leucovorin (Rx)

Brand and Other Names:
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablets

  • 5mg
  • 10mg
  • 15mg
  • 25mg

injection, powder for reconstitution

  • 50mg
  • 100mg
  • 200mg
  • 350mg
  • 500mg

injectable solution

  • 10mg/mL

Methotrexate Overdose

Administer as soon as possible and within 24 hr methotrexate level is >10-6 M or 48 hour level is >9 x 10-7 M, the dose of leucovorin should be increased to 100 mg/m2 IV every 3 hours until methotrexate level is <10-8 M

Dosing considerations

  • Hydration (3 L/day) and urinary alkalinization with sodium bicarbonate solution should be employed concomitantly; bicarbonate dose should be adjusted to maintain urine pH at 7.0 or greater

High Dose Methotrexate Rescue

10 mg/m² IV q6hr for 10 doses; starts 24 hours after beginning of methotrexate infusion  

May give PO after 1st IV dose

Adjust dose as follows:

Normal methotrexate elimination

  • Serum methotrexate level approximately 10 micromolar, 24 hr after administration, 1 micromolar at 48 hr, <0.2 micromolar at 72 hr
    • Administer 15 mg PO, IM, or IV q6hr for 60 hr (10 doses starting at 24 hr after start of methotrexate infusion

Delayed late methotrexate elimination

  • Serum methotrexate level remaining above 0.2 micromolar at 72 hr, and more than 0.05 micromolar at 96 hr after administration
    • Continue 15 mg PO, IM, or IV q6hr, until methotrexate level <0.05 micromolar

Delayed early methotrexate elimination and/or evidence of acute renal injury

  • Serum methotrexate level of 50 micromolar or more at 24 hr, or 5 micromolar or more at 48 hr after administration, or a 100% or greater increase in serum creatinine level at 24 hr after methotrexate administration (eg, increase from 0.5 mg/dL to a level of 1 mg/dL or more)
    • Administer 150 mg IV q3hr until methotrexate level is <1 micromolar; then 15 mg IV q3hr until methotrexate level is <0.05 micromolar

Dosing considerations

  • In presence of gastrointestinal toxicity, nausea or vomiting, administer leucovorin parenterally; do not administer leucovorin intrathecally; serum creatinine and methotrexate levels should be determined at least once daily
  • Administration, hydration, and urinary alkalization (pH of 7.0 or greater) should be continued until methotrexate level is below 5 x 10-8 M (0.05 micromolar)

Megaloblastic Anemia Due to Folate Deficiency

Up to 1 mg daily; there is no evidence that doses >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

Coadministration with Trimetrexate (Discontinued)

20 mg/m² IV/PO q6hr (for PO, round dose up to next 25 mg increment)  

Dose adjustment for both trimetrexate & leucovorin may be necessary if hematologic toxicity occurs

Advanced Colorectal Carcinoma (with 5FU)

Recommended 20 mg/m² IV followed by 425 mg/m² fluorouracil  

Dose reduction treatment pause may be necessary based on hematologic toxicity

Methanol Poisoning

1 mg/kg (50-70 mg adults) IV q4-6hr

Trimethoprim Toxicity

10 mg/m² PO q6hr

Other Indications & Uses

Bone marrow suppression due to folic acid antagonism

Dosage Forms & Strengths

tablets

  • 5mg
  • 10mg
  • 15mg
  • 25mg

injection, powder for reconstitution

  • 50mg
  • 100mg
  • 200mg
  • 350mg
  • 500mg

injectable solution

  • 10mg/mL

Methotrexate Overdose

Administer as soon as possible and within 24 hr methotrexate level is >10-6 M or 48 hour level is >9 x 10-7 M, the dose of leucovorin should be increased to 100 mg/m2 IV every 3 hours until methotrexate level is <10-8 M

Dosing considerations

  • Hydration (3 L/day) and urinary alkalinization with sodium bicarbonate solution should be employed concomitantly; bicarbonate dose should be adjusted to maintain urine pH at 7.0 or greater

High Dose Methotrexate Rescue

10 mg/m² IV q6hr for 10 doses; starts 24 hr after beginning of methotrexate infusion

May give PO after 1st IV dose

Adjust dose as follows:

Normal methotrexate elimination

  • Serum methotrexate level approximately 10 micromolar, 24 hr after administration, 1 micromolar at 48 hr, <0.2 micromolar at 72 hr
    • Administer 15 mg PO, IM, or IV q6hr for 60 hr (10 doses starting at 24 hr after start of methotrexate infusion

Delayed late methotrexate elimination

  • Serum methotrexate level remaining above 0.2 micromolar at 72 hr, and more than 0.05 micromolar at 96 hr after administration
    • Continue 15 mg PO, IM, or IV q6hr, until methotrexate level <0.05 micromolar

Delayed early methotrexate elimination and/or evidence of acute renal injury

  • Serum methotrexate level of 50 micromolar or more at 24 hr, or 5 micromolar or more at 48 hr after administration, or a 100% or greater increase in serum creatinine level at 24 hr after methotrexate administration (eg, increase from 0.5 mg/dL to a level of 1 mg/dL or more)
    • Administer 150 mg IV q3hr until methotrexate level is <1 micromolar; then 15 mg IV q3hr until methotrexate level is <0.05 micromolar

Dosing considerations

  • In 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
  • Administration, hydration, and urinary alkalization (pH of 7.0 or greater) should be continued until methotrexate level is below 5 x 10-8 M (0.05 micromolar)

Megaloblastic Anemia Due to Folate Deficiency

Up to 1 mg daily; there is no evidence that doses > 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

Trimethoprim Toxicity

10 mg/m² PO q6hr

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Interactions

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            Adverse Effects

            Frequency Not Defined

            Diarrhea

            Nausea

            Vomiting

            Stomatitis

            Thrombocytosis

            Anaphylactoid reaction

            Wheezing

            Urticaria

            Anaphylactoid reactions

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            Warnings

            Contraindications

            Vitamin B12 deficiency anemia and pernicious anemia

            Cautions

            Hypersensitivity reactions including anaphylactoid reactions & urticaria

            Risk of severe neurological complications in patients with undiagnosed anemia

            Geriatric or debilitated patients receiving cotreatment with fluorouracil

            May increase treatment failure of sulfamethoxazole-trimethoprim therapies

            Formulations containing benzyl alcohol not to be used in infants

            Thrombocytosis reported during intra-arterial infusion of methotrexate

            In treatment of accidental overdosages of folic acid antagonists, IV leucovorin should be administered as promptly as pos­sible; as the time interval between antifolate administration (eg, methotrexate) and leucovorin rescue increases, leucovorin’s effective­ness in counteracting toxicity decreases

            In the treatment of accidental overdosages of intrathecally administered folic acid antagonists, do not administer leucovorin intrathecally (may be fatal)

            Monitoring of serum methotrexate concentration is essential in determining optimal dose and duration of treatment with leucovorin; delayed methotrexate excretion may be caused by a third space fluid accumulation (ie, 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 IV; because of the benzyl alcohol contained in certain diluents used for reconstituting drug for Injection, when doses > 10 mg/m2 administered, reconstitute leucovorin calcium for Injection with sterile water for Injection, USP, and used immediately

            Because of calcium content of 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 toxicity of 5-fluorouracil; when these drugs are administered concurrently in the palliative therapy of advanced colorectal cancer, the dosage of 5-fluorouracil must be lower than usually administered

            Although toxicities observed in patients treated with combination of leucovorin plus 5-fluorouracil are qualitatively similar to those observed in patients treated with 5-fl uoro­uracil 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 diarrhea has resolved, as rapid clinical deterioration leading to death can occur; in an additional 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

            Seizures and/or syncope reported rarely in cancer patients receiving leucovorin, usually in association with fluoropyrimidine administration, and most commonly in those with CNS metastases or other predisposing factors, however, a causal relationship has not been established

            Parenteral administration is preferable to oral dosing if there is possibility that patient may vomit and not absorb the leucovorin; leucovorin has no effect on non-hematologic toxicities of methotrexate such as nephrotoxicity resulting from drug and/ or metabolite precipitation in the kidney

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            Pregnancy & Lactation

            Pregnancy Category: C

            Lactation: not known whether distributed in breast milk; use caution

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Serves as a cofactor supplement to counteract folic acid antagonists such as methotrexate; leucovorin is an active metabolite of folic acid

            Displaces methotrexate from intracellular binding sites and restores the folate required for DNA/RNA synthesis

            In methanol toxicity it serves as a tetrahydrofolate source to help the body eliminate the formic acid resulting from methanol's toxicity

            Pharmacokinetics

            Distribution: all body tissues, predominantly in liver

            Metabolism: Rapidly converted to THF derivatives

            Excretion: Urine (primarily); feces

            Half-life elimination: 4-8hr

            Peak plasma time: 2 hr (PO); 10 min (as folate); 1 hr (as tetrahydrofolate)

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            Administration

            IV Incompatibilities

            Additive: fluorouracil, trimetrexate

            Syringe: droperidol, trimetrexate, fluorouracil

            Y-site: amphotericin B cholesteryl sulfate, droperidol, foscarnet, NaHCO3

            IV Compatibilities

            Solution: compatible w/ most common fluids

            Additive: cisplatin, cisplatin w/ floxuridine, floxuridine

            Syringe: bleomycin, cisplatin, cyclophosphamide, doxorubicin, droperidol, fluorouracil, furosemide, heparin, methotrexate, metoclopramide, mitomycin, vinblastine, vincristine

            Y-site (partial list): bleomycin, cisplatin, cyclophosphamide, fluorouracil(?), furosemide, heparin, linezolid, methotrexate, metoclopramide, mitomycin

            IV Preparation

            Reconstitute w/ BWI or SWI of 10 mg/mL or 20 mg/mL (for 350 mg vial)

            Available in 10 mg/mL preservative-free solutions

            Do not use benzyl alcohol-containing diluents for doses >10 mg/sq.meter

            Reconstituted solution is stable for 7 d

            Use immediately if reconstituted w/ preservative-free solution

            IV/IM Administration

            Infusion: not to exceed 160 mg/min

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.