DOSAGE AND ADMINISTRATION
levoleucovorin is dosed at one-half the usual dose of the racemic form.
levoleucovorin is indicated for intravenous administration only. Do not
Co-administration of levoleucovorin with other agents
Due to the risk of precipitation, do not co-administer levoleucovorin with
other agents in the same admixture.
levoleucovorin Rescue After High-Dose Methotrexate Therapy
The recommendations for levoleucovorin 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). levoleucovorin 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. levoleucovorin 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 levoleucovorin dose should be adjusted
or rescue extended based on the following guidelines.
Table 1 Guidelines for levoleucovorin Dosage and Administration
||levoleucovorin 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
||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 levoleucovorin
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, levoleucovorin 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 levoleucovorin
or prolonged administration may be indicated.
Although levoleucovorin may ameliorate the hematologic toxicity associated
with high dose methotrexate, levoleucovorin has no effect on other established
toxicities of methotrexate such as the nephrotoxicity resulting from drug and/or
metabolite precipitation in the kidney.
Dosing Recommendations for Inadvertent Methotrexate Overdosage
levoleucovorin 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 levoleucovorin rescue increases, levoleucovorin's effectiveness
in counteracting toxicity may decrease. levoleucovorin 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 levoleucovorin 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.
Reconstitution and Infusion Instructions
- Prior to intravenous injection, the 50 mg vial of levoleucovorin 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
- 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
- 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.
Dosage Forms And Strengths
levoleucovorin for Injection is supplied in sterile, single-use vials containing
64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin
) and 50 mg mannitol.
Each 50 mg single-use vial of levoleucovorin for Injection contains a sterile
lyophilized powder consisting of 64 mg levoleucovorin calcium pentahydrate (equivalent
to 50 mg levoleucovorin) and 50 mg mannitol.
50 mg vial of freeze-dried powder - NDC 68152-101-00.
Store at 25°C (77 °F) in carton until contents are used. Excursions
permitted from 15-30°C (59-86 °F). [See USP Controlled Room Temperature].
Protect from light.
Manufactured for Spectrum Pharmaceuticals, Inc. Irvine, CA 92618. Manufactured
by Chesapeake Biological Laboratories, Inc. Baltimore, MD 21230, Spectrum Pharmaceuticals,
Inc. FDA revision date: 3/7/2008