Oxaliplatin

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)

Solution Reconstituted, Intravenous [preservative free]:

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

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: 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: 0.4 hours; Beta phase: 16.8 hours; Terminal: 391 hours

Protein Binding

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

Use in Specific Populations

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 C_max 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).

Use: Off Label

Biliary adenocarcinoma, advancedb

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, refractoryb

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 cancera

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 cancera

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), refractoryb

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/refractoryb

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, advancedb

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 metastaticayes

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 small phase 2 study also supports 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 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 Eastern Cooperative Oncology Group (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 therapyayes

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, refractoryb

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 refractoryb

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): Pregnancy, breast-feeding; severe renal impairment (CrCl <30 mL/minute)

Dosage and Administration

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 6 months (12 cycles; in combination with infusional fluorouracil/leucovorin).

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

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).

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

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 ≥1500/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 ≥1500/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: 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.

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

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). 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. Solutions diluted for infusion do not require protection from light.

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

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

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 immunosuppressive effect of Immunosuppressants. Avoid combination

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

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. 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

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

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

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

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

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

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

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

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

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

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

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

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

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

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

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) 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

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

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. Consider therapy modification

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Topotecan: Platinum Derivatives may enhance the adverse/toxic effect of Topotecan. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

Percentages reported with monotherapy.

>10%:

Central nervous system: Peripheral neuropathy (may be dose limiting; 76% to 92%; acute 65%; grades 3/4: 5%; persistent 43%; grades 3/4: 3%), fatigue (61%), pain (14%), headache (13%), insomnia (11%)

Gastrointestinal: Nausea (64%), diarrhea (46%), vomiting (37%), abdominal pain (31%), constipation (31%), anorexia (20%), stomatitis (14%)

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

Hepatic: Increased serum AST (54%; grades 3/4: 4%), increased serum ALT (36%; grades 3/4: 1%), increased serum bilirubin (13%; grades 3/4: 5%)

Neuromuscular & skeletal: Back pain (11%)

Respiratory: Dyspnea (13%), cough (11%)

Miscellaneous: Fever (25%)

1% to 10%:

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

Central nervous system: Rigors (9%), dizziness (7%)

Dermatologic: Skin rash (5%), alopecia (3%), palmar-plantar erythrodysesthesia (1%)

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

Gastrointestinal: Dyspepsia (7%), dysgeusia (5%), flatulence (3%), hiccups (2%), mucositis (2%), dysphagia (acute 1% to 2%), gastroesophageal reflux disease (1%)

Genitourinary: Dysuria (1%)

Hematologic & oncologic: Neutropenia (7%)

Hypersensitivity: Hypersensitivity reaction (3%; includes urticaria, pruritus, facial flushing, shortness of breath, bronchospasm, diaphoresis, hypotension, syncope: grades 3/4: 2% to 3%)

Local: Injection site reaction (9%; redness, swelling, pain)

Neuromuscular & skeletal: Arthralgia (7%)

Ocular: Abnormal lacrimation (1%)

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

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

<1%, postmarketing, and/or case reports (reported with mono- and combination therapy): Abnormal gait, acute renal failure, anaphylaxis, anaphylactic shock, anaphylactoid reaction, 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, infusion related reaction (extravasation [including necrosis]), interstitial nephritis (acute), interstitial pulmonary disease, intestinal obstruction, lactic acidosis (Smith 2019), laryngospasm, Lhermittes' sign, metabolic acidosis, muscle spasm, myoclonus, neutropenic enterocolitis, neutropenic infection (sepsis), optic neuritis, pancreatitis, prolonged Q-T interval on ECG, prolonged prothrombin time, pulmonary fibrosis, purpura, rectal hemorrhage, renal tubular necrosis, reversible posterior leukoencephalopathy syndrome (RPLS), rhabdomyolysis, seizure, sepsis, septic shock, temporary vision loss, thrombocytopenia (immuno-allergic), torsades de pointes, trigeminal neuralgia, ventricular arrhythmia, visual field loss, voice disorder

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). Delay oxaliplatin treatment until neutrophils are ≥1500/mm³; withhold treatment for sepsis or septic shock. Reduce the dose after recovery from grade 4 neutropenia or neutropenic fever.
• Cardiotoxicity: QT prolongation and ventricular arrhythmias, including fatal torsades de pointes have been reported in postmarketing surveillance. 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 use in patients with congenital long QT syndrome. Monitor potassium and magnesium prior to and periodically during treatment; correct hypokalemia and hypomagnesemia prior to treatment initiation.
• 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.
• Hypersensitivity/anaphylactoid reactions: [US Boxed Warning]: Anaphylactic reactions have been reported with oxaliplatin (may occur within minutes of administration); symptoms may be managed with epinephrine, corticosteroids, antihistamines, and discontinuation; oxygen and bronchodilators have also been used (Kim 2009). Grade 3 or 4 hypersensitivity has been observed. 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).
• Hepatotoxicity: Hepatotoxicity (including rare cases of hepatitis and hepatic failure) has been reported. Liver biopsy has revealed peliosis, idiopathic noncirrhotic portal hypertension (including nodular regenerative hyperplasia), sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive lesions. The presence of hepatic vascular disorders (including veno-occlusive disease) should be considered, especially in individuals developing portal hypertension or who present with increased liver function tests.
• Neuropathy: Two different types of peripheral sensory neuropathy may occur: The first type of neuropathy is an acute presentation (within hours to 1 to 2 days), reversible (resolves within 14 days), with primarily peripheral symptoms that are often exacerbated by cold (may include pharyngolaryngeal dysesthesia); 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); this 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 often interferes with daily activities (eg, writing, buttoning, swallowing); 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).
• Pulmonary toxicity: May cause pulmonary fibrosis (may be fatal); withhold treatment for unexplained pulmonary symptoms (eg, crackles, dyspnea, nonproductive cough, pulmonary infiltrates) until interstitial lung disease or pulmonary fibrosis are excluded.
• Reversible posterior leukoencephalopathy syndrome: Cases of reversible posterior leukoencephalopathy syndrome (RPLS) have been reported. 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 brain imaging.
• Rhabdomyolysis: Rhabdomyolysis (including fatal cases) has been reported with oxaliplatin. Discontinue if signs/symptoms of rhabdomyolysis occur.

Disease-related concerns:

• Renal impairment: Use with caution in patients with renal impairment; increased toxicity may occur. Reduce initial dose in severe impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Elderly patients are more sensitive to adverse events, particularly diarrhea, 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 (prior to each cycle), electrolytes, including potassium and magnesium (prior to and periodically during treatment); INR and prothrombin time (in patients on oral anticoagulant therapy); neurologic evaluation prior to each dose and periodically thereafter; hypersensitivity; respiratory effects; RPLS

Pregnancy

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were observed in animal reproduction studies at one-tenth the equivalent human dose. Females of reproductive potential should be advised to avoid pregnancy and use effective contraception during treatment. Males and females of reproductive potential desiring children should consider fertility preservation prior to therapy (Levi 2015; O'Neil 2011).

Patient Education

What is this drug used for?

• It is used to treat colon cancer.
• It is used to treat colorectal cancer.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Headache
• Fatigue
• Constipation
• Abdominal pain
• Lack of appetite
• Back pain
• Nausea
• Vomiting
• Mouth sores
• Mouth irritation
• Diarrhea
• Trouble sleeping
• Change in taste
• Joint pain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• 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.
• 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.
• Severe cerebrovascular disease like change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or vision changes
• Severe loss of strength and energy
• Burning, numbness, or tingling
• Trouble swallowing
• Abnormal gait
• Trouble speaking
• Severe dizziness
• Passing out
• Fast heartbeat
• Chest pain
• Sweating a lot
• Flushing
• Swelling
• Jaw tightness
• Abnormal heartbeat
• Eye pain
• Strange feeling in the tongue
• Severe muscle pain
• Severe muscle weakness
• Posterior reversible encephalopathy syndrome like confusion, not alert, vision changes, seizures, or severe headache
• Severe pulmonary disorder like lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse
• Severe injection site redness, burning, swelling, pain, blisters, sores, or fluid leakage
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of 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 brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.