Leucovorin Calcium
Indications: Anemia, megaloblastic; Carcinoma, colorectal, adjunct; Osteosarcoma; Toxicity, methotrexate
DESCRIPTION:
Leucovorin is one of several active, chemically reduced derivatives of folic acid. It is useful as an antidote to drugs which act as folic acid antagonists.
Also known as folinic acid, Citrovorum factor, or 5-formyl-5,6,7,8-tetrahydrofolic acid, this compound has the chemical designation of L -Glutamic acid, N -[4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-,calcium salt (1:1). The formula weight is 511.51.
Tablets: Wellcovorin tablets contain either 5 or 25 mg of leucovorin (equivalent to 5.40 or 27.01 mg of anhydrous leucovorin calcium) and the following inactive ingredients: Corn starch, FD&C yellow no. 6 lake (25 mg tablets only), dibasic calcium phosphate, magnesium stearate, and pregelatinized starch.
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. Leucovorin calcium tablets are indicated for oral administration only.
Injection: Leucovorin calcium for injection is indicated for intravenous or intramuscular administration and is supplied in 100 mg vials. Each vial of Wellcovorin brand leucovorin calcium for injection sterile powder, when reconstituted with 10 ml of sterile diluent, contains leucovorin (as the calcium salt) 10 mg/ml, and the inactive ingredients sodium chloride 80 mg per vial, and sodium hydroxide and/or hydrochloric acid added to adjust the pH to approximately 8.1. The dry product contains no preservative. Reconstitute with bacteriostatic water for injection, which contains benzyl alcohol (see WARNINGS), or with sterile water for injection.
There is 0.004 mEq of calcium per mg of leucovorin.
CLINICAL PHARMACOLOGY:
Leucovorin is a racemic mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid (THF). The biologically active component of the mixture is the (-)-l -isomer, known as Citrovorum factor, or (-)-folinic acid. Leucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of "one-carbon" moieties.
Tablets
Following oral administration, leucovorin is rapidly absorbed and enters the general body pool of reduced folates. The increase in plasma and serum folate activity (determined microbiologically with Lactobacillus casei ) seen after oral administration of leucovorin is predominantly due to 5-methyltetrahydrofolate.
Twenty normal men were given a single oral 15 mg dose (7.5 mg/m2) of leucovorin calcium and serum folate concentrations were assayed with L. casei . Mean values observed (Β± one standard error) were:
a) Time to peak serum folate concentration: 1.72 Β± 0.08 hours.
b) Peak serum folate concentration achieved: 268 Β± 18 mg/ml.
c) Serum folate half-disappearance time: 3.5 hours.
Oral tablets yielded areas under the serum folate concentration-time curves (AUCs) that were 12% greater than equal amounts of leucovorin given intramuscularly and equal to the same amounts given intravenously.
Oral absorption of leucovorin is saturable at doses above 25 mg. The apparent bioavailability of leucovorin was 97% for 25 mg, 75% for 50 mg and 37% for 100 mg.
Injection
l- Leucovorin (l -5- formyltetrahydrofolate) is rapidly metabolized (via 5,10- methenyltetrahydrofolate then 5,10-methylenetetrahydrofolate) to l ,5-methyltetrahydrofolate. l ,5-Methyltetrahydrofolate can in turn be metabolized via other pathways back to 5,10 methylenetetrahydrofolate, which is converted to 5-methyltetrahydrofolate by an irreversible, enzyme catalyzed reduction using the cofactors FADH2 and NADPH.
Administration of leucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase.
In contrast, leucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy, such as 5-fluorouracil. Concurrent administration of leucovorin does not appear to alter the plasma pharmacokinetics of 5-fluorouracil. 5-Fluorouracil is metabolized to fluorodeoxyuridylic acid, which binds to and inhibits the enzyme thymidylate synthase (an enzyme important in DNA repair and replication).
Leucovorin is readily converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of fluorodeoxyuridylic acid to thymidylate synthase and thereby enhances the inhibition of this enzyme.
The pharmacokinetics after intravenous and intramuscular of a 25 mg dose of leucovorin were studied in male volunteers. After intravenous administration, serum total reduced folates (as measured by Lactobacillus casei assay) reached a mean peak of 1259 ng/ml (range 897-1625). The mean time to peak was 10 minutes. This initial rise in total reduced folates was primarily due to the parent compound 5-formyl-THF (measured by Streptococcus faecalis assay) which rose to 1206 ng/ml at 10 minutes. A sharp drop in parent compound followed and coincided with the appearance of the active metabolite 5-methyl-THF which became the predominant circulating form of the drug.
The mean peak of 5-methyl-THF was 258 ng/ml and occurred at 1.3 hours. The terminal half-life for total reduced folates was 6.2 hours. The area under the concentration-versus-time curves (AUCs) for l -leucovorin,d -leucovorin and 5-methyltetrahydrofolate were 28.4 Β± 3.5, 956 Β± 97 and 129 Β± 12 (mg.min/L Β± SE). When a higher dose of d, l -leucovorin (200 mg/m2) was used, similar results were obtained. The d -isomer persisted in plasma at concentrations greatly exceeding those of the l -isomer.
After intramuscular injection, the mean peak of serum total reduced folates was 436 ng/ml (range 240-725) and occurred at 52 minutes. Similar to IV administration, the initial sharp rise due to the parent compound. The mean peak of 5-formyl-THF was 360 ng/ml and occurred at 28 minutes. The level of the metabolite 5-methyl-THF increased subsequently over time until at 1.5 hours it represented 50% of the circulating total folates. The mean peak of 5-methyl -THF was 226 ng/ml at 2.8 hours. The terminal half-life of total reduced folates was 6.2 hours. There was no difference of statistical significance between IM and IV administration in the AUC for total reduced folates, 5-formyl-THF or 5 Methyl-THF.
INDICATIONS AND USAGE:
Tablets: Leucovorin calcium is indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists.
Injection: Leucovorin calcium rescue is indicated after high-dose methotrexate therapy in osteosarcoma. Leucovorin is also indicated for use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer. Leucovorin should not be mixed in the same infusion as 5-fluorouracil because a precipitate may form.
Leucovorin calcium is indicated in the treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible.
CONTRAINDICATIONS:
Leucovorin is improper therapy for pernicious anemia and other megaloblastic anemias secondary to the lack of vitamin B12. A hematologic remission may occur while neurologic manifestations continue to progress.
WARNINGS:
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 (MTX)] and leucovorin rescue increases, leucovorin's effectiveness in counteracting hematologic toxicity decreases. In the treatment of accidental overdosages of intrathecally administered folic acid antagonists, do not administer leucovorin intrathecally. LEUCOVORIN MAY BE HARMFUL OR FATAL IF GIVEN INTRATHECALLY.
Monitoring of serum MTX concentration is essential in determining the optimal dose and duration of treatment with leucovorin.
Delayed MTX 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.
There have been rare reports of seizures and/or syncope associated with the use of leucovorin, particularly high doses, in combination with fluorouracil for treatment of malignancies in patients with a history of prior seizures or in patients with central nervous system abnormalities.
Leucovorin may enhance the toxicity of fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving 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 morbidity in a placebo-controlled study.
Additional Information for Injection: Because of the benzyl alcohol contained in certain diluents used for leucovorin calcium for injection, when doses greater than 10 mg/m2 are administered, leucovorin calcium for injection should be reconstituted with sterile water for injection, and used immediately (see DOSAGE AND ADMINISTRATION).
Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin should be injected intravenously per minute (16 ml of a 10 mg/ml, or 8 ml of a 20 mg/ml solution per minute).
Leucovorin enhances the toxicity of 5-fluorouracil. When these drugs are administered concurrently, the dosage of the 5-fluorouracil must be lower than usually administered. Although the toxicities observed in patients treated with the combination of leucovorin plus 5-fluorouracil are qualitatively similar to those observed in patients treated with 5-fluorouracil alone, gastrointestinal toxicities (particularly stomatitis and diarrhea) are observed more commonly and may be more severe and of prolonged duration in patients treated with the combination.
Therapy with leucovorin and 5-fluorouracil must not be initiated or continued in patients who have symptoms of gastrointestinal toxicity of any severity, until those symptoms have completely resolved. Patients with diarrhea must be monitored with particular care until the diarrhea has resolved, as rapid clinical deterioration leading to death can occur. In a study utilizing higher weekly doses of 5-fluorouracil and leucovorin, elderly and/or debilitated patients were found to be at greater risk for severe gastrointestinal toxicity.1
PRECAUTIONS:
General
Parenteral administration is preferable to oral dosing if there is a possibility that the patient may vomit or not absorb the leucovorin. Leucovorin has no effect on non-hematologic toxicities of MTX such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney.
Injection: Since leucovorin enhances the toxicity of fluorouracil, leucovorin/5 fluorouracil combination therapy for advanced colorectal cancer should be administered under the supervision of a physician experienced in the use of antimetabolite cancer chemotherapy. Particular care should be taken in the treatment of elderly or debilitated colorectal cancer patients, as these patients may be at increased risk of severe toxicity.
Pregnancy, Teratogenic Effects, Pregnancy Category C
Adequate animal reproduction studies have not been conducted with leucovorin. It is also not known whether leucovorin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Leucovorin should be given to a pregnant woman only if clearly needed.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when leucovorin is administered to a nursing mother.
Pediatric Use
See DRUG INTERACTIONS.
Laboratory Tests
Injection: Patients being treated with the leucovorin/5-fluorouracil combination should have a CBC with differential and platelets prior to each treatment. During the first two courses a CBC with differential and platelets has to be repeated weekly and thereafter once each cycle at the time of anticipated WBC nadir. Electrolytes and liver function tests should be performed prior to each treatment for the first three cycles then prior to every other cycle. Dosage modifications of fluorouracil should be instituted as follows, based on the most severe toxicities (see TABLE 1).
TABLE 1
Diarrhea and/or Stomatitis
WBC/mm3 Nadir
Platelets/mm3 Nadir
5-FU Dose
Moderate
1000-1900
25-75,000
decrease 20%
Severe
<1000
<25,000
decrease 30%
If no toxicity occurs, the 5-fluorouracil dose may increase 10%.
Treatment should be deferred until WBC's are 4000/mm3 and platelets 130,000/mm3. If blood counts do not reach these levels within two weeks, treatment should be discontinued. Patients should be followed up with physical examination prior to each treatment course and appropriate radiological examination as needed. Treatment should be discontinued when there is clear evidence of tumor progression.
DRUG INTERACTIONS:
Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible pediatric patients.
Preliminary animal and human studies have shown that small quantities of systemically administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1-3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate.
Leucovorin may enhance the toxicity of 5-fluorouracil (see WARNINGS).
ADVERSE REACTIONS:
Tablets: Allergic sensitization has been reported following both oral and parenteral administration of folic acid.
Injection: Allergic sensitization, including anaphylactoid reactions and urticaria, has been reported following administration of both oral and parenteral leucovorin. No other adverse reactions have been attributed to the use of leucovorin per se .
OVERDOSAGE:
Excessive amounts of leucovorin may nullify the chemotherapeutic effect of folic acid antagonists.
DOSAGE AND ADMINISTRATION:
Tablets
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 a delayed excretion (see WARNINGS). Leucovorin 15 mg/m2 should be administered IV, IM, or PO every 6 hours until the serum methotrexate level is less than 10-8M. In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally. Do not administer leucovorin intrathecally.
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 Γ 10-6M or the 48-hour level is greater than 9 Γ 10-7M, the doses of leucovorin should be increased to 100 mg/m2 IV every 3 hours until the methotrexate level is less than 10-8M.2
Hydration (3 L/day) and urinary alkalinization with sodium bicarbonate solution 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 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. The 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 of 14 doses over 84 hours) is 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.
Injection
Leucovorin Rescue After High-Dose Methotrexate Therapy: The recommendations for leucovorin rescue are based on a methotrexate dose of 12-15 grams/m2 administered by intravenous infusion over 4 hours (see methotrexate package insert for full prescribing information).3
Leucovorin rescue at a dose of 15 mg (approximately 10 mg/m2) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion. In the presence of gastrointestinal toxicity, nausea or vomiting, leucovorin should be administered parenterally. Do not administer leucovorin intrathecally.
Serum creatinine and methotrexate levels should be determined at least once daily. Leucovorin administration, hydration, and urinary alkalinization (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 Γ 10-8 M (0.05 micromolar). The leucovorin dose should be adjusted or leucovorin rescue extended based on the guidelines established in TABLE 2.
TABLE 2 Guidelines For Leucovorin Dosage and Administration
DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY
Clinical Situation
Laboratory Findings
Leucovorin 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.
15 mg PO, IM, or 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 15 mg PO, IM, or 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).
150 mg IV q 3 hours, until methotrexate level is less than 1 micromolar; then 15 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 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 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 TABLE 2. 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 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.
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 a delayed excretion (see WARNINGS). Leucovorin 15 mg/m2 should be administered IV, IM, or PO every 6 hours until the serum methotrexate level is less than 10-8M. In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally. Do not administer leucovorin intrathecally.
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 Γ 10-6M or the 48-hour level is greater than 9 Γ 10-7M, the doses of leucovorin should be increased to 100 mg/m2 IV every 3 hours until the methotrexate level is less than 10-8M.2
Megaloblastic Anemia Due to Folic Acid Deficiency: Up to 1 mg daily. There is no evidence that doses greater than 1 mg/day have greater efficacy than those of 1 mg; additionally, loss of folate in urine becomes roughly logarithmic as the amount administered exceeds 1 mg.
Preparation: Each 100-mg vial of Wellcovorin brand leucovorin calcium for injection when reconstituted with 10 ml of sterile diluent yields a leucovorin concentration of 10 mg per ml. leucovorin calcium for injection contains no preservative. Reconstitute with bacteriostatic water for injection, which contains benzyl alcohol, or with sterile water for injection. When reconstituted with bacteriostatic water for injection, the resulting solution must be used within 7 days. If the product is reconstituted with sterile water for injection, it must be used immediately.
Because of the benzyl alcohol contained in bacteriostatic water for injection, when doses greater than 10 mg/m2 are administered, leucovorin calcium for injection should be reconstituted with sterile water for injection, and used immediately.
Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin should be injected intravenously per minute (16 ml of a 10-mg/ml, or 8 ml of a 20-mg/ml solution per minute).
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Leucovorin and fluorouracil should not be admixed in the same PVC bag because a precipitate may form.
REFERENCES:
1. Grem, JL, Shoemaker, DD, Petrelli, NJ, Douglas, HO, "Severe and Fatal Toxic Effects Observed in Treatment with High- and Low-Dose Leucovorin Plus 5-Fluorouracil for Colorectal Carcinoma,"Cancer Treat Rep 1987; 71:1122.
2. Link, MP, Goorin, AM, Miser, AW, et al, "The Effect of Adjuvant Chemotherapy on Relapse-Free Survival in Patients with Osteosarcoma of the Extremity," N Engl J Med 1986; 314:1600-1606.