levoleucovorin (Rx)

Brand and Other Names:Fusilev, Khapzory
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injectable solution

  • 175 mg/17.5 mL (generic)
  • 250 mg/25 mL (generic)

injection, lyophilized powder for reconstitution

  • 50mg/vial (Fusilev, generic); vial contains 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin)
  • 175mg/vial (Khapzory, generic)
  • 300mg/vial (Khapzory)
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High-dose Methotrexate Rescue

Indicated for rescue after high-dose methotrexate therapy in osteosarcoma

Recommended initial dose of 7.5 mg q6hr based on methotrexate IV dose of 12 g/m²

Monitor serum creatinine and methotrexate levels at least once daily; continue levoleucovorin, hydration, and urinary alkalinization (pH ≥7) until methotrexate level <5 x 10-8 M (0.05 micromolar)

Normal methotrexate elimination

  • Serum methotrexate level ~10 micromolar at 24 hr, 1 micromolar at 48 hr, and <0.2 micromolar at 96 hr post methotrexate infusion
  • Initiate at 7.5 mg (~5 mg/m²) q6hr 24 hr after beginning methotrexate infusion for 60 hr (10 doses)

Delayed late methotrexate elimination

  • Serum methotrexate levels >0.2 micromolar at 72 hr and >0.05 micromolar at 96 hr post methotrexate infusion
  • Continue 7.5 mg IV q6hr until methotrexate level <0.05 micromolar

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

  • Serum methotrexate level ≥50 micromolar at 24 hr, ≥5 micromolar at 48 hr, or serum creatinine level increased ≥100% at 24 hr post methotrexate infusion
  • 75 mg IV q3hr until methotrexate level is <1 micromolar, followed by 7.5 mg IV q3hr until methotrexate level is <0.05 micromolar
  • Extend levoleucovorin treatment for an additional 24 hr (total of 14 doses) in subsequent cycles if there is significant clinical toxicity in the presence of impaired methotrexate elimination or renal impairment

Delayed methotrexate elimination due to third space fluid accumulation, renal insufficiency, or inadequate hydration

  • May require higher levoleucovorin doses or prolonged administration

Folic Acid Antagonists Overdose or Impaired Elimination

Indicated for diminishing toxicity and counteracting effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists

7.5 mg (~5 mg/m²) q6hr until methotrexate level is <0.05 micromolar

Start as soon as possible after methotrexate overdosage or 24 hr of delayed elimination

Increase dose 50 mg/m² q3hr until methotrexate level <0.05 micromolar for the following:

  • If serum creatinine at 24 hr increases ≥50% compared to baseline
  • If methotrexate level at 24 hr >5 x 10^6 M
  • If methotrexate level at 48 hr >9 x 10^7 M
  • Continue hydration (3 L/day) and urinary alkalinization with sodium bicarbonate Adjust bicarbonate dose to maintain urine pH at ≥7

Metastatic Colorectal Cancer

Indicated, in combination with 5-fluorouracil (5-FU), for palliative treatment in patients with advanced metastatic colorectal cancer

Regimens are used for treatment of colorectal cancer

  • Levoleucovorin 100 mg/m² IV over a minimum of 3 min, followed by 5-FU 370 mg/m² qDay for 5 consecutive days OR
  • Levoleucovorin 10 mg/m² IV followed by 5-FU 425 mg/m2 qDay for 5 consecutive days
  • Repeat q4Weeks for 2 courses, then q4-5Weeks, if patient recovered from toxicity from the prior course
  • Do not adjust levoleucovorin dosage for toxicity

Refer to fluorouracil prescribing information for information on dosage and dosage modifications for adverse reactions

Dosing Considerations

Fusilev is dosed at one-half the usual dose of racemic d,l-leucovorin

Limitations of use

  • Not indicated for pernicious anemia and megaloblastic anemia secondary to lack of vitamin B12
  • Refer to prescribing information for complete monitoring instructions

Dosage Forms & Strengths

injectable solution

  • 175 mg/17.5 mL (generic)
  • 250 mg/25 mL (generic)

injection, lyophilized powder for reconstitution

  • 50mg/vial (Fusilev, generic); vial contains 64 mg levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin)
  • 175mg/vial (Khapzory, generic)
  • 300mg/vial (Khapzory)
more...

High-dose Methotrexate Rescue

<6 years: Safety and efficacy not established

≥6 years

  • Indicated for rescue after high-dose methotrexate therapy in osteosarcoma
  • Recommended initial dose of 7.5 mg q6hr based on methotrexate IV dose of 12 g/m²
  • Monitor serum creatinine and methotrexate levels at least once daily; continue levoleucovorin, hydration, and urinary alkalinization (pH ≥7) until methotrexate level <5 x 10-8 M (0.05 micromolar)
  • Normal methotrexate elimination
    • Serum methotrexate level ~10 micromolar at 24 hr, 1 micromolar at 48 hr, and <0.2 micromolar at 96 hr post methotrexate infusion
    • Initiate at 7.5 mg (~5 mg/m²) q6hr 24 hr after beginning methotrexate infusion for 60 hr (10 doses)
  • Delayed late methotrexate elimination
    • Serum methotrexate levels >0.2 micromolar at 72 hr and >0.05 micromolar at 96 hr post methotrexate infusion
    • Continue 7.5 mg IV q6hr until methotrexate level <0.05 micromolar
  • Delayed early methotrexate elimination and/or evidence of acute renal injury
    • Serum methotrexate level ≥50 micromolar at 24 hr, ≥5 micromolar at 48 hr, or serum creatinine level increased ≥100% at 24 hr post methotrexate infusion
    • 75 mg IV q3hr until methotrexate level is <1 micromolar, followed by 7.5 mg IV q3hr until methotrexate level is <0.05 micromolar
    • Extend levoleucovorin treatment for an additional 24 hr (total of 14 doses) in subsequent cycles if there is significant clinical toxicity in the presence of impaired methotrexate elimination or renal impairment
  • Delayed methotrexate elimination due to third space fluid accumulation, renal insufficiency, or inadequate hydration
    • May require higher levoleucovorin doses or prolonged administration
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Interactions

Interaction Checker

and levoleucovorin

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            >10% (Levoleucovorin)

            Stomatitis (38%)

            Vomiting (38%)

            Nausea (19%)

            >10% (Levoleucovorin/5-FU)

            Stomatitis (72%)

            Diarrhea (70%)

            Nausea (62%)

            Vomiting (40%)

            Asthenia/fatigue/malaise (29%)

            Dermatitis (29%)

            Alopecia (26%)

            Anorexia/decreased appetite (24%)

            Abdominal pain (14%)

            Grade 3-4

            • Diarrhea (19%)
            • Stomatitis (12%)

            1-10% (Levoleucovorin/5-FU)

            Grade 3-4

            • Nausea (8%)
            • Vomiting (5%)
            • Asthenia/fatigue/malaise (5%)
            • Anorexia/decreased appetite (4%)
            • Abdominal pain (3%)
            • Dermatitis (1%)

            6% (Levoleucovorin)

            Diarrhea

            Dyspepsia

            Typhlitis

            Dyspnea

            Dermatitis

            Confusion

            Neuropathy

            Abnormal renal function

            Taste perversion

            Postmarketing Reports

            Dyspnea

            Pruritus, rash

            Temperature change, rigors, allergic reactions

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            Warnings

            Contraindications

            Hypersensitivity reactions to leucovorin products, folic acid, or folinic acid

            Cautions

            Increased gastrointestinal toxicities with 5-FU

            Do not initiate or continue therapy with levoleucovorin and 5-FU in patients with symptoms of gastrointestinal toxicity until symptoms resolve; monitor patients with diarrhea until it resolves

            Increased rates of treatment failure and morbidity with concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for Pneumocystis jiroveci pneumonia in patients with HIV

            Exercise caution when taking folinic acid in combination with anticonvulsant drugs

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            Pregnancy & Lactation

            Pregnancy

            No animal reproduction studies were conducted

            Unknown whether fetal harm may occur when administered to a pregnant woman or can affect reproduction capacity

            Give to a pregnant woman only if clearly needed

            Lactation

            Unknown if distributed in human breast milk

            Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

            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

            High dose methotrexate therapy

            • An active isomer of 5-formyl tetrahydrofolic acid (THF)
            • Counteracts therapeutic and toxic effects of folic acid antagonists (eg, methotrexate), which act by inhibiting dihydrofolate reductase

            Combination with fluorouracil in colorectal cancer

            • Enhances therapeutic and toxic effects of 5-FU
            • 5-FU is metabolized to 5-fluoro-2'- deoxyuridine-5'-monophosphate (FdUMP), which binds to and inhibits thymidylate synthase
            • Levoleucovorin converts to another reduced folate, 5,10-methylenetetrahydrofolate, which then acts to stabilize the binding of FdUMP to thymidylate synthase, thereby enhances inhibition of thymidylate synthase

            Absorption

            Mean peak serum total tetrahydrofolate (total-THF) concentration: 1722 ng/mL

            Mean peak serum (6S)-5-methyl-5, 6, 7, 8-tetrahydrofolate concentration: 275 ng/mL (0.9-hr postinjection

            Elimination

            Half-life: 5.1 hr (total-THF); 6.8 hr ([6S]-5-methyl-5, 6, 7, 8-tetrahydrofolate)

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            Administration

            IV Compatibilities

            0.9% NaCl

            D5W

            IV Incompatibilities

            Due to precipitation risk, do not coadminister Fusilev with other agents in the same admixture

            IV Preparation

            Reconstitution with NaCl solutions with preservatives (eg, benzyl alcohol) not studied

            Fusilev: Reconstitute with 5.3 mL of 0.9% NaCl to yield a concentration of 10 mg/mL

            Khapzory: Reconstitute with 3.6 mL (175-mg vial) and 6.2 mL (300-mg vial) of 0.9% NaCl, to obtain a clear, colorless to yellowish solution (final concentration: 50 mg/mL levoleucovorin)

            Dilute reconstituted solution immediately (if possible), to concentrations of 0.5-5 mg/mL in 0.9% NaCl or D5W

            Visually inspect for particulate matter and discoloration prior to administration; discard if particulate matter or discoloration is observed

            IV Administration

            IV use only

            Do not administer intrathecally

            Fusilev: Inject ≤16 mL/min (160 mg/min), because of calcium content of reconstituted solution

            Storage

            Fusilev

            • Protect from light
            • Unused vials: Refrigerate at 2-8°C (36-46°F)
            • Dilutions in D5W: Store at room temperature for ≤4 hr
            • Reconstituted vials or dilutions in 0.9% NaCl: Store at room temperature for ≤12 hr

            Khapzory

            • Protect from light
            • Unused vials: Store at 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)
            • Reconstituted vials and diluted solutions: Store at room temperature for ≤12 hr
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            Images

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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

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            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            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.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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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.