Fusilev

Fusilev Manufacturers

• Spectrum Pharmaceuticals, Inc.
  

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  Fusilev | Spectrum Pharmaceuticals, Inc.

  

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  2.1 Administration Guidelines

  Fusilev is dosed at one-half the usual dose of racemic d,l-leucovorin.

  Fusilev is indicated for intravenous administration only. Do not administer intrathecally.

  2.2 Co-administration of Fusilev with other agents

  Due to the risk of precipitation, do not co-administer Fusilev with other agents in the same admixture.

  2.3 Fusilev Rescue After High-Dose Methotrexate Therapy

  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.

  Table 1 Guidelines for Fusilev Dosage and Administration Clinical Situation Laboratory Findings Fusilev Dosage and Duration Normal Methotrexate Elimination Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours 7.5 mg IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion). Delayed Late Methotrexate Elimination Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration. Continue 7.5 mg IV q 6 hours, until methotrexate level is less than 0.05 micromolar. Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more). 75 mg IV q 3 hours until methotrexate level is less than 1 micromolar; then 7.5 mg IV q 3 hours until methotrexate level is less than 0.05 micromolar.

  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.

  2.4 Dosing Recommendations for Inadvertent Methotrexate Overdosage

  Fusilev rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion. As the time interval between antifolate administration [e.g., methotrexate] and Fusilev rescue increases, Fusilev’s effectiveness in counteracting toxicity may decrease. Fusilev 7.5 mg (approximately 5 mg/m2 ) should be administered IV every 6 hours until the serum methotrexate level is less than 10-8 M.

  Serum creatinine and methotrexate levels should be determined at 24 hour intervals. If the 24 hour serum creatinine has increased 50% over baseline or if the 24 hour methotrexate level is greater than 5 x 10-6 M or the 48 hour level is greater than 9 x 10-7 M, the dose of Fusilev should be increased to 50 mg/m2 IV every 3 hours until the methotrexate level is less than 10-8 M. Hydration (3 L/day) and urinary alkalinization with NaHCO3 should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.

  2.5 Fusilev Administration in Combination with 5-Fluorouracil (5-FU)

  The following regimens have been used historically for the treatment of colorectal cancer:

  Fusilev is administered at 100 mg/m2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-FU at 370 mg/m2 by intravenous injection. Fusilev is administered at 10 mg/m2 by intravenous injection followed by 5-FU at 425 mg/m2 by intravenous injection.

  5-FU and Fusilev should be administered separately to avoid the formation of a precipitate.

  Treatment is repeated daily for five days. This five-day treatment course may be repeated at 4 week (28-day) intervals, for 2 courses and then repeated at 4 to 5 week (28 to 35 day) intervals provided that the patient has completely recovered from the toxic effects of the prior treatment course.

  In subsequent treatment courses, the dosage of 5-FU should be adjusted based on patient tolerance of the prior treatment course. The daily dosage of 5-FU should be reduced by 20% for patients who experienced moderate hematologic or gastrointestinal toxicity in the prior treatment course, and by 30% for patients who experienced severe toxicity. For patients who experienced no toxicity in the prior treatment course, 5-FU dosage may be increased by 10%. Fusilev dosages are not adjusted for toxicity.

  2.6 Reconstitution and Infusion Instructions

  Fusilev for Injection

  Prior to intravenous injection, the 50 mg vial of Fusilev for Injection is reconstituted with 5.3 mL of 0.9% Sodium Chloride Injection, USP to yield a levoleucovorin concentration of 10 mg per mL. Reconstitution with Sodium Chloride solutions with preservatives (e.g. benzyl alcohol) has not been studied. The use of solutions other than 0.9% Sodium Chloride Injection, USP is not recommended. The reconstituted 10 mg per mL levoleucovorin contains no preservative. Observe strict aseptic technique during reconstitution of the drug product. Saline reconstituted levoleucovorin solutions may be further diluted, immediately, to concentrations of 0.5 mg/mL to 5 mg/mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Initial reconstitution or further dilution using 0.9% Sodium Chloride Injection, USP may be held at room temperature for not more than a total of 12 hours. Dilutions in 5% Dextrose Injection, USP may be held at room temperature for not more than 4 hours. Visually inspect the reconstituted solution for particulate matter and discoloration, prior to administration. CAUTION: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if cloudiness or precipitate is observed. No more than 16 mL of reconstituted solutions (160 mg of levoleucovorin) should be injected intravenously per minute, because of the calcium content of the levoleucovorin solution.

  Fusilev Injection

  Levoleucovorin contains no preservative. Observe strict aseptic technique during reconstitution of the drug product. Levoleucovorin solutions may be further diluted to concentrations of 0.5 mg/mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. The diluted solution using 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP may be held at room temperature for not more than 4 hours. Visually inspect the diluted solution for particulate matter and discoloration, prior to administration. CAUTION: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if cloudiness or precipitate is observed. No more than 16 mL of Fusilev Injection (160 mg of levoleucovorin) should be injected intravenously per minute, because of the calcium content of the levoleucovorin solution. 2.5 Fusilev Administration in Combination with 5-Fluorouracil (5-FU)

  The following regimens have been used historically for the treatment of colorectal cancer:

  Fusilev is administered at 100 mg/m2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-FU at 370 mg/m2 by intravenous injection. Fusilev is administered at 10 mg/m2 by intravenous injection followed by 5-FU at 425 mg/m2 by intravenous injection.

  5-FU and Fusilev should be administered separately to avoid the formation of a precipitate.

  Treatment is repeated daily for five days. This five-day treatment course may be repeated at 4 week (28-day) intervals, for 2 courses and then repeated at 4 to 5 week (28 to 35 day) intervals provided that the patient has completely recovered from the toxic effects of the prior treatment course.

  In subsequent treatment courses, the dosage of 5-FU should be adjusted based on patient tolerance of the prior treatment course. The daily dosage of 5-FU should be reduced by 20% for patients who experienced moderate hematologic or gastrointestinal toxicity in the prior treatment course, and by 30% for patients who experienced severe toxicity. For patients who experienced no toxicity in the prior treatment course, 5-FU dosage may be increased by 10%. Fusilev dosages are not adjusted for toxicity.

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