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Allergic Reactions: Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to oxaliplatin has been observed in colon cancer patients. These allergic reactions which can be fatal, can occur within minutes of administration and at any cycle, and were similar in nature and severity to those reported with other platinum-containing compounds, such as rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension. The symptoms associated with hypersensitivity reactions reported in the previously untreated patients were urticaria, pruritus, flushing of the face, diarrhea associated with oxaliplatin infusion, shortness of breath, bronchospasm, diaphoresis, chest pains, hypotension, disorientation and syncope. These reactions are usually managed with standard epinephrine, corticosteroid, antihistamine therapy, and require discontinuation of therapy. Rechallenge is contraindicated in these patients. Drug-related deaths associated with platinum compounds from anaphylaxis have been reported.
Neurologic Toxicity: Neuropathy: Oxaliplatin is associated with two types of neuropathy: An acute, reversible, primarily peripheral, sensory neuropathy that is of early onset, occurring within hours or one to two days of dosing, that resolves within 14 days, and that frequently recurs with further dosing. The symptoms may be precipitated or exacerbated by exposure to cold temperature or cold objects and they usually present as transient paresthesia, dysesthesia and hypoesthesia in the hands, feet, perioral area, or throat. Jaw spasm, abnormal tongue sensation, dysarthria, eye pain, and a feeling of chest pressure have also been observed.
An acute syndrome of pharyngolaryngeal dysesthesia seen (grade 3/4) in patients previously untreated for advanced colorectal cancer, and the previously treated patients, is characterized by subjective sensations of dysphagia or dyspnea, without any laryngospasm or bronchospasm (no stridor or wheezing). Ice (mucositis prophylaxis) should be avoided during the infusion of oxaliplatin because cold temperature can exacerbate acute neurological symptoms.
A persistent (>14 days), primarily peripheral, sensory neuropathy that is usually characterized by paresthesias, dysesthesias, hypoesthesias, but may also include deficits in proprioception that can interfere with daily activities (e.g., writing, buttoning, swallowing, and difficulty walking from impaired proprioception).
Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as PRES, Posterior Reversible Encephalopathy Syndrome) has been observed. Signs and symptoms of RPLS could be headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension. Diagnosis of RPLS is based upon confirmation by brain imaging.
Severe Myelosuppression: Grade 3 or 4 neutropenia occurred in patients with colorectal cancer treated with oxaliplatin in combination with 5-flurouracil (5-FU) and leucovorin compared to 5-FU plus leucovorin alone. Sepsis, neutropenic sepsis and septic shock have been reported in patients treated with oxaliplatin, including fatal outcomes. Delay oxaliplatin until neutrophils are ≥1.5 × 109/L. Withhold oxaliplatin for sepsis or septic shock. Dose reduce oxaliplatin after recovery from Grade 4 neutropenia or febrile neutropenia.
Pulmonary Toxicity: Oxaliplatin has been associated with pulmonary fibrosis, which may be fatal. In case of unexplained respiratory symptoms such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, oxaliplatin should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.
Hepatotoxicity: Hepatotoxicity is reported. Changes noted on liver biopsies include: peliosis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive lesions. Hepatic vascular disorders should be considered, and if appropriate, should be investigated in case of abnormal liver function test results or portal hypertension, which cannot be explained by liver metastases.
Cardiovascular Toxicity: QT prolongation and ventricular arrhythmias including fatal Torsade de Pointes have been observed following oxaliplatin administration. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating oxaliplatin and monitor these electrolytes periodically during therapy. Avoid oxaliplatin in patients with congenital long QT syndrome.
Rhabdomyolysis: Rhabdomyolysis, including fatal cases, has been observed in patients treated with oxaliplatin. Discontinue oxaliplatin if any signs or symptoms of rhabdomyolysis occur.
Recommended Laboratory Tests: Standard monitoring of the white blood cell count with differential, hemoglobin, platelet count, and blood chemistries (including ALT, AST, bilirubin and creatinine) is recommended before each Oxaliplatin cycle. There have been reports of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received Oxaliplatin plus 5-fluorouracil/leucovorin while on anticoagulants. Patients receiving Oxaliplatin plus 5-fluorouracil/leucovorin and requiring oral anticoagulants may require closer monitoring. Thrombocytopenia and immune-mediated thrombocytopenia have been observed with oxaliplatin. Rapid onset of thrombocytopenia and greater risk of bleeding have been observed in immune-mediated thrombocytopenia. In this case, consider discontinuing oxaliplatin.
Patients with Renal Impairment: The exposure (AUC) of unbound platinum in plasma ultrafiltrate tends to increase in renally impaired patients. Caution and close monitoring should be exercised when oxaliplatin is administered to patients with renal impairment. The starting oxaliplatin dose does not need to be reduced in patients with mild (creatinine clearance=50-80 mL/min) or moderate (creatinine clearance=30-49 mL/min) renal impairment. However, the starting dose of oxaliplatin should be reduced in patients with severe renal impairment (creatinine clearance <30 mL/min).
Use in Pregnancy: See Use in Pregnancy & Lactation section for further information.
Use in Children: The effectiveness of oxaliplatin in children has not been established. Oxaliplatin has been tested in 2 Phase I and 2 Phase II trials in 235 patients ages 7 months to 22 years with solid tumors and no significant activity observed.
The mean clearance in pediatric patients estimated by the population pharmacokinetic analysis was 4.7 L/h. The inter-patient variability of platinum clearance in pediatric cancer patients was 41%. Mean platinum pharmacokinetic parameters in ultrafiltrate were Cmax of 0.75±0.24 mcg/mL, AUC0-48 of 7.52±5.07 mcg·h/mL and AUCinf of 8.83±1.57 mcg·h/mL at 85 mg/m2 of oxaliplatin and Cmax of 1.10±0.43 mcg/mL, AUC0-48 of 9.74±2.52 mcg·h/mL and AUCinf of 17.3±5.34 mcg·h/mL at 130 mg/m2 of oxaliplatin.
Use in the Elderly: No significant effect of age on the clearance of ultrafilterable platinum has been observed.
No adjustment to starting dose was required in patients ≥65 years old.
