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    <p style="font-size: 12px">
        ELOXATIN, used in combination with infusional 5-FU/LV, is indicated for</p>
    <ul>
        <li>Adjuvant treatment of stage III colon cancer patients who have undergone complete
            resection of the primary tumor. The indication is based on an improvement in disease-free
            survival, with no demonstrated benefit in overall survival after a median follow-up
            of 4 years</li>
        <li>Treatment of advanced carcinoma of the colon or rectum</li>
    </ul>
    <p style="font-size: 12px; text-decoration: underline">
        <strong>Clinical Safety Considerations</strong></p>
    <p style="font-size: 12px">
        ELOXATIN should be administered under the supervision of a physician experienced
        in the use of cancer chemotherapeutic agents. Appropriate management of therapy
        and complications is possible only when adequate diagnostic and treatment facilities
        are readily available.</p>
    <p style="font-size: 12px">
        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, and discontinuation of ELOXATIN therapy
        may be required.</p>
    <ul>
        <li>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</li>
        <li>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</li>
        <li>ELOXATIN has been associated with pulmonary fibrosis (&lt;1% of study patients),
            which may be fatal. The combined incidence of cough and dyspnea was 7.4% (&lt;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-FU/LV 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</li>
        <li>ELOXATIN is associated with two types of primarily peripheral sensory neuropathy:
            an acute, reversible type of early onset and a persistent type (&gt;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</li>
        <li>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</li>
        <li>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</li>
        <li>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</li>
        <li>The incidence of diarrhea, dehydration, hypokalemia, leukopenia, fatigue, and syncope
            was higher in patients 65 years old</li>
        <li>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</li>
        <li>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</li>
        <li>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</li>
    </ul>

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