Clinical Safety Considerations

Anaphylactic-like reactions to ELOXATIN have been reported and may occur within minutes of ELOXATIN administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms.

• ELOXATIN should not be administered to patients with a history of known allergy to ELOXATIN or other platinum compounds. Hypersensitivity and anaphylactic/anaphylactoid reactions to ELOXATIN have been reported and were similar in nature and severity to those reported with other platinum compounds (ie, rash, urticaria, erythema, pruritus, and, rarely, bronchospasm and hypotension). These reactions occur within minutes of administration and should be managed with appropriate supportive therapy. Drug-related deaths from this reaction have been reported.
• ELOXATIN may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant while receiving ELOXATIN. It is not known whether ELOXATIN or its derivatives are excreted in human milk.
• ELOXATIN has been associated with pulmonary fibrosis (<1% of study patients), which may be fatal. The combined incidence of cough and dyspnea was 7.4% (<1 % grade 3, no grade 4) in the ELOXATIN plus 5-FU/LV arm compared to 4.5% (no grade 3, 0.1% grade 4) in the 5-FU/LV alone arm in the adjuvant colon cancer study. In this study, one patient died from eosinophilic pneumonia in the ELOXATIN combination arm. The combined incidence of cough, dyspnea, and hypoxia was 43% (7% grade 3 and 4) in the ELOXATIN plus 5-FULV arm compared to 32% (5% grade 3 and 4) in the irinotecan plus 5-FU/LV arm in patients with previously untreated colorectal cancer. In case of unexplained respiratory symptoms, ELOXATIN should be discontinued until pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.
• ELOXATIN is associated with two types of primarily peripheral sensory neuropathy: an acute, reversible type of early onset and a persistent type (>14 days). In patients with advanced colorectal cancer, paresthesias occurred in 77% (all grades) and 18% (grade 3/4) of previously untreated patients. In previously treated patients, acute neuropathy occurred in 56% (all grades) and 2% (grade 3/4) of patients; persistent neuropathy occurred in 48% (all grades) and 6% (grade 3/4) of patients. In patients with stage II and III colon cancer, paresthesia was seen in 92% (all grades) and 13% (grade 3/4) of patients; 21% (all grades) and 0.5% (grade 3/4) of patients had residual paresthesia at 18-month follow-up.
• Hepatotoxicity, as evidenced in the adjuvant study by increase in transaminases and alkaline phosphatase, was observed more commonly in the ELOXATIN combination arm. 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. Hepatic vascular disorders should be considered and, if appropriate, investigated in case of abnormal liver function test results or portal hypertension not explained by liver metastases.
• Monitoring of white blood cell count with differential, hemoglobin, platelet count, and blood chemistries (including ALT, AST, bilirubin, and creatinine) is recommended before each ELOXATIN cycle.
• The safety and effectiveness of ELOXATIN plus 5-FU/LV in patients with renal impairment have not been evaluated. Since the primary route of platinum elimination is renal, this combination should be used with caution in patients with preexisting renal impairment. Clearance of these products may be decreased by coadministration of potentially nephrotoxic compounds, although this has not been specifically studied.
• The incidence of diarrhea, dehydration, hypokalemia, leukopenia, fatigue, and syncope was higher in patients ? 65 years old.
• Extravasation may result in local pain and inflammation that may be severe and lead to complications, including necrosis. Injection site reaction, including redness, swelling, and pain, has been reported.
• There have been reports of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients receiving ELOXATIN plus 5-FU/LV while on anticoagulants. Patients receiving ELOXATIN plus 5-FU/LV and requiring oral anticoagulants may require closer monitoring.
• The most common adverse reactions in patients with stage II or III colon cancer receiving adjuvant therapy were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue, and stomatitis. The most common adverse reactions in patients with advanced colorectal cancer were peripheral sensory neuropathy, fatigue, neutropenia, nausea, emesis, and diarrhea.

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Elitek^® Important Safety Information

Among the 703 patients for whom serious adverse reactions were assessed, the most serious adverse reactions caused by ELITEK were allergic reactions including anaphylaxis (<1%), rash (1%), hemolysis (<1%), and methemoglobinemia (<1%). The commonly observed adverse events were fever (5%), neutropenia with fever (4%), respiratory distress (3%), sepsis (3%), neutropenia (2%), and mucositis (2%). Among the 347 patients for whom all adverse reactions regardless of severity were assessed, the most frequently observed adverse reactions (incidence ?10%) were vomiting (50%), fever (46%), nausea (27%), headache (26%), abdominal pain (20%), constipation (20%), diarrhea (20%), mucositis (15%), and rash (13%).

INDICATIONS

ELITEK is indicated for the initial management of plasma uric acid levels in pediatric patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anticancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid.

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