Levoleucovorin

LEVOLEUCOVORIN- levoleucovorin calcium injection, powder, lyophilized, for solution
Hikma Pharmaceuticals USA Inc.

1 INDICATIONS AND USAGE

Levoleucovorin for Injection is indicated for:

  • rescue after high-dose methotrexate therapy in adult and pediatric patients with osteosarcoma.
  • diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination in adult and pediatric patients.
  • the treatment of adults with metastatic colorectal cancer in combination with fluorouracil.

Limitations of Use

Levoleucovorin for Injection is not indicated for pernicious anemia and megaloblastic anemia secondary to the lack of vitamin B12, because of the risk of progression of neurologic manifestations despite hematologic remission.

2 DOSAGE AND ADMINISTRATION

2.1 Important Use Information

Levoleucovorin for Injection is indicated for intravenous administration only. Do not administer intrathecally.

2.2 Co-administration of Levoleucovorin for Injection with other agents

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

2.3 Recommended Dosage for Rescue After High-Dose Methotrexate Therapy

The recommended dosage for Levoleucovorin for Injection is based on a methotrexate dose of 12 grams/m2 administered by intravenous infusion over 4 hours. Twenty-four hours after starting the methotrexate infusion, initiate Levoleucovorin for Injection at a dose of 7.5 mg (approximately 5 mg/m2) as an intravenous infusion every 6 hours.

Monitor serum creatinine and methotrexate levels at least once daily. Continue Levoleucovorin for Injection administration, hydration, and urinary alkalinization (pH of 7 or greater) until the methotrexate level is below 5 x 10-8 M (0.05 micromolar). Adjust the Levoleucovorin for Injection dose or extend the duration as recommended in Table 1.

Table 1 Recommended Dosage for Levoleucovorin for Injection based on Serum Methotrexate and Creatinine Levels

Clinical Situation Laboratory Findings Recommendation
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 Administer 7.5 mg by intravenous infusion every 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 by intravenous infusion every 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

Administer 75 mg by intravenous infusion every 3 hours until methotrexate level is less than 1 micromolar; then 7.5 mg by intravenous infusion every 3 hours until methotrexate level is less than 0.05 micromolar.

* These patients are likely to develop reversible renal failure. In addition to appropriate Levoleucovorin for Injection therapy, continue hydration and urinary alkalinization and monitor fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved.

Impaired Methotrexate Elimination or Renal Impairment

Decreased methotrexate elimination or renal impairment which are clinically important but less severe than the abnormalities described in Table 1 can occur following methotrexate administration. If toxicity associated with methotrexate is observed, in subsequent courses extend Levoleucovorin for Injection rescue for an additional 24 hours (total of 14 doses over 84 hours).

Third-Space Fluid Collection and Other Causes of Delayed Methotrexate Elimination

Accumulation in a third space fluid collection (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration can delay methotrexate elimination. Under such circumstances, higher doses of Levoleucovorin for Injection or prolonged administration may be indicated.

2.4 Recommended Dosage for Overdosage of Folic Acid Antagonists or Impaired Methotrexate Elimination

Start Levoleucovorin for Injection as soon as possible after an overdosage of methotrexate or within 24 hours of methotrexate administration when methotrexate elimination is impaired. As the time interval between methotrexate administration and Levoleucovorin for Injection increases, the effectiveness of Levoleucovorin for Injection to diminish methotrexate toxicity may decrease. Administer Levoleucovorin for Injection 7.5 mg (approximately 5 mg/m2) by intravenous infusion every 6 hours until the serum methotrexate level is less than 5 x 10-8 M (0.05 micromolar).

Monitor serum creatinine and methotrexate levels at least every 24 hours. Increase the dosage of Levoleucovorin for Injection to 50 mg/m2 intravenously every 3 hours and continue Levoleucovorin for Injection at this dosage until the methotrexate level is less than 5 x 10-8 M for the following:

  • if serum creatinine at 24-hours increases 50% or more compared to baseline
  • if the methotrexate level at 24-hours is greater than 5 x 10-6 M
  • if the methotrexate level at 48-hours is greater than 9 x 10-7 M,

Continue concomitant hydration (3 L per day) and urinary alkalinization with sodium bicarbonate. Adjust the sodium bicarbonate dose to maintain urine pH at 7 or greater.

2.5 Dosage in Combination with Fluorouracil for Metastatic Colorectal Cancer

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

  • Levoleucovorin for Injection 100 mg/m2 by intravenous injection over a minimum of 3 minutes, followed by fluorouracil at 370 mg/m2 by intravenous injection, once daily for 5 consecutive days.
  • Levoleucovorin for Injection 10 mg/m2 by intravenous injection, followed by fluorouracil 425 mg/m2 by intravenous injection, once daily for 5 consecutive days.

Administer fluorouracil and Levoleucovorin for Injection separately to avoid the formation of a precipitate.

This five-day course may be repeated every 4 weeks for 2 courses, then every 4 to 5 weeks, if the patient has recovered from the toxicity from the prior course. Do not adjust Levoleucovorin for Injection dosage for toxicity.

Refer to fluorouracil prescribing information for information on fluorouracil dosage and dosage modifications for adverse reactions.

2.6 Preparation for Administration

Levoleucovorin for Injection

  • Prior to intravenous injection, reconstitute the 50 mg vial of Levoleucovorin for Injection 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. Discard unused portion.
  • 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. Do not store the reconstituted product or reconstituted product diluted using 0.9% Sodium Chloride Injection, USP for more than 12 hours at room temperature. Do not store reconstituted product diluted using 5% Dextrose Injection, USP for more than 4 hours at room temperature.
  • Visually inspect the reconstituted solution for particulate matter and discoloration prior to administration. Do not use if cloudiness or precipitate is observed.
  • Do not intravenously inject more than 16 mL of reconstituted solutions (160 mg of levoleucovorin) per minute, because of the calcium content of the levoleucovorin solution.
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