Leucovorin (oral)

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{{DrugProjectFormSinglePage |authorTag=Adeel Jamil, M.D. [1] |genericName=Leucovorin calcium |aOrAn=a |drugClass=antidote, methotrexate rescue and nutritive agent |indicationType=treatment |indication=and to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists. |adverseReactions=diarrhea, nausea, stomatitis, vomiting, fatigue, allergic reaction. |blackBoxWarningTitle=TITLE |blackBoxWarningBody=Condition Name: (Content) |fdaLIADAdult=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.

Dosing Information

  • 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. Leucovorin 15 mg (10 mg/m2) 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/m2) IV every 3 hours until the methotrexate level is less than 10-8 M. Doses greater than 25 mg should be given parenterally.
  • 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.

|offLabelAdultGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Leucovorin (oral) in adult patients. |offLabelAdultNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Leucovorin (oral) in adult patients. |offLabelPedGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Leucovorin (oral) in pediatric patients. |offLabelPedNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Leucovorin (oral) in pediatric patients. |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) 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. 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.

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 other established toxicities of methotrexate such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney.

|clinicalTrials=* Allergic sensitization, including anaphylactoid reactions and urticaria, has been reported following the administration of both oral and parenteral leucovorin. |drugInteractions=* Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible children.

  • 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 to 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 fluorouracil.

|FDAPregCat=C |useInPregnancyFDA=* 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. |useInNursing=* 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. |administration=* Oral |overdose=* Excessive amounts of leucovorin may nullify the chemotherapeutic effect of folic acid antagonists. |drugBox={{Drugbox | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 470454241 | IUPAC_name = (2S)-2-{[4-[(2-amino-5-formyl-4-oxo-5,6,7,8-
tetrahydro-1H-pteridin-6-yl)methylamino]
benzoyl]amino}pentanedioic acid | image = Folinic acid.svg

| tradename = Many | Drugs.com = Monograph | pregnancy_AU = A | pregnancy_US = C | legal_status = Rx-only | routes_of_administration = Intravenous, oral

| bioavailability = Dose dependent | protein_bound = ~15% | metabolism = | elimination_half-life = 6.2 hours | excretion = Urinary

| CASNo_Ref =  ☑Y | CAS_number_Ref =  ☑Y | CAS_number = 1492-18-8 | ATC_prefix = V03 | ATC_suffix = AF03 | PubChem = 6006 | DrugBank_Ref =  ☒N

| DrugBank = DB00650

| ChemSpiderID_Ref =  ☑Y | ChemSpiderID = 5784 | UNII_Ref =  ☑Y | UNII = RPR1R4C0P4 | ChEMBL_Ref =  ☑Y | ChEMBL = 1679

| C=20 | H=23 | N=7 | O=7 | molecular_weight = 473.44 g/mol | smiles = O=C(O)[C@@H](NC(=O)c1ccc(cc1)NCC3N(/C2=C(/N/C(=N\C2=O)N)NC3)C=O)CCC(=O)O | InChI = 1/C20H23N7O7/c21-20-25-16-15(18(32)26-20)27(9-28)12(8-23-16)7-22-11-3-1-10(2-4-11)17(31)24-13(19(33)34)5-6-14(29)30/h1-4,9,12-13,22H,5-8H2,(H,24,31)(H,29,30)(H,33,34)(H4,21,23,25,26,32)/t12?,13-/m0/s1 | InChIKey = VVIAGPKUTFNRDU-ABLWVSNPBN | StdInChI_Ref =  ☑Y | StdInChI = 1S/C20H23N7O7/c21-20-25-16-15(18(32)26-20)27(9-28)12(8-23-16)7-22-11-3-1-10(2-4-11)17(31)24-13(19(33)34)5-6-14(29)30/h1-4,9,12-13,22H,5-8H2,(H,24,31)(H,29,30)(H,33,34)(H4,21,23,25,26,32)/t12?,13-/m0/s1 | StdInChIKey_Ref =  ☑Y | StdInChIKey = VVIAGPKUTFNRDU-ABLWVSNPSA-N | density = | melting_point = 245 | melting_high = | melting_notes = decomp | solubility = }} |mechAction=* Leucovorin is a mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid (THF). The biologically active compound 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.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.

|structure=

This image is provided by the National Library of Medicine.

|PK=* Leucovorin is a racemic mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid. The biologically active compound 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. 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 (± one standard error) were:
  • Time to peak serum folate concentration: 1.72 ± 0.08 hours,
  • Peak serum folate concentration achieved: 268 ± 18 ng/mL,
  • 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.

|howSupplied=Leucovorin Calcium Tablets USP are available for oral administration as:

5 mg white, scored tablets (Identified 54 293).

NDC 0054-8496-19: Unit dose, 10 tablets per strip, 5 strips per shelf pack.

NDC 0054-4496-13: Bottles of 30 tablets.

NDC 0054-4496-25: Bottles of 100 tablets.

10 mg white, scored tablets (Identified 54 942).

NDC 0054-4497-05: Bottles of 12 tablets.

NDC 0054-4497-10: Bottles of 24 tablets.

15 mg yellow, scored tablets (Identified 54 650).

NDC 0054-4498-10: Bottles of 24 tablets.

25 mg yellow, scored tablets (Identified 54 013).

NDC 0054-4499-11: Bottles of 25 tablets.

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.

Roxane Laboratories, Inc.

Columbus, Ohio 43216


4055309//05 Revised October 2014

© RLI, 2014 |storage=* Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

  • Protect From Light and Moisture.

|packLabel======NDC 0054-8496-19: UNIT DOSE, 10 TABLETS PER STRIP, 5 STRIPS PER SHELF PACK=====

5 mg white, scored tablets (Identified 54 293).

Rx Only

Roxane Laboratories, Inc.

This image is provided by the National Library of Medicine.
NDC 0054-4496-13: BOTTLES OF 30 TABLETS

5 mg white, scored tablets (Identified 54 293).

Rx Only

Roxane Laboratories, Inc.

This image is provided by the National Library of Medicine.
NDC 0054-4497-05: BOTTLES OF 12 TABLETS

10 mg white, scored tablets (Identified 54 942).

Rx Only

Roxane Laboratories, Inc.

This image is provided by the National Library of Medicine.
NDC 0054-4498-10: BOTTLES OF 24 TABLETS

15 mg yellow, scored tablets (Identified 54 650).

Rx Only

Roxane Laboratories, Inc.

This image is provided by the National Library of Medicine.
NDC 0054-4499-11: BOTTLES OF 25 TABLETS

25 mg yellow, scored tablets (Identified 54 013).

Rx Only

Roxane Laboratories, Inc.

This image is provided by the National Library of Medicine.

|alcohol=Alcohol-Leucovorin (oral) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. |lookAlike=* folinic acid - folic acid[1]

  • leucovorin calcium - Leukeran

}}


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