fluorouracil/leucovorin compared with 38% of those receiving fluorouracil/leucovorin alone. The incidence of fatigue was higher in patients with advanced disease receiving oxaliplatin as monotherapy or in combination with chemotherapy (61% to 70%; grade 3 or 4, 7% to 16%); somnolence was also reported in 2% to 5% of patients with previously-treated advanced colorectal cancer receiving oxaliplatin in combination with fluorouracil/leucovorin. Generalized pain was reported in 6% to 15% (grade 3 or 4, 1% to 3%) of patients with advanced disease receiving oxaliplatin therapy. Back pain (11% to 19%; grade 3 or 4, 3%), bone pain (2% to 5%), and rectal pain (2% to 5%) were additionally reported in those with previously-treated advanced colorectal cancer.[41958]
Infection in patients with a normal ANC occurred in 7% to 10% (grade 3 or 4, 2% to 4%) of patients with previously untreated advanced colorectal cancer receiving oxaliplatin in combination with chemotherapy; neutropenic infection occurred in 8% to 9% (grade 3 or 4, 8%) of these patients. Documented neutropenic infection occurred in 1.1% of patients receiving adjuvant therapy for colorectal cancer with oxaliplatin plus fluorouracil/leucovorin. Specific infections reported in clinical trials with oxaliplatin have included rhinitis (6% to 15%), upper respiratory tract infection (7% to 10%), pharyngitis (2% to 9%), catheter infection (2% to 5%), pneumonia (2% to 5%), proctitis (2% to 5%), gingivitis (2% to 5%), and unknown infection (2% to 5%); allergic rhinitis has also occurred in less than 10% of oxaliplatin-treated patients. Septic shock, including fatal outcomes, was reported in postmarketing experience with oxaliplatin.[41958]
QT prolongation leading to ventricular arrhythmias, including fatal torsade de pointes, was observed in postmarketing experience. Monitor ECGs in appropriate patients; monitor and correct any electrolyte abnormalities. Chest pain (unspecified) occurred in 2% to 8% (grade 3 or 4, 1% or less) of patients with advanced colorectal cancer receiving oxaliplatin as monotherapy or in combination with fluorouracil/leucovorin. Sinus tachycardia occurred in 2% to 5% of patients with previously-treated advanced colorectal cancer receiving oxaliplatin plus fluorouracil/leucovorin. Additionally, bradyarrhythmias (bradycardia) have been reported in postmarketing experience with oxaliplatin.[41958]
Rhabdomyolysis, including fatal cases, has been reported in postmarketing experience with oxaliplatin; permanently discontinue oxaliplatin for any signs or symptoms of rhabdomyolysis. Myalgia occurred in 2% to 14% (grade 3 or 4, 2% or less) and arthralgia in 5% to 10% (grade 3 or 4, less than 1%) of patients with advanced colorectal cancer treated with oxaliplatin as monotherapy or in combination with fluorouracil/leucovorin or irinotecan; muscle weakness was also reported in 2% to 5% of patients with previously treated advanced colorectal cancer treated with oxaliplatin in combination with fluorouracil/leucovorin. Fall-related injuries have been reported in patients treated with oxaliplatin in postmarketing experience.[41958]
Hypokalemia occurred in 3% to 11% (grade 3 or 4, 2% to 3%) of patients with advanced colorectal cancer who received oxaliplatin as monotherapy or in combination with chemotherapy (fluorouracil/leucovorin or irinotecan) in clinical trials. Hyponatremia (4% to 8%; grade 3 or 4, 1% to 2%) and hypocalcemia (4% to 7%; grade 3 or 4, less than 1%) were additionally reported in patients with previously untreated advanced colorectal cancer treated with oxaliplatin plus chemotherapy in one randomized trial.[41958]
Treatment with oxaliplatin has been associated with thrombotic thrombocytopenic purpura (TTP).[54400][54401] One case presented 2 years after initial treatment with FOLFOX-bevacizumab, after a partial infusion of oxaliplatin on cycle 2 of FOLFOX for progressive disease. Two weeks after treatment with high dose prednisone and plasma exchange, repeat indirect and direct Coombs tests were negative.[54400] A similar case occurred in another patient 5 years after initial treatment with FOLFOX. After a partial infusion of oxaliplatin on the third cycle of FOLFOX for progressive disease, the patient experienced acute, severe thrombocytopenia which responded to a platelet transfusion and normalized by the following day.[54401]
Thrombocytopenia occurred in 30% (grade 3 or 4, 3%) of patients with previously-treated advanced colorectal cancer receiving oxaliplatin monotherapy, in 64% to 77% (grade 3 or 4, 2% to 5%) of patients receiving oxaliplatin in combination with fluorouracil/leucovorin as adjuvant therapy or treatment for advanced disease, and in 44% (grade 3 or 4, 4%) of those receiving oxaliplatin with irinotecan for advanced disease. Rapid onset of thrombocytopenia and greater risk of bleeding have been observed in immune-mediated thrombocytopenia, which has been reported in postmarketing experience with oxaliplatin.[41958]
Bone marrow suppression has occurred in patients treated with oxaliplatin in clinical trials. Neutropenia occurred in 7% of patients with previously-treated advanced colorectal cancer receiving oxaliplatin monotherapy (n = 153) in one clinical trial, and in 73% to 81% (grade 3 or 4, 36% to 53%) of patients receiving oxaliplatin in combination with fluorouracil/leucovorin or irinotecan as adjuvant therapy or treatment for advanced disease across 3 clinical trials. Grade 3 or 4 neutropenia was more common in females than males, and in older patients (65 years or older) than in younger patients. Leukopenia occurred in 13% of patients with advanced colorectal cancer receiving oxaliplatin monotherapy and in 76% to 85% (grade 3 or 4, 19% to 24%) of those with advanced disease receiving oxaliplatin in combination with chemotherapy. Lymphopenia occurred in 5% to 6% (grade 3 or 4, 2%) of patients with previously untreated advanced colorectal cancer receiving oxaliplatin with fluorouracil/leucovorin or irinotecan.[41958]
The incidence of anemia varies between studies. The most common incidence of anemia ranges from 64% to 81% (grade 3 or 4, 1% to 2%) when oxaliplatin is given either as monotherapy for previously-treated advanced colorectal cancer or in combination with fluorouracil/leucovorin for either adjuvant treatment or previously-treated advanced disease in 2 clinical trials. It occurred in 25% to 27% (grade 3 or 4, 3%) of patients with previously untreated advanced colorectal cancer receiving oxaliplatin with either fluorouracil/leucovorin or irinotecan in another clinical trial. Immune-mediated hemolytic anemia has also been reported in postmarketing experience with oxaliplatin.[41958]
Bleeding occurred more often in patients treated with oxaliplatin plus fluorouracil/leucovorin compared to those receiving fluorouracil/leucovorin alone in clinical trials, including GI bleeding, hematuria, and epistaxis. In a clinical trial of adjuvant oxaliplatin plus fluorouracil/leucovorin for colorectal cancer, grade 3 or 4 GI bleeding occurred in 0.2% of patients; 2 patients died from intracranial bleeding. Epistaxis occurred in 9% to 16% (grade 3 or 4, less than 1%) of colorectal cancer patients receiving oxaliplatin plus fluorouracil/leucovorin, in 2% (grade 3 or 4, less than 1%) of those receiving oxaliplatin plus irinotecan, and in 2% of patients receiving oxaliplatin monotherapy. Rectal bleeding occurred in 2% to 5% of patients treated with advanced colorectal cancer receiving oxaliplatin plus fluorouracil/leucovorin. Additionally, hematuria (6%; grade 3 or 4, less than 1%), hemoptysis (2% to 5%), purpura (2% to 5%), vaginal bleeding (2% to 5%), and melena (2% to 5%) occurred in patients with previously-treated colorectal cancer receiving oxaliplatin plus fluorouracil/leucovorin.[41958]
Prolonged bleeding time (prothrombin time) occurred in 2% to 5% of patients with previously untreated advanced colorectal cancer treated with oxaliplatin plus fluorouracil/leucovorin in a randomized clinical trial. Additionally, there have been postmarketing reports of prolonged prothrombin time and INR in patients receiving oxaliplatin and anticoagulants.[41958]
Posterior Reversible Encephalopathy Syndrome (PRES), also known as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), occurred in less than 0.1% of patients treated with oxaliplatin across clinical trials. Signs and symptoms can include headache, altered mental status, seizures, and abnormal vision (e.g., blurred vision, blindness). Confirm the diagnosis of PRES with magnetic resonance imaging; permanently discontinue therapy in patients who develop PRES.[41958]
Constipation occurred in 21% to 32% (grade 3 or 4, 4% or less) and abdominal pain in 18% to 32% (grade 3 or 4, 1%) of patients with colorectal cancer who received oxaliplatin as monotherapy or in combination with fluorouracil/leucovorin or irinotecan in clinical trials. Abdominal pain occurred in 18% to 33% (grade 3 or 4, 1% to 8%) of colorectal cancer patients who received oxaliplatin as monotherapy or in combination with fluorouracil/leucovorin; it was more common in patients receiving oxaliplatin plus irinotecan (39%; grade 3 or 4, 10%). Hemorrhoids and GI obstruction each occurred in 2% to 5% of patients with previously-treated advanced colorectal cancer treated with oxaliplatin in combination with fluorouracil/leucovorin. GI obstruction has also been reported in postmarketing experience with oxaliplatin, along with ileus.[41958]
Nausea (64% to 74%; grade 3 or 4, 4% to 11%) and vomiting (37% to 47%; grade 3 or 4, 4% to 9%) have been reported in patients receiving oxaliplatin as monotherapy or in combination with fluorouracil/leucovorin in clinical trials; the incidence of nausea (83%; grade 3 or 4, 19%) and vomiting (64%; grade 3 or 4, 23%) were higher in patients treated with oxaliplatin plus irinotecan. Oxaliplatin monotherapy caused nausea in 64% (grade 3 or 4, 4%) and vomiting in 37% (grade 3 or 4, 4%) of patients with previously-treated advanced colorectal cancer; the incidence of nausea (65%; grade 3 or 4, 11%) and vomiting (40%; grade 3 or 4, 9%) were similar in patients receiving oxaliplatin in combination with fluorouracil/leucovorin. The addition of oxaliplatin to fluorouracil/leucovorin increased the incidence of nausea (74% vs. 61%; grade 3 or 4, 5% vs. 2%) and vomiting (47% vs. 24%; grade 3 or 4, 6% vs. 1%) compared with fluorouracil/leucovorin alone in patients receiving adjuvant treatment for colorectal cancer in a randomized clinical trial; grade 3 or 4 nausea and vomiting were more common in females compared to males in this study. Severe vomiting resulting in hypokalemia has been reported in postmarketing experience with oxaliplatin.[41958]
Dyspepsia occurred in 5% to 14% (grade 3 or 4, less than 1%) of patients with colorectal cancer treated with oxaliplatin as monotherapy or in combination with chemotherapy (fluorouracil/leucovorin or irinotecan). Gastroesophageal reflux was separately reported in 1% of patients with previously-treated advanced colorectal cancer receiving oxaliplatin monotherapy compared versus 5% (grade 3 or 4, 2%) of those receiving oxaliplatin plus fluorouracil/leucovorin.[41958]
Stomatitis occurred in 14% of patients with previously-treated advanced colorectal cancer treated with oxaliplatin monotherapy compared with 37% (grade 3 or 4, 3%) of those receiving oxaliplatin in combination with fluorouracil/leucovorin in a randomized clinical trial; mucositis was separately reported in 2% versus 7% of patients, respectively. The incidence of stomatitis in patients treated with oxaliplatin plus fluorouracil/leucovorin was consistent across clinical trials (37% to 42%; grade 3 or 4, 3% or less) and is similar to patients receiving fluorouracil/leucovorin alone (40%; grade 3 or 4, 2%). Stomatitis occurred in 19% (grade 3 or 4, 1%) of patients with previously untreated advanced colorectal cancer treated with oxaliplatin in combination with irinotecan. Esophagitis has also been reported in postmarketing experience with oxaliplatin.[41958]
Anorexia occurred in 13% (grade 3 or 4, 1%) of patients receiving adjuvant therapy for colorectal cancer with oxaliplatin plus fluorouracil/leucovorin compared with 8% (grade 3 or 4, less than 1%) of those receiving fluorouracil/leucovorin alone in a randomized clinical trial. Anorexia was more common in patients with advanced colorectal cancer treated with oxaliplatin as monotherapy or in combination with chemotherapy (fluorouracil/leucovorin or irinotecan) in clinical trials (20% to 35%; grade 3 or 4, 2% to 5%). Taste perversion/dysgeusia occurred in 5% to 14% (grade 3 or 4, less than 1%) of patients treated with oxaliplatin across clinical trials.[41958]
Weight loss occurred in 2% to 11% (grade 3 or 4, less than 1%) of patients with colorectal cancer treated with oxaliplatin as monotherapy or in combination with chemotherapy (fluorouracil/leucovorin or irinotecan) across clinical trials.[41958]
Flatulence occurred in 3% to 9% (grade 3 or 4, less than 1%) of patients with advanced colorectal cancer treated with oxaliplatin as monotherapy or in combination with chemotherapy (fluorouracil/leucovorin or irinotecan) in clinical trials.[41958]
Pancreatitis has been reported in postmarketing experience with oxaliplatin.[41958]
Xerostomia occurred in 2% to 5% (grade 3 or 4, less than 1%) of patients with advanced colorectal cancer treated with oxaliplatin as monotherapy or in combination with chemotherapy (fluorouracil/leucovorin or irinotecan) in clinical trials.[41958]
Hearing loss and deafness have been reported in postmarketing experience with oxaliplatin.[41958]
Alopecia occurred in 30% of patients with colorectal cancer receiving adjuvant therapy with oxaliplatin plus fluorouracil/leucovorin compared with 28% of those receiving fluorouracil/leucovorin alone in a randomized clinical trial. In patients with previously untreated advanced colorectial cancer, alopecia occurred in 38% of those receiving oxaliplatin in combination with fluorouravil/leucovorin compared with 67% of those treated with oxaliplatin plus irinotecan. The incidence of alopecia was much lower in one clinical trial of patients with previously-treated advanced colorectal cancer (3% to 7%). No complete alopecia was reported in these studies.[41958]
Flushing occurred in 3% to 10% (grade 3 or 4, less than 1%) and diaphoresis in 2% to 12% (grade 3 or 4, less than 1%) of patients with advanced colorectal cancer who received oxaliplatin in clinical trials. Hot flashes were also reported in 2% to 5% of patients with previously-treated advanced colorectal cancer who received oxaliplatin in combination with fluorouracil/leucovorin.[41958]
Fever occurred in 27% (grade 3 or 4, 1%) of patients with colorectal cancer receiving adjuvant therapy with oxaliplatin plus fluorouracil/leucovorin compared with 12% (grade 3 or 4, 1%) of those receiving fluorouracil/leucovorin alone in a randomized clinical trial; across clinical trials, fever occurred in 9% to 29% (grade 3 or 4, 1% or less) of those who received oxaliplatin. In the adjuvant study, neutropenic fever occurred in 0.7% of patients receiving oxaliplatin. Neutropenic fever was not reported in patients receiving oxaliplatin monotherapy for advanced disease but occurred in 4% to 6% of patients treated with oxaliplatin plus fluorouracil/leucovorin (all grade 3 or 4) and in 12% (grade 3 or 4, 11%) of patients receiving oxaliplatin plus irinotecan. Rigors were reported in 7% to 9% of patients with advanced colorectal cancer who received oxaliplatin.[41958]
Dehydration occurred in 5% to 14% (grade 3 or 4, 3% to 7%) of patients with advanced colorectal cancer treated with oxaliplatin as monotherapy or in combination with chemotherapy (fluorouracil/leucovorin or irinotecan) in clinical trials.[41958]
Hypoalbuminemia occurred in 8% to 9% (grade 3 or 4, 1% or less) of patients with previously untreated advanced colorectal cancer who received oxaliplatin in combination with chemotherapy (fluorouracil/leucovorin or irinotecan) in a randomized clinical trial.[41958]
Hyperglycemia occurred in 12% to 14% (grade 3 or 4, 2% to 3%) of patients with previously untreated advanced colorectal cancer who received oxaliplatin in combination with chemotherapy (fluorouracil/leucovorin or irinotecan) in a randomized clinical trial.[41958]
Hemolytic-uremic syndrome has been reported in postmarketing experience with oxaliplatin.[41958]
Headache occurred in 7% to 17% (grade 3 or 4, less than 1%) of patients treated with oxaliplatin as monotherapy or in combination with chemotherapy (fluorouracil/leucovorin or irinotecan) across clinical trials.[41958]
Dizziness occurred in 7% to 13% of patients with advanced colorectal cancer treated with oxaliplatin as monotherapy or in combination with chemotherapy (fluorouracil/leucovorin or irinotecan) in clinical trials. Vertigo and syncope were also each reported in 2% to 5% of patients with previously untreated advanced colorectal cancer receiving oxaliplatin plus chemotherapy in a randomized trial.[41958]
In a randomized trial of patients with previously untreated advanced colorectal cancer, 5% of patients who received oxaliplatin plus fluorouracil/leucovorin (grade 3 or 4, 1%) and 3% of those treated with oxaliplatin plus irinotecan (grade 3 or 4, 2%) experienced hiccups.[41958]
Hypotension occurred in 4% to 5% (grade 3 or 4, 3%) of patients with previously untreated advanced colorectal cancer treated with oxaliplatin in combination with chemotherapy (fluorouracil/leucovorin or irinotecan) in a randomized clinical trial. Hypertension was reported in 2% to 5% of patients who received oxaliplatin plus fluorouracil/leucovorin in this trial.[41958]
Various urinary adverse reactions have been reported in patients treated with oxaliplatin. Dysuria occurred in 1% to 6% (grade 3 or 4, less than 1%) of patients with advanced colorectal cancer treated with oxaliplatin as monotherapy or in combination with chemotherapy (fluorouracil/leucovorin or irinotecan) in clinical trials. Increased urinary frequency was reported in 3% to 5% of patients with previously untreated advanced colorectal cancer receiving oxaliplatin in combination with chemotherapy (grade 3 or 4, 1% or less). Abnormal micturition frequency and urinary incontinence were each reported in 2% to 5% of patients with previously treated advanced colorectal cancer who received oxaliplatin plus fluorouracil/leucovorin.[41958]
A new primary malignancy (leukemia) has been reported in patients previously treated with oxaliplatin in postmarketing experience.[41958]
Generalized edema was reported in 10% to 15% (grade 3 or 4, 1% or less) of patients with advanced colorectal cancer treated with oxaliplatin as monotherapy or in combination with chemotherapy (fluorouracil/leucovorin or irinotecan) in clinical trials; this was not meaningfully different from patients in these trials receiving chemotherapy without oxaliplatin (13%; grade 3 or 4, 1% or less). The incidence of peripheral edema was lower in patients with previously-treated advanced colorectal cancer who received oxaliplatin monotherapy compared to those receiving fluorouracil/leucovorin with or without oxaliplatin (5% vs. 10% to 11%; grade 3 or 4, less than 1% vs. less than 1%).[41958]
Dysphagia occurred in 3% to 5% of patients with previously untreated advanced colorectal cancer treated with oxaliplatin in combination with chemotherapy (fluorouracil/leucovorin or oxaliplatin) in a randomized clinical trial (grade 3 or 4, less than 1%).[41958]
Insomnia occurred in 9% to 13% (grade 3 or 4, less than 1%) of patients with advanced colorectal cancer treated with oxaliplatin as monotherapy or in combination with chemotherapy (fluorouracil/leucovorin or irinotecan) compared with 4% to 9% of those receiving chemotherapy without oxaliplatin in 2 clinical trials.[41958]
Anxiety (2% to 6%; grade 3 or 4, less than 1%) and depression (2% to 9%; grade 3 or 4, less than 1%) have been reported in patients with advanced colorectal cancer treated with oxaliplatin in combination with chemotherapy (fluorouracil/leucovorin or irinotecan) in 2 randomized clinical trials. Nervousness was separately reported in 2% to 5% of patients with previously-treated advanced colorectal cancer who received oxaliplatin plus fluorouracil/leucovorin in one of these trials.[41958]
Oxaliplatin is contraindicated in patients who have exhibited platinum compound hypersensitivity to oxaliplatin or other platinum compounds. Administration of oxaliplatin is associated with a risk of serious hypersensitivity reactions or anaphylaxis, which may occur during any cycle within minutes of oxaliplatin administration. These reactions are similar in nature and severity to those reported with other platinum-containing compounds, including rash, urticaria, erythema, pruritus, and rarely, bronchospasm and hypotension. Monitor patients for signs and symptoms of hypersensitivity. Discontinue oxaliplatin in patients who develop a hypersensitivity reaction to oxaliplatin, and do not rechallenge.[41958]
Due to dose-limiting neurotoxicity, oxaliplatin should be used cautiously in patients with pre-existing peripheral neuropathy. Instruct patients to avoid the topical application of ice for mucositis prophylaxis or other conditions, as cold temperature can exacerbate acute neurological symptoms. This acute type of neuropathy is usually sensory and peripheral and can occur within hours or up to 2 days after dosing. This type of neuropathy is usually reversible although it frequently recurs with further dosing, and generally resolves within 14 days. Prolongation of the oxaliplatin infusion time from 2 hours to 6 hours may mitigate acute toxicities. A persistent (longer than 14 days), primarily peripheral, sensory neuropathy has also been reported, and may occur without any prior acute neuropathy event; these symptoms may improve in some patients upon discontinuation of oxaliplatin. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for persistent neurosensory reactions based upon severity.[41958]
Use oxaliplatin with caution in patients who have a history of myopathy, as symptoms of rhabdomyolysis could be masked. Rhabdomyolysis, including fatal cases, has been reported in patients treated with oxaliplatin. Patients should be instructed to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or pyrexia or elevated body temperature. Discontinue oxaliplatin if signs or symptoms of rhabdomyolysis occur.[41958]
Avoid the use of oxaliplatin in patients with congenital long QT syndrome. QT prolongation and ventricular arrhythmias, including fatal Torsade de Pointes, have been reported in postmarketing experience with oxaliplatin. Correct hypokalemia or hypomagnesemia before starting therapy and monitor these electrolytes periodically during therapy. Use oxaliplatin with caution in patients with conditions that may increase the risk of QT prolongation including bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalance. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.[28432] [28457] [41958] [56592] [65180]
Bone marrow suppression including neutropenia and thrombocytopenia has been reported in patients treated with oxaliplatin in clinical trials; neutropenic sepsis including fatal occurrences has also occurred. Monitor complete blood counts at baseline, before each subsequent cycle, and as clinically indicated. Do not administer oxaliplatin until the ANC is 1,500 cells/mm3 or more and platelets are 75,000 cells/mm3 or more. Hold oxaliplatin for sepsis or septic shock. A dose reduction is necessary after recovery from grade 4 neutropenia, neutropenic fever, or grade 3 or 4 thrombocytopenia. Consider discontinuing therapy for patients with a rapid onset of thrombocytopenia or thrombocytopenia that may be immune-mediated.[41958]
Use oxaliplatin with caution in patients with pre-existing hepatic disease, as hepatotoxicity manifested by increased transaminases and alkaline phosphatase has been reported with treatment. Monitor liver function tests at baseline, before each subsequent cycle, and as clinically indicated. Changes noted on liver biopsies have included peliosis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive lesions. If abnormal liver function tests or portal hypertension occur which cannot be explained by liver metastases, investigate other hepatic vascular disorders.[41958]
Posterior Reversible Encephalopathy Syndrome (PRES), also known as Reversible Posterior Leukoencephalopathy Syndrome (RPLS), has been reported with oxaliplatin use. Symptoms of PRES include seizures, headache, visual disturbances (e.g., blurry vision or blindness), confusion, and altered mental status. Confirm the diagnosis of PRES with magnetic resonance imaging; permanently discontinue therapy in patients who develop PRES.[41958]
Use oxaliplatin with caution in patients with pre-existing pulmonary disease or chronic lung disease (CLD), as treatment has been associated with pulmonary fibrosis. Hold oxaliplatin therapy if unexplained respiratory symptoms (e.g., nonproductive cough, dyspnea, crackles, or radiological pulmonary infiltrates) occur, until a diagnosis of interstitial lung disease/pneumonitis or pulmonary fibrosis can be excluded.[41958]
Increase the frequency of PT/INR monitoring in patients receiving oral anticoagulant therapy with oxaliplatin. Also, monitor for bleeding in all patients. The incidence of bleeding was higher in patients treated with oxaliplatin plus fluorouracil/leucovorin compared to those receiving fluorouracil/leucovorin without oxaliplatin in clinical trials. Prolonged prothrombin time and INR occasionally associated with hemorrhage have been reported in patients who received oxaliplatin with fluorouracil/leucovorin while on anticoagulants.[41958]
In randomized clinical trials, the rates of overall adverse events were similar across and between patients younger than 65 years and geriatric patients (65 years and older) treated with oxaliplatin in combination with fluorouracil and leucovorin. The incidence of diarrhea, dehydration, hypokalemia, leukopenia, syncope, and fatigue may be higher in elderly patients. Geriatric patients may also be at increased risk for developing a prolonged QT interval when using oxaliplatin.[28432] [28457] [41958] [56592] [65180]
The safety and effectiveness of oxaliplatin have not been established in children. No responses were observed in pediatric patients with relapsed or refractory malignant solid tumors (primarily neuroblastoma and osteosarcoma) in a multicenter, noncomparative trial (n = 43); the dose-limiting toxicity was sensory neuropathy at a dose of 110 mg/m2. In another noncomparative trial (n = 23), no responses were observed in pediatric patients with metastatic or unresectable solid tumors (primarily neuroblastoma and ganglioneuroblastoma); sensory neuropathy was the dose-limiting toxicity at a dose of 160 mg/m2.[41958]
Pregnancy should be avoided by females of reproductive potential during oxaliplatin treatment and for at least 9 months after the last dose. Although there are no adequately controlled studies in pregnant women, oxaliplatin can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving oxaliplatin should be apprised of the potential hazard to the fetus. Oxaliplatin caused developmental mortality (increased early resorptions) when administered to pregnant rats on gestational days 6 to 16 and adversely affected fetal growth when given on gestational days 6 to 10 (decreased fetal weight, delayed ossification).[41958]
Counsel patients about the reproductive risk and contraception requirements during oxaliplatin treatment. Oxaliplatin can be cause fetal harm if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 9 months after treatment with oxaliplatin. Females of reproductive potential should undergo pregnancy testing prior to initiation of regorafenib. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should use effective contraception for 6 months after the last dose of oxaliplatin. Women who become pregnant while receiving oxaliplatin should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of oxaliplatin on human fertility, male and female infertility has been observed in animal studies.[41958]
Due to the potential for serious adverse reactions in nursing infants from oxaliplatin, advise women to discontinue breast-feeding during treatment and for 3 months after the final dose. It is not known whether oxaliplatin is present in human milk, although many drugs are excreted in human milk.[41958]
Oxaliplatin is a non cell-cycle specific, alkylating agent that inhibits DNA replication and transcription via formation of inter- and intrastrand platinum-DNA crosslinks.[41958] It contains a bulky carrier ligand (1,2-diaminocyclohexane [DACH]), which is not present in either cisplatin or carboplatin, that determines the cytotoxicity of oxaliplatin and influences tissue distribution.[27028] Oxaliplatin undergoes nonenzymatic conversion to active metabolites via displacement of the labile oxalate ligand, forming several transient reactive species are formed (e.g., monoaquo and diaquo DACH platinum) which covalently bind with macromolecules.[41958] The DACH carrier ligand is thought to contribute to the enhanced cytotoxicity and lack of cross-resistance between oxaliplatin and cisplatin.[27029] Oxaliplatin produces fewer DNA cross-links compared to cisplatin and is less able to form these cross-links; however, it is more efficient (potent) than cisplatin and thus requires fewer DNA adducts to inhibit DNA chain elongation and produce cytotoxicity.[27028] The DACH ligand may also inhibit DNA repair by preventing or reducing the binding of repair proteins (e.g., the mismatch repair enzyme complex).[27029] Oxaliplatin showed antitumor activity against colon cancer in vitro. In combination with fluorouracil, oxaliplatin exhibits antiproliferative activity in vitro and in vivo greater than either drug alone in several tumor models.[41958]
Tumor cell resistance mechanisms to platinum compounds include reduced accumulation in cells, increased DNA repair mechanisms (e.g., changes in mismatch repair and enhanced replicative bypass), inactivation by conjugation with glutathione or sequestration involving metallothionine, and enhanced tolerance to platinum-DNA adducts. Changes in mismatch repair and enhanced replicative bypass do not appear to contribute to oxaliplatin resistance as compared to cisplatin or carboplatin.[27029]
Revision Date: 02/02/2024, 02:07:00 AMOxaliplatin is administered intravenously. It is highly (greater than 90%) and irreversibly bound to plasma proteins (primarily albumin and gamma-globulins). Platinum also binds irreversibly and accumulates in erythrocytes, where it appears to have no relevant activity. No platinum accumulation was observed in plasma ultrafiltrate following an oxaliplatin dose of 85 mg/m2 every 2 weeks.[41958] Oxaliplatin has a large volume of distribution (440 to 582 liters) compared to cisplatin (19.2 liters) and carboplatin (17 liters); this could be due to the 1,2-diaminocyclohexane (DACH) moiety associated with oxaliplatin, which may confer some advantages in terms of enhanced tissue penetration due to altered cell membrane permeability.[27030][41958] After a 2-hour oxaliplatin infusion, 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. Due to the rapid biotransformation of oxaliplatin, its elimination is described based on platinum levels rather than the parent compound. The decline of ultrafiltrable platinum levels following oxaliplatin administration is triphasic, characterized by 2 relatively short distribution phases (alpha half-life; 0.43 hours; beta half-life, 16.8 hours) and a long terminal elimination phase (half-life 391 hours). Platinum clearance was 10 to 17 liters/hour, exceeding the average human glomerular filtration rate (GFR; 7.5 liters/hour); the renal clearance of ultrafiltrable platinum is significantly correlated with GFR). The major route of platinum elimination is renal excretion, accounting for 54% of a single dose of oxaliplatin after 5 days; fecal excretion accounted for 2% of the dose.[41958] However, because tissue distribution is also important for oxaliplatin clearance, renal clearance alone is not a useful predictor of platinum exposure and toxicity after oxaliplatin administration.[27030]
Affected cytochrome P450 isoenzymes and drug transporters: None
Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation in the blood; there is no evidence of CYP450-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, monoaquo DACH platinum, and diaquo DACH platinum) as well as several noncytotoxic, conjugated species. Oxaliplatin does not inhibit human CYP450 isoenzymes in vitro.[41958]
After a single 85 mg/m2 dose of oxaliplatin over 2 hours, the Cmax of the ultrafiltrable platinum was 0.814 mcg/mL. Interpatient and intrapatient variability in ultrafiltrable platinum exposure (AUC0-48) assessed over 3 cycles was 23% and 6%, respectively.[41958]
The renal clearance of ultrafilterable platinum is significantly correlated with GFR. The mean dose-adjusted AUC of unbound platinum was 40% higher for patients with mild renal impairment (CrCl 50 to 80 mL/min), 95% higher in patients with moderate renal impairment (CrCl 30 to 49 mL/min), and 342% higher in patients with severe renal impairment (CrCl less than 30 mL/min) compared to patients with normal renal function; patients with normal renal function as well as those with mild and moderate renal impairment received oxaliplatin 85 mg/m2 and those with severe renal impairment received oxaliplatin 65 mg/m2. The mean dose-adjusted Cmax of unbound platinum was similar in patients with normal renal function and mild-to-moderate renal impairment but was 38% higher in patients with severe renal impairment.[41958]
In a population pharmacokinetic analysis (n = 105), the mean clearance of ultrafiltrable platinum in pediatric patients was 4.7 liters/hour (CV, 41%). After a dose of oxaliplatin 85 mg/m2, the mean platinum pharmacokinetic parameters in ultrafiltrate were Cmax of 0.75 mcg/mL +/- 0.24 mcg/mL, AUC0-48 of 7.52 mcg x hour/mL +/- 5.07 mcg x hour/mL, and AUCinf of 8.83 mcg x hour/mL +/- 1.57 mcg x hour/mL. After a dose of oxaliplatin 130 mg/m2, the mean Cmax was 1.1 mcg/mL +/- 0.43 mcg/mL, AUC0-48 was 9.74 mcg x hour/mL +/- 2.52 mcg x hour/mL, and AUCinf was 17.3 mcg x hour/mL +/- 5.34 mcg x hour/mL.[41958]
No significant effect of age on the clearance of ultrafiltrable platinum has been observed.[41958]
There is no significant effect of gender on the clearance of ultrafiltrable platinum.[41958]
Pregnancy should be avoided by females of reproductive potential during oxaliplatin treatment and for at least 9 months after the last dose. Although there are no adequately controlled studies in pregnant women, oxaliplatin can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving oxaliplatin should be apprised of the potential hazard to the fetus. Oxaliplatin caused developmental mortality (increased early resorptions) when administered to pregnant rats on gestational days 6 to 16 and adversely affected fetal growth when given on gestational days 6 to 10 (decreased fetal weight, delayed ossification).[41958]
Due to the potential for serious adverse reactions in nursing infants from oxaliplatin, advise women to discontinue breast-feeding during treatment and for 3 months after the final dose. It is not known whether oxaliplatin is present in human milk, although many drugs are excreted in human milk.[41958]
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