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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Peripheral Sensory Neuropathy: Acute and delayed neuropathy can occur. Avoid topical application of ice. Reduce the dose or permanently discontinue oxaliplatin for injection as recommended. (5.2)• Severe Myelosuppression: Delay oxaliplatin for injection until neutrophils are greater than or equal to 1.5 × 109/L and platelets are greater than or equal to 75 × 109/L. Withhold oxaliplatin for injection for sepsis or septic shock. Dose reduce after recovery from grade 4 neutropenia, febrile neutropenia, or grade 3-4 thrombocytopenia as recommended. (5.3)• Posterior Reversible Encephalopathy Syndrome (PRES): Permanently discontinue oxaliplatin for injection in patients who develop PRES. (5.4) • Pulmonary Toxicity: Withhold oxaliplatin for injection until investigation excludes interstitial lung disease or pulmonary fibrosis. (5.5) • Hepatotoxicity: Monitor liver function tests at baseline, before each subsequent cycle, and as clinically indicated. (5.6)• QT Interval Prolongation: Avoid in patients with congenital long QT syndrome. Monitor electrocardiograms in patients with congestive heart failure, bradyarrhythmias, and electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Correct electrolyte abnormalities prior to initiating oxaliplatin for injection and periodically during treatment. (5.7) • Rhabdomyolysis: Permanently discontinue oxaliplatin for injection if rhabdomyolysis occurs. (5.8) • Hemorrhage: Increase frequency of monitoring in patients who are receiving oxaliplatin for injection with fluorouracil/leucovorin and oral anticoagulants (5.9) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise males and females of reproductive potential to use an effective method of contraception. (5.10, 8.1, 8.3) 5.1 Hypersensitivity Reactions Serious and fatal hypersensitivity reactions, including anaphylaxis, can occur with oxaliplatin within minutes of administration and during any cycle. Grade 3-4 hypersensitivity reactions, including anaphylaxis, occurred in 2% to 3% of patients with colon cancer who received oxaliplatin. Hypersensitivity reactions, including rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension, were similar in nature and severity to those reported with other platinum-based drugs. Oxaliplatin is contraindicated in patients with hypersensitivity reactions to platinum-based drugs [see Contraindications ( 4 )]. Immediately and permanently discontinue oxaliplatin for hypersensitivity reactions and administer appropriate treatment for management of hypersensitivity reactions. 5.2 Peripheral Sensory Neuropathy Oxaliplatin can cause acute and delayed neuropathy. Reduce the dose or permanently discontinue oxaliplatin for persistent neurosensory reactions based on the severity of the adverse reaction [see Dosage and Administration ( 2.3 )]. Acute Neuropathy Acute neuropathy typically presents as a reversible, primarily peripheral sensory neuropathy that occurs within hours or 2 days following a dose, resolves within 14 days, and frequently recurs with further dosing. The symptoms can 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. The acute, reversible pattern of sensory neuropathy was observed in about 56% of patients who received oxaliplatin with fluorouracil/leucovorin. In any individual cycle, acute neuropathy occurred in approximately 30% of patients. For grade 3 peripheral sensory neuropathy, the median time to onset was 9 cycles for adjuvant treatment and 6 cycles for previously treated advanced colorectal cancer. An acute syndrome of pharyngolaryngeal dysesthesia occurred in 1% to 2% (grade 3-4) of patients previously untreated for advanced colorectal cancer. Subjective sensations of dysphagia or dyspnea, without any laryngospasm or bronchospasm (no stridor or wheezing) occurred in patients previously treated for advanced colorectal cancer. Avoid topical application of ice for mucositis prophylaxis or other conditions, because cold temperature can exacerbate acute neurological symptoms . Delayed Neuropathy Delayed neuropathy typically presents as a persistent (greater than 14 days), primarily peripheral sensory neuropathy that is usually characterized by paresthesias, dysesthesias, and 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). These forms of neuropathy occurred in 48% of patients receiving oxaliplatin. Delayed neuropathy can occur without any prior acute neuropathy. Most patients (80%) who developed grade 3 persistent neuropathy progressed from prior grade 1 or 2 reactions. These symptoms may improve in some patients upon discontinuation of oxaliplatin. Adjuvant treatment In the adjuvant treatment trial, neuropathy was graded using NCI CTC, version 1 as summarized in Table 3 . Table 3: Grading for Neuropathy in Adjuvant Treatment Trial Grade Definition 0 No change or none 1 Mild paresthesias, loss of deep tendon reflexes 2 Mild or moderate objective sensory loss, moderate paresthesias 3 Severe objective sensory loss or paresthesias that interfere with function 4 Not applicable Peripheral sensory neuropathy occurred in 92% of patients (all grades), including 13% of patients (grade 3) who received oxaliplatin with fluorouracil/leucovorin. At the 28-day follow-up after the last treatment cycle, 60% of patients had any grade (grade 1=40%, grade 2=16%, grade 3=5%) peripheral sensory neuropathy, decreasing to 39% at 6 months of follow-up (grade 1=31%, grade 2=7%, grade 3=1%) and 21% at 18 months of follow-up (grade 1=17%, grade 2=3%, grade 3=1%). Advanced colorectal cancer In the advanced colorectal cancer trials, neuropathy was graded using the neurotoxicity scale summarized in Table 4 . Table 4: Grading for Neuropathy in Advanced Colorectal Cancer Trials Grade Definition 1 Resolved and did not interfere with functioning 2 Interfered with function but not daily activities 3 Pain or functional impairment that interfered with daily activities 4 Persistent impairment that is disabling or life-threatening Neuropathy occurred in 82% (all grades) of patients previously untreated for advanced colorectal cancer, including 19% grade 3-4; and in 74% (all grades) of patients previously treated for advanced colorectal cancer, including 7% grade 3-4. 5.3 Severe Myelosuppression Grade 3 or 4 neutropenia occurred in 41% to 44% of patients with colorectal cancer who received oxaliplatin with fluorouracil/leucovorin. Sepsis, neutropenic sepsis and septic shock, including fatal outcomes, occurred in patients who received oxaliplatin Grade 3 or 4 neutropenia occurred in 41% to 44% of patients with colorectal cancer who received oxaliplatin with fluorouracil/leucovorin. Sepsis, neutropenic sepsis and septic shock, including fatal outcomes, occurred in patients who received oxaliplatin [see Adverse Reactions ( 6.1 , 6.2 )]. Grade 3 or 4 thrombocytopenia occurred in 2% to 5% of patients with colorectal cancer who received oxaliplatin with fluorouracil/leucovorin. Grade 3 or 4 thrombocytopenia occurred in 2% to 5% of patients with colorectal cancer who received oxaliplatin with fluorouracil/leucovorin. Monitor complete blood cell count at baseline, before each subsequent cycle and as clinically indicated Delay oxaliplatin until neutrophils are greater than or equal to 1.5 × 10 /L and platelets are greater than or equal to 75 × 10 /L. Withhold oxaliplatin for sepsis or septic shock. Dose reduce oxaliplatin after recovery from grade 4 neutropenia, febrile neutropenia or grade 3-4 thrombocytopenia as recommended Monitor complete blood cell count at baseline, before each subsequent cycle and as clinically indicated . Delay oxaliplatin until neutrophils are greater than or equal to 1.5 × 10 9 /L and platelets are greater than or equal to 75 × 10 9 /L. Withhold oxaliplatin for sepsis or septic shock. Dose reduce oxaliplatin after recovery from grade 4 neutropenia, febrile neutropenia or grade 3-4 thrombocytopenia as recommended [see Dosage and Administration ( 2.2 )]. 5.4 Posterior Reversible Encephalopathy Syndrome PRES occurred in less than 0.1% of patients across clinical trials [see Adverse Reactions ( 6.1 )] . Signs and symptoms of PRES can include headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension. Confirm the diagnosis of PRES with magnetic resonance imaging. Permanently discontinue oxaliplatin in patients who develop PRES. 5.5 Pulmonary Toxicity Oxaliplatin has been associated with pulmonary fibrosis (less than 1% of patients), which may be fatal [see Adverse Reactrions ( 6.1 )]. In the adjuvant treatment trial, the combined incidence of cough and dyspnea was 7.4% (any grade), including less than 1% (grade 3) in the oxaliplatin arm. One patient died from eosinophilic pneumonia in the oxaliplatin arm. In the previously untreated advanced colorectal cancer trial, the combined incidence of cough, dyspnea and hypoxia was 43% (any grade), including 7% (grade 3-4) in the oxaliplatin with fluorouracil/leucovorin arm. In case of unexplained respiratory symptoms, such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, withhold oxaliplatin until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis. Permanently discontinue oxaliplatin for confirmed interstitial lung disease or pulmonary fibrosis. 5.6 Hepatotoxicity In the adjuvant treatment trial, increased transaminases (57% vs 34%) and alkaline phosphatase (42% vs 20%) occurred more commonly in the oxaliplatin arm than in the fluorouracil/leucovorin arm [see Adverse Reactions ( 6.1 )] . The incidence of increased bilirubin was similar on both arms. Changes noted on liver biopsies include: peliosis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and veno-occlusive lesions. Consider evaluating patients who develop abnormal liver tests or portal hypertension which cannot be explained by liver metastases, for hepatic vascular disorders. Monitor liver function tests at baseline, before each subsequent cycle and as clinically indicated. 5.7 QT Interval Prolongation and Ventricular Arrhythmias QT prolongation and ventricular arrhythmias, including fatal torsade de pointes, have been reported with oxaliplatin [see Adverse Reactions ( 6.2 )]. Avoid oxaliplatin in patients with congenital long QT syndrome . Monitor electrocardiograms (ECG) in patients with congestive heart failure, bradyarrhythmias, and electrolyte abnormalities and in patients taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics [see Drug Interactions ( 7.1 )] . Monitor and correct electrolyte abnormalities prior to initiating oxaliplatin and periodically during treatment. 5.8 Rhabdomyolysis Rhabdomyolysis, including fatal cases, has been reported with oxaliplatin [see Adverse Reactions ( 6.2 )]. Permanently discontinue oxaliplatin for any signs or symptoms of rhabdomyolysis. 5.9 Hemorrhage The incidence of hemorrhage in clinical trials was higher on the oxaliplatin combination arm compared to the fluorouracil/leucovorin arm. These reactions included gastrointestinal bleeding, hematuria, and epistaxis. In the adjuvant treatment trial, 2 patients died from intracerebral hemorrhage [see Adverse Reactions ( 6.1 )] . Prolonged prothrombin time and INR occasionally associated with hemorrhage have been reported in patients who received oxaliplatin with fluorouracil/leucovorin while on anticoagulants [see Adverse Reactions ( 6.2 )] . Increase frequency of monitoring in patients who are receiving oxaliplatin with fluorouracil/leucovorin and oral anticoagulants [see Drug Interactions ( 7.3 )] . 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. 5.10 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, oxaliplatin can cause fetal harm when administered to a pregnant woman. The available human data do not establish the presence or absence of major birth defects or miscarriage related to the use of oxaliplatin. Reproductive toxicity studies demonstrated adverse effects on embryo-fetal development in rats at maternal doses that were below the recommended human dose based on body surface area. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with oxaliplatin and for at least 9 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with oxaliplatin and for 6 months after the final dose [see Use in Specific Populations ( 8.1 , 8.3 )]. .