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Oxaliplatin

Medically reviewed by Drugs.com. Last updated on Sep 13, 2020.

Pronunciation

(ox AL i pla tin)

Index Terms

  • Diaminocyclohexane Oxalatoplatinum
  • Eloxatin
  • L-OHP
  • Oxalatoplatin
  • Oxalatoplatinum

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Generic: 50 mg/10 mL (10 mL); 100 mg/20 mL (20 mL); 200 mg/40 mL (40 mL)

Solution Reconstituted, Intravenous [preservative free]:

Generic: 50 mg (1 ea); 100 mg (1 ea)

Pharmacologic Category

  • Antineoplastic Agent, Alkylating Agent
  • Antineoplastic Agent, Platinum Analog

Pharmacology

Oxaliplatin, a platinum derivative, is an alkylating agent. Following intracellular hydrolysis, the platinum compound binds to DNA forming cross-links which inhibit DNA replication and transcription, resulting in cell death. Cytotoxicity is cell-cycle nonspecific.

Distribution

Vd: 440 L

Metabolism

Nonenzymatic (rapid and extensive), forms active and inactive derivatives

Excretion

Urine (~54%); feces (~2%)

Half-Life Elimination

Children: Oxaliplatin ultrafilterable platinum (terminal): Median: 293 hours; range: 187 to 662 hours (Beaty 2010).

Adults: Oxaliplatin ultrafilterable platinum: Distribution: Alpha phase: 0.43 hours; Beta phase: 16.8 hours; Terminal: 392 hours.

Protein Binding

>90% primarily albumin and gamma globulin (irreversible binding to platinum)

Special Populations: Renal Function Impairment

The mean AUC of unbound platinum increases as renal function decreases: 40% increase with mild (CrCl 50 to 80 mL/minute), 95% increase with moderate (CrCl 30 to 49 mL/minute), and 342% increase with severe (CrCl <30 mL/minute) renal impairment compared with patients with normal renal function. The mean Cmax was 38% higher in patients with severe impairment compared with patients with normal renal function.

Use: Labeled Indications

Colon cancer, stage III (adjuvant therapy): Adjuvant treatment of stage III colon cancer (in combination with infusional fluorouracil and leucovorin) after complete resection of primary tumor.

Colorectal cancer, advanced: Treatment of advanced colorectal cancer (in combination with infusional fluorouracil and leucovorin).

Off Label Uses

Biliary adenocarcinoma, advanced

Data from two phase II studies support the use of oxaliplatin (in combination with gemcitabine or with capecitabine) in the treatment of advanced biliary adenocarcinoma [Andre 2004], [Nehls 2008].

Chronic lymphocytic leukemia, refractory

Data from a phase II study support the use of oxaliplatin (in combination with fludarabine, cytarabine, and rituximab) in the treatment of fludarabine-refractory chronic lymphocytic leukemia [Tsimberidou 2008].

Esophageal cancer

Data from a large randomized controlled study support the use of oxaliplatin (in combination with epirubicin and either capecitabine or fluorouracil) in the treatment of advanced esophageal cancer [Cunningham 2008]. Data from two phase II studies also support the use of oxaliplatin (in combination with fluorouracil, leucovorin and docetaxel) in metastatic esophageal cancer [Al-Batran 2008] or (in combination with fluorouracil, leucovorin and radiotherapy) in previously untreated esophageal cancer [Conroy 2010].

Gastric cancer

Data from two large randomized controlled studies support the use of oxaliplatin (in combination with epirubicin and either capecitabine or fluorouracil or in combination with capecitabine) in the treatment of advanced gastric cancer [Bang 2012], [Cunningham 2008]. Data from two phase II studies also support the use of oxaliplatin (in combination with fluorouracil, leucovorin and docetaxel or in combination with fluorouracil and leucovorin) in advanced or metastatic gastric cancer [Al-Batran 2008].

Neuroendocrine tumors (carcinoid), refractory

Data from a small phase II study support the use of oxaliplatin (in combination with capecitabine) for the treatment of well-differentiated neuroendocrine tumors after progression on a somatostatin analog [Bajetta 2007].

Non-Hodgkin lymphoma, relapsed/refractory

Data from small phase II studies support the use of oxaliplatin (in combination with gemcitabine and rituximab) in the treatment of relapsed/refractory non-Hodgkin lymphoma [Lopez 2008], [Rodriguez 2007].

Ovarian cancer, advanced

Data from two phase II studies support the use of oxaliplatin (as a single agent) in the management of previously-treated advanced ovarian cancer [Dieras 2002], [Piccart 2000].

Pancreatic cancer, advanced or metastatic

Data from a randomized phase 2-3 study support the use of oxaliplatin (in combination with fluorouracil, leucovorin, and irinotecan [FOLFIRINOX]) in the management of metastatic pancreatic cancer [Conroy 2011]. Data from a phase 3 study support the use of oxaliplatin (in combination with fluorouracil and leucovorin; OFF regimen) as second-line treatment of advanced pancreatic cancer in patients who had progressed on gemcitabine first-line therapy [Oettle 2014], [Pelzer 2011]. Data from a small phase 2 study also support the use of oxaliplatin (in combination with capecitabine) in the management of advanced pancreatic cancer [Xiong 2008].

According to the American Society of Clinical Oncology (ASCO) guidelines for locally advanced, unresectable pancreatic cancer, induction with at least 6 months of initial systemic therapy (with a combination regimen) is generally recommended in patients with Eastern Cancer Cooperative Group (ECOG) performance status of 0 or 1, a favorable comorbidity profile, a preference for aggressive therapy, and a suitable support system; there is no clear evidence to encourage one regimen over another. If disease progression occurs, treatment according to guidelines for metastatic pancreatic cancer should be offered.

According to the ASCO guidelines for metastatic pancreatic cancer, oxaliplatin, as part of the FOLFIRINOX regimen (fluorouracil, leucovorin, oxaliplatin, and irinotecan), is recommended as first-line therapy in patients with the ECOG performance status of 0 or 1, a favorable comorbidity profile, a preference for aggressive therapy, a suitable support system, and access to a chemotherapy port/infusion pump management service. For patients who received an alternative first-line therapy and meet the above criteria, oxaliplatin (in combination with fluorouracil) may be considered as second-line therapy.

Pancreatic cancer, potentially curable, adjuvant therapy

Data from a multicenter, randomized, phase 3 study support the use of oxaliplatin (in combination with fluorouracil, leucovorin, and irinotecan [modified FOLFIRINOX regimen]) as adjuvant therapy following complete resection of pancreatic ductal adenocarcinoma [Conroy 2018].

According to the ASCO guidelines for potentially curable pancreatic cancer, oxaliplatin, as part of the modified FOLFIRINOX regimen (fluorouracil, leucovorin, oxaliplatin, and irinotecan), is the preferred adjuvant therapy in patients without concerns for toxicity or tolerance and in the absence of medical or surgical contraindications.

Testicular cancer, refractory

Data from three small phase II studies support the use of oxaliplatin (in combination with gemcitabine or with gemcitabine and paclitaxel) in the treatment of refractory testicular cancer [Bokemeyer 2008], [DeGiorgi 2006], [Kollmannsberger 2004], [Pectasides 2004].

Unknown primary cancer, recurrent or refractory

Data from a small multicenter phase II trial support the use of oxaliplatin (in combination with capecitabine) for the treatment of recurrent or refractory cancer of unknown primary [Hainsworth 2010].

Contraindications

Hypersensitivity to oxaliplatin, other platinum-containing compounds, or any component of the formulation.

Canadian labeling: Additional contraindications (not in the US labeling): Preexisting peripheral sensitive neuropathy with functional impairment; pregnancy; breastfeeding; severe renal impairment (CrCl <30 mL/minute).

Dosing: Adult

Note: Oxaliplatin is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017; Roila 2016).

Biliary adenocarcinoma, advanced (off-label use): IV:

GEMOX regimen: 100 mg/m2 on day 2 every 2 weeks (in combination with gemcitabine) until disease progression or unacceptable toxicity (Andre 2004).

or

CAPOX regimen: 130 mg/m2 on day 1 every 3 weeks (in combination with capecitabine) until disease progression or unacceptable toxicity (Nehls 2008).

Chronic lymphocytic leukemia, fludarabine refractory (off-label use): IV: OFAR regimen: 25 mg/m2/day for 4 days every 4 weeks (in combination with fludarabine, cytarabine, and rituximab) for up to 6 cycles (Tsimberidou 2008).

Colorectal cancer (advanced): IV: 85 mg/m2 every 2 weeks until disease progression or unacceptable toxicity (in combination with infusional fluorouracil/leucovorin).

Colorectal cancer (advanced) (off-label dosing/combinations): IV:

FOLFOXIRI regimen: 85 mg/m2 every 2 weeks in combination with fluorouracil/leucovorin/irinotecan (Falcone 2007).

CAPOX regimens: 130 mg/m2 every 3 weeks in combination with capecitabine (Cassidy 2008) or 130 mg/m2 every 3 weeks in combination with capecitabine and bevacizumab (Saltz 2008).

Colon cancer, stage III (adjuvant therapy): IV: 85 mg/m2 every 2 weeks (in combination with infusional fluorouracil/leucovorin) for up to 12 cycles.

Colon cancer (adjuvant therapy) (off-label dosing/combinations): IV:

FLOX regimen: 85 mg/m2/dose on days 1, 15, and 29 of an 8-week treatment cycle in combination with fluorouracil/leucovorin (Kuebler 2007).

XELOX regimen: 130 mg/m2 every 3 weeks in combination with capecitabine (Haller 2011).

Adjuvant therapy duration; completely resected stage III colon cancer (off label):

Low risk (T1, T2, or T3 and N1): A duration of therapy of 3 or 6 months of oxaliplatin (when used in combination with fluoropyrimidine-based therapy) may be offered (ASCO [Lieu 2019]). A pooled analysis of 6 phase III studies demonstrated non-inferiority (based on 3-year disease-free survival) with a 3-month (compared to a 6-month) adjuvant oxaliplatin-capecitabine (CAPOX) treatment duration in the subgroup of patients with T1, T2, or T3 and N1 stage III colon cancer (Grothey 2018).

High risk (T4 and/or N2): A duration of therapy of 6 months of oxaliplatin (when used in combination with fluoropyrimidine-based therapy) should be offered (ASCO [Lieu 2019]). In a pooled analysis of 6 phase III studies, superior disease-free survival has been demonstrated with 6 months (compared to 3 months) of adjuvant FOLFOX therapy in the subgroup of patients with T4 and/or N2 stage III colon cancer (Grothey 2018).

Esophageal/gastric cancers (off-label use): IV: 130 mg/m2 on day 1 every 3 weeks (in combination with epirubicin and either capecitabine or fluorouracil) for up to 8 cycles (Cunningham 2008) or 85 mg/m2 on day 1 every 2 weeks (in combination with docetaxel, leucovorin, and fluorouracil) for up to 8 cycles (Al-Batran 2008) or 85 mg/m2 on day 1 every 2 weeks (in combination with leucovorin and fluorouracil; FOLFOX4) for 6 cycles (Conroy 2010).

or

Gastric cancer: IV: 130 mg/m2 on day 1 every 3 weeks (in combination with capecitabine) for 8 cycles (Bang 2012).

or

Gastroesophageal cancer, advanced, palliative treatment: Frail and/or elderly patients: A dose optimization study which examined 60%, 80%, or 100% of a 130 mg/m2 dose once every 21 days (in combination with capecitabine) found that the 60% dose was not inferior (for progression-free survival) and had less toxicity compared to the full dose (Hall 2019).

Neuroendocrine tumors (carcinoid), refractory (off-label use): IV: 130 mg/m2 on day 1 every 3 weeks (in combination with capecitabine) for up to 6 cycles (Bajetta 2007).

Non-Hodgkin lymphoma, relapsed/refractory (off-label use): IV: 100 mg/m2 on day 1 every 3 weeks (in combination with gemcitabine and rituximab) (Lopez 2008; Rodriguez 2007).

Ovarian cancer, advanced (off-label use): IV: 130 mg/m2 once every 3 weeks until disease progression or unacceptable toxicity (Dieras 2002; Piccart 2000).

Pancreatic cancer, advanced or metastatic (off-label use): IV:

FOLFIRINOX regimen: 85 mg/m2 every 2 weeks (in combination with fluorouracil, leucovorin, and irinotecan) for up to 6 months (Conroy 2011).

OFF regimen (second-line therapy): 85 mg/m2 on days 8 and 22 every 6 weeks (in combination with fluorouracil and leucovorin) until disease progression or unacceptable toxicity (Oettle 2014; Pelzer 2011).

Xelox regimen: 110 to 130 mg/m2 on day 1 every 3 weeks (in combination with capecitabine) until disease progression or unacceptable toxicity (Xiong 2008).

Pancreatic cancer, potentially curable, adjuvant therapy (off-label use): Note: American Society of Clinical Oncology (ASCO) guidelines recommend 6 months of adjuvant therapy if recovery is complete; if preoperative chemotherapy therapy was received, a total of 6 months of adjuvant therapy (including the preoperative regimen) is recommended (ASCO [Khorana 2019]).

mFOLFIRINOX regimen: IV: 85 mg/m2 every 2 weeks (in combination with fluorouracil, leucovorin, and irinotecan; modified FOLFIRINOX regimen) for 24 weeks (Conroy 2018). According to ASCO guidelines, mFOLFIRINOX is the preferred first-line adjuvant regimen for potentially curable disease (ASCO [Khorana 2019]).

Testicular cancer, refractory (off-label use): IV: 130 mg/m2 every 3 weeks in combination with gemcitabine (De Georgi 2006; Kollmannsberger 2004; Pectasides 2004) or 130 mg/m2 on day 1 every 3 weeks (in combination with gemcitabine and paclitaxel) for up to 8 cycles (Bokemeyer 2008).

Unknown primary cancer, recurrent or refractory (off-label use): IV: 130 mg/m2 on day 1 of a 21-day cycle (in combination with capecitabine) for 6 cycles or may continue until clinical benefit no longer realized (Hainsworth 2010).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

No dosage adjustment necessary. Refer to adult dosing.

Dosing: Pediatric

Refer to individual protocols; details concerning dosing in combination regimens should also be consulted.

Solid tumors; refractory or relapsed: Limited data available; several regimens reported; efficacy results highly variable; has shown limited activity in pediatric patients (primarily some delayed tumor progression reported) and an acceptable safety profile; should not be used first-line; reserved for refractory cases; patients should be hydrated prior to and during administration (eg, 3 L/m2/day) (Hartmann 2011; Lam 2015).

Lam 2015; McGregor 2009: Children and Adolescents: IV: 130 mg/m2 over 2 hours on day 1 in combination with etoposide with/without ifosfamide every 21 days.

Geoerger 2011; Macy 2013: Children and Adolescents: IV: 100 mg/m2 over 2 hours on day 1 of a 14-day cycle in combination with gemcitabine or fluorouracil/leucovorin.

Hartmann 2011: Children and Adolescents: IV: 85 mg/m2 over 2 hours on day 1 in combination with irinotecan (day 1) and gemcitabine (day 1 and 8).

Neuroblastoma; refractory or relapsed: Limited data available; efficacy results highly variable; should not be used first-line; reserved for refractory case. Children ≥2 years and Adolescents: IV: 105 mg/m2 on day 1 in combination with doxorubicin on a 21-day cycle (Mascarenhas 2013; Tran 2015).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing adjustments for toxicity: The presented dosing adjustments are based on experience in adult patients. Refer to specific protocol management in pediatric patients if available.

Adult:

Acute toxicities: Longer infusion time (6 hours) may mitigate acute toxicities (eg, pharyngolaryngeal dysesthesia).

Neurosensory events:

Persistent (>7 days) grade 2 neurosensory events:

Adjuvant treatment of stage III colon cancer: Reduce dose to 75 mg/m2.

Advanced colorectal cancer: Reduce dose to 65 mg/m2.

Consider withholding oxaliplatin for grade 2 neuropathy lasting >7 days despite dose reduction.

Persistent (>7 days) grade 3 neurosensory events: Consider discontinuing oxaliplatin.

Gastrointestinal toxicity (grade 3/4) occurring despite prophylactic treatment:

Adjuvant treatment of stage III colon cancer: Delay next dose until recovery from toxicity, then reduce dose to 75 mg/m2.

Advanced colorectal cancer: Delay next dose until recovery from toxicity, then reduce dose to 65 mg/m2.

Hematologic toxicity (grade 4 neutropenia, febrile neutropenia, or grade 3/4 thrombocytopenia):

Adjuvant treatment of stage III colon cancer: Delay next dose until neutrophils recover to ≥1,500/mm3 and platelets recover to ≥75,000/mm3, then reduce dose to 75 mg/m2.

Advanced colorectal cancer: Delay next dose until neutrophils recover to ≥1,500/mm3 and platelets recover to ≥75,000/mm3, then reduce dose to 65 mg/m2.

Pulmonary toxicity (unexplained respiratory symptoms, including nonproductive cough, dyspnea, crackles, pulmonary infiltrates): Discontinue until interstitial lung disease or pulmonary fibrosis have been excluded.

Rhabdomyolysis: Discontinue for signs/symptoms of rhabdomyolysis.

Sepsis or septic shock: Withhold treatment.

Dosing: Adjustment for Toxicity

Oxaliplatin Dosage Adjustment for Adjuvant Therapy in Stage III Colon Cancer

Adverse reaction

Severity

Oxaliplatin dose modification

GI toxicity

Grades 3 or 4

After recovery, reduce oxaliplatin dose to 75 mg/m2 (also reduce fluorouracil doses)

Hematologic toxicity

Grade 4 neutropenia or neutropenic fever

Delay next dose until neutrophils recover to ≥1,500/mm3, then reduce oxaliplatin dose to 75 mg/m2

Grade 3 or 4 thrombocytopenia

Delay next dose until platelets recover to ≥75,000/mm3, then reduce oxaliplatin dose to 75 mg/m2

Peripheral sensory neuropathy

Persistent grade 2

Consider reducing oxaliplatin dose to 75 mg/m2

Persistent grade 3

Consider discontinuing oxaliplatin

Grade 4

Discontinue oxaliplatin

Acute toxicities (including nonlife-threatening infusion reaction)

Longer infusion time (increasing infusion duration from 2 hours to 6 hours) may mitigate acute toxicities

Hypersensitivity

Permanently discontinue oxaliplatin

Posterior reversible encephalopathy syndrome

Permanently discontinue oxaliplatin

Pulmonary toxicity (confirmed interstitial lung disease or pulmonary fibrosis)

Permanently discontinue oxaliplatin

Rhabdomyolysis (signs or symptoms)

Permanently discontinue oxaliplatin

Sepsis or septic shock

Withhold treatment

Oxaliplatin Dosage Adjustment for Advanced Colorectal Cancer

Adverse reaction

Severity

Oxaliplatin dose modification

GI toxicity

Grades 3 or 4

After recovery, reduce oxaliplatin dose to 65 mg/m2 (also reduce fluorouracil doses)

Hematologic toxicity

Grade 4 neutropenia or neutropenic fever

Delay next dose until neutrophils recover to ≥1,500/mm3, then reduce oxaliplatin dose to 65 mg/m2

Grade 3 or 4 thrombocytopenia

Delay next dose until platelets recover to ≥75,000/mm3, then reduce oxaliplatin dose to 65 mg/m2

Neuropathy

Persistent grade 2

Consider reducing oxaliplatin dose to 65 mg/m2

Persistent grade 3

Consider discontinuing oxaliplatin

Grade 4

Discontinue oxaliplatin

Acute toxicities (including nonlife-threatening infusion reaction)

Longer infusion time (increasing infusion duration from 2 hours to 6 hours) may mitigate acute toxicities

Hypersensitivity

Permanently discontinue oxaliplatin

Posterior reversible encephalopathy syndrome

Permanently discontinue oxaliplatin

Pulmonary toxicity (confirmed interstitial lung disease or pulmonary fibrosis)

Permanently discontinue oxaliplatin

Rhabdomyolysis (signs or symptoms)

Permanently discontinue oxaliplatin

Sepsis or septic shock

Withhold treatment

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient's actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

Reconstitution

Do not prepare using a chloride-containing solution such as NaCl due to rapid conversion to monochloroplatinum, dichloroplatinum, and diaquoplatinum; all highly reactive in sodium chloride (Takimoto 2007). Do not use needles or administration sets containing aluminum during preparation (aluminum degrades platinum compounds).

Aqueous solution: Dilution with D5W (250 or 500 mL) is required prior to administration.

Lyophilized powder: Use only SWFI or D5W to reconstitute powder. To obtain final concentration of 5 mg/mL add 10 mL of diluent to 50 mg vial or 20 mL diluent to 100 mg vial. Gently swirl vial to dissolve powder. Dilution with D5W (250 or 500 mL) is required prior to administration. Discard unused portion of vial.

Administration

IV: Administer as IV infusion over 2 hours; extend infusion time to 6 hours for acute toxicities.

Off-label rate: A fixed infusion rate of 1 mg/m2/minute (eg, an 85 mg/m2 dose infused over 85 minutes) has been used and did not show a statistically significant difference in the rate of hypersensitivity reactions (Cercek 2016).

Flush infusion line with D5W prior to administration of any concomitant medication. Avoid mucositis prophylaxis with ice chips, exposure to cold temperatures, or consumption of cold food/beverages during or within hours after oxaliplatin infusion (may exacerbate acute neurological symptoms). Do not use needles or administration sets containing aluminum. When used in combination with a fluoropyrimidine (eg, 5-FU), infuse oxaliplatin first.

Oxaliplatin is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017; Roila 2016).

Irritant with vesicant-like properties; ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation; monitor IV site for redness, swelling, or pain.

Extravasation management: If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; elevate extremity.

Information conflicts regarding use of warm or cold compresses. Cold compresses may cause local vasoconstriction and reduce cellular injury; however, may cause or exacerbate peripheral neuropathy; warm compresses may increase local drug removal, although may also increase cellular uptake and injury (de Lemos 2005).

Storage

Storage time varies by product; refer to individual product labeling for details. Store intact vials at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); do not freeze. Protect concentrated solution from light (store in original outer carton). According to the manufacturer, solutions diluted in D5W for infusion are stable up to 6 hours at room temperature of 20°C to 25°C (68°F to 77°F) or up to 24 hours under refrigeration at 2°C to 8°C (36°F to 46°F). Solutions diluted for infusion do not require protection from light. Oxaliplatin solution diluted with D5W to a final concentration of 0.7 mg/mL (polyolefin container) has been shown to retain >90% of the original concentration for up to 30 days when stored at room temperature or refrigerated; artificial light did not affect the concentration (Andre 2007). As this study did not examine sterility, refrigeration would be preferred to limit microbial growth. Follow USP 797 recommendations for beyond use dates based on the level of risk for preparation.

Drug Interactions

5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Erdafitinib: May increase the serum concentration of OCT2 Substrates. Monitor therapy

Fosphenytoin-Phenytoin: Platinum Derivatives may decrease the serum concentration of Fosphenytoin-Phenytoin. Monitor therapy

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Tafenoquine: May increase the serum concentration of OCT2 Substrates. Management: Avoid use of OCT2 substrates with tafenoquine, and if the combination cannot be avoided, monitor closely for evidence of toxicity of the OCT2 substrate and consider a reduced dose of the OCT2 substrate according to that substrate's labeling. Consider therapy modification

Taxane Derivatives: Platinum Derivatives may enhance the myelosuppressive effect of Taxane Derivatives. Administer Taxane derivative before Platinum derivative when given as sequential infusions to limit toxicity. Management: Administer paclitaxel before cisplatin, when given as sequential infusions, to limit toxicity. Problems associated with other taxane/platinum combinations are possible, although unsubstantiated. Administering the taxane before platinum is likely warranted Consider therapy modification

Topotecan: Platinum Derivatives may enhance the adverse/toxic effect of Topotecan. Management: Consider administering platinum derivatives after topotecan when possible to minimize toxicity or using lower doses if administering platinum derivatives prior to topotecan. Monitor for hematologic toxicity (eg, neutropenia, thrombocytopenia). Consider therapy modification

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

Percentages reported with monotherapy.

>10%:

Gastrointestinal: Abdominal pain (31%), anorexia (20%), constipation (31%), diarrhea (46%), nausea (64%), stomatitis (2% to 14%), vomiting (37%)

Hematologic & oncologic: Anemia (64%; grades 3/4: 1%), leukopenia (13%). thrombocytopenia (30%; grades 3/4: 3%)

Hepatic: Increased serum alanine aminotransferase (36%), increased serum aspartate aminotransferase (54%), increased serum bilirubin (13%)

Nervous system: Fatigue (61%), headache (13%), insomnia (11%), pain (14%), peripheral neuropathy (may be dose limiting; 76%, grades 3/4: 7%; acute 65%; grades 3/4: 5%; persistent 43%; grades 3/4: 3%)

Neuromuscular & skeletal: Back pain (11%)

Respiratory: Cough (11%), dyspnea (13%)

Miscellaneous: Fever (25%)

1% to 10%:

Cardiovascular: Chest pain (5%), edema (10%), flushing (3%), peripheral edema (5%), thromboembolism (2%)

Dermatologic: Alopecia (3%), palmar-plantar erythrodysesthesia (1%), skin rash (5%)

Endocrine & metabolic: Dehydration (5%), hypokalemia (3%)

Gastrointestinal: Dysgeusia (5%), dyspepsia (7%), dysphagia (acute 1% to 2%), flatulence (3%), gastroesophageal reflux disease (1%), hiccups (2%)

Genitourinary: Dysuria (1%)

Hematologic & oncologic: Neutropenia (7%)

Hypersensitivity: Hypersensitivity reaction (3%)

Local: Injection site reaction (9%)

Nervous system: Dizziness (7%), rigors (9%)

Neuromuscular & skeletal: Arthralgia (7%)

Ocular: Abnormal lacrimation (1%)

Renal: Increased serum creatinine (5% to 10%)

Respiratory: Epistaxis (2%), pharyngitis (2%), pharyngolaryngeal dysesthesia (grades 3/4: 1% to 2%), rhinitis (6%), upper respiratory tract infection (7%)

<1%, postmarketing, and/or case reports (reported with mono- and combination therapy): Abnormal gait, acute renal failure, anaphylaxis, anaphylactic shock, angioedema, aphonia, ataxia, blepharoptosis, cerebral hemorrhage, colitis, cranial nerve palsy, decreased deep tendon reflex, deafness, decreased visual acuity, diplopia, dysarthria, eosinophilic pneumonitis, fasciculations, febrile neutropenia, hematuria, hemolysis, hemolytic anemia (immuno-allergic), hemolytic-uremic syndrome, hemorrhage, hepatic failure, hepatic fibrosis (perisinusoidal), hepatic sinusoidal obstruction syndrome (SOS; veno-occlusive disease), hepatitis, hepatotoxicity, hypertension, hypomagnesemia, hypoxia, idiopathic noncirrhotic portal hypertension (nodular regenerative hyperplasia), increased INR, increased serum alkaline phosphatase, interstitial nephritis (acute), interstitial pulmonary disease, intestinal obstruction, lactic acidosis (Smith 2019), laryngospasm, leukemia, Lhermittes' sign, metabolic acidosis, muscle spasm, myoclonus, neutropenic enterocolitis, neutropenic infection (sepsis), nonimmune anaphylaxis, optic neuritis, pancreatitis, prolonged QT interval on ECG, prolonged prothrombin time, pulmonary fibrosis, purpura, rectal hemorrhage, renal tubular necrosis, reversible posterior leukoencephalopathy syndrome, rhabdomyolysis, seizure, sepsis, septic shock, temporary vision loss, thrombocytopenia (immuno-allergic), torsades de pointes, trigeminal neuralgia, ventricular arrhythmia, visual field loss, voice disorder

ALERT: U.S. Boxed Warning

Hypersensitivity/Anaphylactic reactions:

Serious and fatal hypersensitivity adverse reactions, including anaphylaxis, can occur with oxaliplatin within minutes of administration and during any cycle. Oxaliplatin is contraindicated in patients with hypersensitivity reactions to oxaliplatin and other platinum-based drugs. Immediately and permanently discontinue oxaliplatin for hypersensitivity reactions and administer appropriate treatment for management of the hypersensitivity reaction.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Grade 3 and 4 neutropenia occurs commonly with oxaliplatin in combination with fluorouracil and leucovorin; sepsis, neutropenic sepsis, and septic shock have been reported with oxaliplatin (some fatal). Grade 3 and 4 thrombocytopenia has also occurred. Monitor blood counts at baseline, prior to each cycle, and as clinically indicated. Hematologic toxicity may require treatment interruption and/or dose reduction; withhold treatment for sepsis or septic shock.

• Cardiotoxicity: QT prolongation and ventricular arrhythmias, including fatal torsades de pointes, have been reported with oxaliplatin. ECG monitoring is recommended in patients with heart failure, bradyarrhythmias, concomitant medications known to cause QT prolongation (including class Ia and III antiarrhythmics), and electrolyte abnormalities. Avoid oxaliplatin in patients with congenital long QT syndrome. Monitor electrolytes (particularly potassium and magnesium) prior to and periodically during treatment; correct hypokalemia and hypomagnesemia prior to and during treatment.

• Extravasation: Oxaliplatin is an irritant with vesicant-like properties; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation.

• GI toxicity: Oxaliplatin is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011; Hesketh 2017; Roila 2016). Fluorouracil and leucovorin are associated with GI adverse events; the incidence of GI toxicity is increased when oxaliplatin is administered with fluorouracil and leucovorin. Mucositis, stomatitis, GI bleeding, and GI obstruction have been reported.

• Hemorrhage: GI bleeding, hematuria, and epistaxis have been reported with oxaliplatin; there have been case reports of death due to intracerebral hemorrhage. Prolonged PT and INR occasionally associated with hemorrhage have been reported in patients also receiving anticoagulants while on oxaliplatin. Increase the frequency of monitoring in patients who receive oxaliplatin and oral anticoagulants. Thrombocytopenia and immune-mediated thrombocytopenia have been observed with oxaliplatin; immune-mediated thrombocytopenia has been associated with a rapid thrombocytopenia onset along with a greater risk of bleeding. Consider discontinuing oxaliplatin if immune-mediated thrombocytopenia occurs.

• Hepatotoxicity: Elevated transaminases and alkaline phosphatase have occurred with oxaliplatin. Liver biopsy has revealed peliosis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive lesions. Consider evaluating for hepatic vascular disorders in patients who develop portal hypertension or increased LFTs that cannot be explained by liver metastases. Monitor LFTs at baseline, prior to each cycle, and as clinically indicated.

• Hypersensitivity: [US Boxed Warning]: Serious and fatal hypersensitivity reactions (including anaphylaxis) may occur within minutes of oxaliplatin administration and during any cycle. Oxaliplatin is contraindicated in patients with hypersensitivity to oxaliplatin and other platinum-based drugs. Immediately and permanently discontinue for hypersensitivity reactions and administer appropriate treatment for hypersensitivity management. Oxygen and bronchodilators have also been used for management (Kim 2009). Grade 3 or 4 hypersensitivity has been observed (rare). Allergic reactions are similar to reactions reported with other platinum analogs and may occur with any cycle. Reactions typically occur after multiple cycles; in retrospective reviews, reaction occurred at a median of 7 to 9 cycles, with an onset of 5 to 70 minutes (Kim 2009; Polyzos 2009). Symptoms may include bronchospasm (rare), erythema, hypotension (rare), pruritus, rash, and/or urticaria; previously-untreated patients have also experienced flushing, diaphoresis, diarrhea, shortness of breath, chest pain, hypotension, syncope, and disorientation. According to the manufacturer, rechallenge is contraindicated (deaths due to anaphylaxis have been associated with platinum derivatives). In patients rechallenged after mild hypersensitivity, reaction recurred at a higher level of severity; for patients with severe hypersensitivity, rechallenge (with 2 to 3 days of antihistamine and corticosteroid premedication, and prolongation of infusion time) allowed for 2 to 4 additional oxaliplatin cycles; however, rechallenge was not feasible in nearly two-thirds of patients due to the severity of the initial reaction (Polyzos 2009).

• Neuropathy: Two types of peripheral sensory neuropathy may occur: The first type of neuropathy is an acute presentation (within hours to 2 days), reversible (resolves within 14 days), with primarily peripheral symptoms that are often exacerbated by cold. Symptoms may include transient paresthesia, dysesthesia, and hypoesthesia in the hands, feet, perioral area, or throat; jaw spasm, abnormal tongue sensation, pharyngolaryngeal dysesthesia, dysarthria, eye pain, and a feeling of chest pressure have also been observed. Avoid mucositis prophylaxis with ice chips, exposure to cold temperatures, or consumption of cold food/beverages during or within hours after oxaliplatin infusion (may exacerbate symptoms). Acute neuropathy commonly recurs with subsequent doses. Cold-triggered neuropathy may last up to 7 days after oxaliplatin administration (Grothey 2011). The second type of neuropathy is a more persistent (>14 days) presentation that usually is characterized by paresthesia, dysesthesias, and hypoesthesias and may interfere with daily activities (eg, writing, buttoning, swallowing, difficulty walking). These symptoms may improve in some patients upon discontinuing treatment. In a retrospective evaluation of patients treated with oxaliplatin for colorectal cancer, the incidence of peripheral sensory neuropathy was similar between diabetic and nondiabetic patients (Ramanathan 2010). Several retrospective studies (as well as a small, underpowered randomized trial) have suggested calcium and magnesium infusions before and after oxaliplatin administration may reduce incidence of cumulative sensory neuropathy; however, a randomized, placebo-controlled, double-blind study in patients with colorectal cancer suggests there is no benefit of calcium and magnesium in preventing sensory neuropathy or in decreasing oxaliplatin discontinuation rates (Loprinzi 2014).

• Posterior reversible encephalopathy syndrome: Cases of posterior reversible encephalopathy syndrome (PRES) have been reported (rare). Signs/symptoms include headache, mental status changes, seizure, blurred vision, blindness, and/or other vision changes; may be associated with hypertension. Diagnosis is confirmed with MRI. Permanently discontinue oxaliplatin in patients who develop PRES.

• Pulmonary toxicity: Oxaliplatin is associated with pulmonary fibrosis (rare), which may be fatal. Pulmonary toxicity may present with dyspnea, cough, and/or hypoxia; grade 3 and 4 events have occurred. Eosinophilic pneumonia has been reported rarely. Withhold oxaliplatin for unexplained pulmonary symptoms (eg, crackles, dyspnea, nonproductive cough, pulmonary infiltrates) until interstitial lung disease or pulmonary fibrosis are excluded. Permanently discontinue oxaliplatin for interstitial lung disease or pulmonary fibrosis.

• Rhabdomyolysis: Rhabdomyolysis (including fatal cases) has been reported with oxaliplatin. Discontinue permanently with any signs/symptoms of rhabdomyolysis.

Disease-related concerns:

• Renal impairment: The AUC of unbound plasma platinum ultrafiltrate was increased in patients with renal impairment. Reduce initial dose in severe impairment.

Special populations:

• Elderly: Elderly patients experienced a higher incidence of diarrhea and grade 3 or 4 neutropenia and may be more susceptible to dehydration, hypokalemia, leukopenia, fatigue, and syncope.

Other warnings/precautions:

• Administration: Oxaliplatin is for IV administration. Administration via the intraperitoneal route (not an approved administration route) is associated with peritoneal hemorrhage and hemorrhagic complications (Charrier 2016).

Monitoring Parameters

CBC with differential, blood chemistries, including serum creatinine, ALT, AST, and bilirubin (baseline, prior to each cycle, and as clinically indicated), electrolytes, including potassium and magnesium (prior to and periodically during treatment); INR and PT (in patients on oral anticoagulant therapy). Evaluate pregnancy status prior to treatment initiation in females of reproductive potential. ECG monitoring is recommended in patients at risk for QT prolongation. Perform neurologic evaluation prior to each dose and periodically thereafter; monitor for signs/symptoms of hypersensitivity, pulmonary toxicity, posterior reversible encephalopathy syndrome, neuropathy, bleeding, and GI toxicity.

Reproductive Considerations

Evaluate pregnancy status prior to treatment initiation in females of reproductive potential. Females of reproductive potential should use effective contraception during treatment and for at least 9 months after the last oxaliplatin dose. Males with female partners of reproductive potential should use effective contraception during treatment and for 6 months after the last oxaliplatin dose. Males and females of reproductive potential desiring children should consider fertility preservation prior to therapy (Levi 2015; O'Neil 2011).

Pregnancy Considerations

Based on findings from animal reproduction studies and the mechanism of action, in utero exposure to oxaliplatin may result in fetal harm. Reports of oxaliplatin for the treatment of advanced colorectal cancer in pregnancy are limited (Frydenberg 2020; Makoshi 2015; Robson 2017).

The European Society for Medical Oncology has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy; the guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team). In general, if chemotherapy is indicated, it should be avoided in the first trimester, there should be a 3-week time period between the last chemotherapy dose and anticipated delivery, and chemotherapy should not be administered beyond week 33 of gestation (Peccatori 2013).

A pregnancy registry is available for all cancers diagnosed during pregnancy at Cooper Health (877-635-4499).

Patient Education

What is this drug used for?

• It is used to treat cancer.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache

• Constipation

• Abdominal pain

• Lack of appetite

• Loss of strength and energy

• Back pain

• Nausea

• Vomiting

• Mouth sores

• Mouth irritation

• Diarrhea

• Trouble sleeping

• Change in taste

• Joint pain

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Infection

• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding.

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes

• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, fast heartbeat, increased thirst, seizures, severe loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting

• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight

• Burning, numbness, or tingling

• Trouble swallowing

• Abnormal gait

• Trouble speaking

• Dizziness

• Passing out

• Fast heartbeat

• Chest pain

• Sweating a lot

• Flushing

• Swelling

• Jaw tightness

• Abnormal heartbeat

• Eye pain

• Strange feeling in the tongue

• Muscle pain

• Muscle weakness

• Posterior reversible encephalopathy syndrome like confusion, not alert, vision changes, seizures, or severe headache

• Lung problems like shortness of breath or other trouble breathing, cough that is new or worse

• Severe injection site redness, burning, swelling, pain, blisters, skin sores, or leaking of fluid

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.