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  • Methotrexate Rescue in Osteosarcoma

    Methotrexate Rescue in Osteosarcoma

    Rescue After High-dose Methotrexate Therapy
    in Osteosarcoma1

    The safety and efficacy of FUSILEV rescue following high-dose methotrexate were evaluated in 16 patients age 6-21 who received 58 courses of therapy for osteogenic sarcoma. High-dose methotrexate was one component of several different combination chemotherapy regimens evaluated across several trials. Methotrexate 12 g/m2 IV over 4 hours was administered to 13 patients, who received FUSILEV 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate. Three patients received methotrexate 12.5 g/m2 IV over 6 hours, followed by FUSILEV 7.5 mg every 3 hours for 18 doses beginning 12 hours after completion of methotrexate. The mean number of FUSILEV doses per course was 18.2 and the mean total dose per course was 350 mg. The efficacy of FUSILEV rescue following high-dose methotrexate was based on the adverse reaction profile.

    Adverse Reactions with High-dose
    Methotrexate Therapy

    Adverse Reactions with High-dose Methotrexate Therapy

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    The incidence of adverse reactions may be underestimated because not all patients were fully evaluable for toxicity for all cycles in the clinical trials. Leukopenia and thrombocytopenia were observed, but could not be attributed to high-dose methotrexate with FUSILEV rescue because patients were receiving other myelosuppressive chemotherapy.

    Dosing and Administration

    The recommendations for FUSILEV rescue are based on a methotrexate dose of 12 grams/m2 administered by intravenous infusion over 4 hours (see methotrexate package insert for full prescribing information). FUSILEV rescue at a dose of 7.5 mg (approximately 5 mg/m2) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion.

    Serum creatinine and methotrexate levels should be determined at least once daily. FUSILEV administration, hydration, and urinary alkalinization (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 10-8 M (0.05 micromolar). The FUSILEV dose should be adjusted or rescue extended based on the following guidelines.

    Guidelines for FUSILEV Dosage and Administration

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    Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure. In addition to appropriate FUSILEV therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved.

    Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table above. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, FUSILEV rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

    Delayed methotrexate excretion may be caused by accumulation in a third space fluid collection (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration. Under such circumstances, higher doses of FUSILEV or prolonged administration may be indicated.

    Although FUSILEV may ameliorate the hematologic toxicity associated with high-dose methotrexate, FUSILEV has no effect on other established toxicities of methotrexate such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney.

    Indications and Usage

    FUSILEV is a folate analog indicated for:

    • Rescue after high-dose methotrexate therapy in osteosarcoma.
    • Diminishing the toxicity and counteracting the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists.
    • Use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer.

    Limitations of Use

    • FUSILEV is not approved for pernicious anemia and megaloblastic anemias. Improper use may cause a hematologic remission while neurologic manifestations continue to progress.

    Important Safety Information

    Contraindications

    • FUSILEV is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid.

    Warnings and Precautions

    • Due to Ca++ content, no more than 16 mL (160 mg) of levoleucovorin solution should be injected intravenously per minute.
    • FUSILEV enhances the toxicity of fluorouracil.
    • Concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in HIV patients was associated with increased rates of treatment failure in a placebo-controlled study.

    Adverse Reactions

    • Allergic reactions were reported in patients receiving FUSILEV.
    • The most common adverse reactions (>50%) in patients with advanced colorectal cancer receiving FUSILEV in combination with 5-FU were diarrhea, nausea and stomatitis.
    • Vomiting (38%), stomatitis (38%) and nausea (19%) were reported in patients receiving FUSILEV as rescue after high-dose methotrexate therapy.

    Drug Interactions

    • FUSILEV may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible patients.

    Please click here to see full Prescribing Information for FUSILEV.


    Reference:
    1. Fusilev [prescribing information]. Irvine, CA: Spectrum Pharmaceuticals, Inc; 2011.