Label: LEUCOVORIN CALCIUM tablet

  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: Abbreviated New Drug Application

Drug Label Information

Updated December 7, 2018

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  • SPL UNCLASSIFIED SECTION

    Rx only

  • DESCRIPTION

    Leucovorin calcium tablets USP contain either 5 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 5.4 mg or 27.01 mg of anhydrous leucovorin calcium, respectively. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The 25 mg tablet also contains D&C yellow no. 10 aluminum lake and FD&C blue no. 1 aluminum lake.

    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 is as follows:

    structural formula

    C 20H 21CaN 7O 7 M.W. 511.5

  • CLINICAL PHARMACOLOGY

    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/m 2) 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.

  • INDICATIONS AND USAGE

    Leucovorin calcium tablets are indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists.

  • CONTRAINDICATIONS

    Leucovorin is improper therapy for pernicious anemia and other megaloblastic anemias secondary to the lack of vitamin B 12. 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. 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.

  • 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.

    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 children.

    Preliminary animal and human studies have shown that small quantities of systemically administered leucovorin enter CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than 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 (see WARNINGS).

    Pregnancy

    Teratogenic Effects

    Pregnancy Category C

    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 subsection.

  • ADVERSE REACTIONS

    Allergic sensitization, including anaphylactoid reactions and urticaria, has been reported following the administration of both oral and parenteral leucovorin.

  • OVERDOSAGE

    Excessive amounts of leucovorin may nullify the chemotherapeutic effect 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 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 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. 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.

  • HOW SUPPLIED:

    Leucovorin Calcium Tablets USP, 5 mg are available as white, round, unscored, biconvex tablets, debossed with b on one side and 484 on the other side. They are available as follows:

    NDC 51079-581-06 - Unit dose blister packages of 50 (5 cards of 10 tablets each).

    Leucovorin Calcium Tablets USP, 25 mg are available as pale green, round, unscored, biconvex tablets, debossed with b on one side and 485 on the other side. They are available as follows:

    NDC 51079-582-05 – Unit dose blister packages of 20 (2 cards of 10 tablets each).

    Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]
    Protect from light and moisture.

  • 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.
  • SPL UNCLASSIFIED SECTION

    Manufactured by:
    Teva Pharmaceuticals USA, Inc.
    North Wales, PA 19454

    Distributed by:
    Mylan Institutional Inc.
    Rockford, IL 61103

    S-12078 R1
    7/17

  • PRINCIPAL DISPLAY PANEL – 5 mg

    NDC 51079-581-06

    Leucovorin Calcium
    Tablets, USP
    5 mg*

    50 Tablets (5 x 10)

    *Each tablet contains leucovorin
    calcium, USP equivalent to 5 mg leucovorin.

    Usual Dosage: See accompanying
    prescribing information.

    Store at 20° to 25°C (68° to 77°F). [See
    USP Controlled Room Temperature.]
    Protect from light and moisture.

    Manufactured by:
    Teva Pharmaceuticals USA, Inc.
    North Wales, PA 19454

    Rx only

    S-10767 R3

    Packaged and Distributed by:

    Mylan Institutional Inc.

    Rockford, IL 61103 U.S.A.

    This unit dose package is not child resistant.

    For institutional use only.

    Keep this and all drugs out of the reach of children.

    This container provides light-resistance.

    See window for lot number and expiration date.

    Leucovorin Calcium 5 mg Tablets Unit Carton Label
    Serialized Unit Carton
  • PRINCIPAL DISPLAY PANEL – 25 mg

    NDC 51079-582-05

    Leucovorin Calcium
    Tablets USP
    25 mg*

    20 Tablets (2 x 10)

    *Each tablet contains leucovorin
    calcium, USP equivalent to 25 mg leucovorin.

    Usual Dosage: See accompanying
    prescribing information.

    Store at 20° to 25°C (68° to 77°F). [See
    USP Controlled Room Temperature.]
    Protect from light and moisture.

    Manufactured by:
    Teva Pharmaceuticals USA, Inc.
    North Wales, PA 19454

    Rx only

    S-10768 R3

    Packaged and Distributed by:

    Mylan Institutional Inc.

    Rockford, IL 61103 U.S.A.

    This unit dose package is not child resistant.

    For institutional use only.

    Keep this and all drugs out of the reach of children.

    This container provides light-resistance.

    See window for lot number and expiration date.

    Leucovorin Calcium Tablets Unit Carton Label
    Serialized Unit Carton
  • INGREDIENTS AND APPEARANCE
    LEUCOVORIN CALCIUM 
    leucovorin calcium tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:51079-581(NDC:0555-0484)
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    LEUCOVORIN CALCIUM (UNII: RPR1R4C0P4) (LEUCOVORIN - UNII:Q573I9DVLP) LEUCOVORIN5 mg
    Inactive Ingredients
    Ingredient NameStrength
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    Product Characteristics
    ColorwhiteScoreno score
    ShapeROUNDSize8mm
    FlavorImprint Code b;484
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:51079-581-0650 in 1 CARTON02/26/1996
    1NDC:51079-581-011 in 1 BLISTER PACK; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA07119802/26/1996
    LEUCOVORIN CALCIUM 
    leucovorin calcium tablet
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:51079-582(NDC:0555-0485)
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    LEUCOVORIN CALCIUM (UNII: RPR1R4C0P4) (LEUCOVORIN - UNII:Q573I9DVLP) LEUCOVORIN25 mg
    Inactive Ingredients
    Ingredient NameStrength
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)  
    FD&C BLUE NO. 1 (UNII: H3R47K3TBD)  
    Product Characteristics
    Colorgreen (pale green) Scoreno score
    ShapeROUNDSize8mm
    FlavorImprint Code b;485
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:51079-582-0520 in 1 CARTON08/27/1997
    1NDC:51079-582-011 in 1 BLISTER PACK; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA07119908/27/1997
    Labeler - Mylan Institutional Inc. (039615992)