In the treatment of accidental overdosage of folic acid antagonists, leucovorin should be administered as promptly as possible.
As the time interval between antifolate administration (e.g., methotrexate) and leucovorin rescue increases, leucovorin’s effectiveness in counteracting hematologic toxicity decreases.
Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin.
Delayed methotrexate excretion may be caused by a third space fluid accumulation (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration.
Under such circumstances, higher doses of leucovorin or prolonged administration may be indicated.
Doses higher than those recommended for oral use must be given intravenously.
Leucovorin may enhance the toxicity of fluorouracil.
Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.
1 Concomitant granulocytopenia and fever were present in some but not all of the patients.
The concomitant use of leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection was associated with increased rates of treatment failure and mortality in a placebo-controlled study.
Excessive amounts of leucovorin may nullify the chemotherapeutic effect of folic acid antagonists.
Leucovorin Calcium Tablets USP contain either 5 mg, 10 mg, 15 mg or 25 mg leucovorin as the calcium salt of N-[4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl] amino]benzoyl]-L-glutamic acid.
This is equivalent to either 5.40 mg, 10.80 mg, 16.21 mg or 27.01 mg of anhydrous leucovorin calcium, respectively.
In addition, each tablet contains the following inactive ingredients : microcrystalline cellulose, corn starch, croscarmellose sodium, povidone, colloidal silicon dioxide, magnesium stearate, D&C yellow #10 (15mg and 25 mg).
Leucovorin is a water soluble form of reduced folate in the folate group; it is useful as an antidote to drugs which act as folic acid antagonists.
These tablets are intended for oral administration only.
The structural formula of leucovorin calcium is: C 20 H 21 CaN 7 O 7 M.W.
511.51 image of chemical structure
Leucovorin Calcium Tablets USP are available for oral administration as: 5 mg white, scored tablets (Identified 54 293).
NDC 54868-3310-3 Bottles of 2 NDC 54868-3310-4 Bottles of 4 NDC 54868-3310-2 Bottles of 10 NDC 54868-3310-1 Bottles of 50 NDC 54868-3310-0 Bottles of 60 15 mg yellow, scored tablets (Identified 54 650).
NDC 54868-5915-0 Bottles of 24 Store at Controlled Room Temperature 15°-30°C (59°-86°F).
Protect From Light and Moisture.
Relabeling and Repackaging by: Physicians Total Care, Inc.
Tulsa, OK 74146
INDICATIONS AND USAGE
Leucovorin Calcium Tablets USP are indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists.
DOSAGE AND ADMINISTRATION
Leucovorin calcium tablets are intended for oral administration.
Because absorption is saturable, oral administration of doses greater than 25 mg is not recommended.
Impaired Methotrexate Elimination or Inadvertent Overdosage Leucovorin rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion (see WARNINGS ).
Leucovorin 15 mg (10 mg/m 2 ) should be administered IM, IV, or PO every 6 hours until the serum methotrexate level is less than 10 -8 M.
In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally.
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 leucovorin should be increased to 150 mg (100 mg/m 2 ) IV every 3 hours until the methotrexate level is less than 10 -8 M.
Doses greater than 25 mg should be given parenterally (see CLINICAL PHARMACOLOGY ).
Hydration (3 L/d) and urinary alkalinization with sodium bicarbonate should be employed concomitantly.
The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.
The recommended dose of leucovorin to counteract hematologic toxicity from folic acid antagonists with less affinity for mammalian dihydrofolate reductase than methotrexate (i.e., trimethoprim, pyrimethamine) is substantially less, and 5 to 15 mg of leucovorin per day has been recommended by some investigators.
Patients who experience delayed early methotrexate elimination are likely to develop reversible non-oliguric renal failure.
In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen 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.
These abnormalities may or may not be associated with significant clinical toxicity.
If significant clinical toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total 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.