LEVOleucovorin (Monograph)

Brand name: Fusilev
Drug class: Chemotherapy antidotes/protectants

Medically reviewed by Drugs.com on May 10, 2024. Written by ASHP.

Introduction

Folic acid derivative; active levorotatory (l) isomer of racemic leucovorin.

Uses for LEVOleucovorin

Toxicity Associated with Folic Acid Antagonists

IV rescue therapy after high-dose methotrexate therapy (to control the duration of exposure of sensitive cells to methotrexate) for treatment of osteosarcoma (designated an orphan drug by FDA for this use).

Antidote to diminish the toxicity and counteract the effects of unintentional overdosage of methotrexate (e.g., resulting from impaired elimination) and other folic acid antagonists (designated an orphan drug by FDA for this use).

Colorectal Cancer

In combination with fluorouracil for the palliative treatment of advanced-stage colorectal cancer.

Has been studied for treatment of advanced-stage colorectal cancer in combination with fluorouracil and other agents (i.e., irinotecan, oxaliplatin)^{† [off-label]}. However, use in such combination regimens not fully established.

Other Uses

Manufacturer states that levoleucovorin should not be used for the treatment of pernicious anemia and megaloblastic anemias secondary to lack of vitamin B12; such use may alleviate hematologic manifestations while allowing neurologic complications to progress.

LEVOleucovorin Dosage and Administration

General

Toxicity Associated with Folic Acid Antagonists

Methotrexate Overdosage or Rescue after High-dose Methotrexate Therapy

• Monitoring of serum methotrexate concentration and patient's renal function required to determine optimum dose and duration of levoleucovorin therapy. Monitor S_cr and methotrexate concentrations at least once daily.

• Maintain adequate hydration (3 L daily) and administer sodium bicarbonate to maintain urinary pH at ≥7 during therapy.

• Monitor fluid and electrolyte status in patients experiencing delayed early methotrexate elimination and renal failure until methotrexate concentration declines to 0.05 micromolar (5 × 10^-8 M) and renal failure has resolved.

Administration

Administer IV. Do not administer intrathecally.

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV injection; has been administered by IV infusion in various published studies.

Use strict aseptic technique since drug product contains no preservatives.

Do not admix or infuse concomitantly with other drugs.

Reconstitution and Dilution (Powder for Injection)

Add 5.3 mL of 0.9% sodium chloride injection to vial containing 50 mg of levoleucovorin to provide a solution containing 10 mg/mL.

Use of sodium chloride containing preservatives (e.g., benzyl alcohol) not studied. Use of solutions other than 0.9% sodium chloride to reconstitute levoleucovorin not recommended.

Levoleucovorin solution may be administered following reconstitution or may be further diluted with 0.9% sodium chloride injection or 5% dextrose injection to a concentration of 0.5–5 mg/mL.

Dilution (Commercially Available Solution)

Commercially available solution (10 mg/mL) may be further diluted with 0.9% sodium chloride injection or 5% dextrose injection to a concentration of 0.5 mg/mL.

Rate of Administration

Administer by IV injection at a rate not >160 mg of levoleucovorin per minute (e.g., 16 mL/minute as 10-mg/mL solution). (See Rate of Administration under Cautions.)

Dosage

Available as levoleucovorin calcium; dosage expressed in terms of levoleucovorin.

Levoleucovorin is dosed at one-half the usual dosage of racemic leucovorin.

Pediatric Patients

Toxicity Associated with Folic Acid Antagonists

Rescue after High-dose Methotrexate Therapy

IV

The manufacturer makes no specific recommendations regarding dosage in pediatric patients; however, safety and efficacy of levoleucovorin have been evaluated in 16 patients 6–21 years of age.

7.5 mg every 6 hours for 60 hours or longer starting 24 hours after completion of methotrexate (12 g/m² over 4 hours) has been evaluated in clinical studies.

7.5 mg every 3 hours for 18 doses starting 12 hours completion of methotrexate (12 g/m² over 6 hours) also has been evaluated in clinical studies.

Adults

Toxicity Associated with Folic Acid Antagonists

Rescue after High-dose Methotrexate Therapy

IV

7.5 mg (approximately 5 mg/m²) every 6 hours for 10 doses, starting at 24 hours after initiation of methotrexate (12 g/m²) infusion for patients with normal methotrexate elimination (i.e., serum methotrexate concentration approximately 10 micromolar [10^-5 M] at 24 hours, 1 micromolar [10^-6 M] at 48 hours, and 0.2 micromolar [2 × 10^-7 M]) at 72 hours after administration).

Continue therapy and maintain adequate hydration and urinary alkalinization (pH ≥7) until methotrexate concentration declines to <0.05 micromolar (5 × 10^-8 M).

If substantial clinical toxicity occurs in patients with mild abnormalities in methotrexate elimination or renal function, extend rescue therapy for an additional 24 hours (i.e., 14 doses over 84 hours) for subsequent methotrexate courses.

Adjust dosage and duration of therapy based on methotrexate elimination pattern and patient’s renal function. (See Table 1 and Table 2.)

Methotrexate Overdosage

IV

7.5 mg (approximately 5 mg/m²) every 6 hours until serum methotrexate concentration declines to <0.01 micromolar (10^-8 M); initiate administration as soon as possible after overdosage and within 24 hours following methotrexate administration if delayed elimination is detected.

If 24-hour S_cr increases 50% over baseline, 24-hour methotrexate concentration is >5 micromolar (5×10^-6 M), or 48-hour methotrexate concentration is >0.9 micromolar (9 × 10^-7 M), increase dosage immediately to 50 mg/m² IV every 3 hours until serum methotrexate concentration declines to <0.01 micromolar (10^-8 M).

Colorectal Cancer

IV

Levoleucovorin 100 mg/m² by IV injection over ≥3 minutes followed by IV fluorouracil (370 mg/m²) or levoleucovorin 10 mg/m² followed by IV fluorouracil (425 mg/m²); administer both drugs daily for 5 days and repeat regimen at 4-week intervals for 2 additional courses; thereafter may repeat regimen at intervals of 4–5 weeks provided toxicity from the previous course has resolved completely.

Other fluorouracil/levoleucovorin regimens have been used.

Levoleucovorin dosage is not adjusted for toxicity. Reduce daily fluorouracil dosage by 20% for moderate hematologic or GI toxicity in the prior course and by 30% for severe toxicity. If no toxicity occurred in the prior course, may increase fluorouracil dosage by 10%.

Special Populations

Patients with Delayed Methotrexate Elimination

Higher dosages and extended duration of therapy may be required if delayed methotrexate excretion is caused by third space fluid accumulation (i.e., ascites, pleural effusion), renal impairment, or inadequate hydration.

Cautions for LEVOleucovorin

Contraindications

• Known hypersensitivity to folic acid or folinic acid.

Warnings/Precautions

Rate of Administration

Injection rate should not exceed 160 mg of levoleucovorin per minute (e.g., 16 mL/minute as 10-mg/mL solution) because of the calcium concentration (4.26 mg of Ca⁺⁺ per 64 mg of levoleucovorin calcium pentahydrate) of the solution.

Toxicity Potentiation with Concomitant Therapy

Levoleucovorin potentiates fluorouracil toxicity; must reduce fluorouracil dosage when the drugs are used concomitantly.

GI toxicities (particularly stomatitis and diarrhea) observed more frequently, and possibly more severe and prolonged, with combined fluorouracil/levoleucovorin compared with fluorouracil monotherapy. Increased risk of severe GI toxicity in debilitated or geriatric patients. Diarrhea may result in clinical deterioration, leading to death; if diarrhea occurs, closely monitor patients until manifestations have completely resolved. Do not initiate or continue combination therapy in patients with manifestations of GI toxicity until such manifestations have completely resolved.

Toxicity reported more frequently in patients receiving regimens containing low-dose (20 mg/m²) versus high-dose (200 mg/m²) racemic leucovorin in combination with fluorouracil.

Concomitant use of racemic leucovorin and co-trimoxazole for treatment of Pneumocystis jiroveci (formerly P. carinii) pneumonia in HIV-infected patients associated with increased rates of treatment failure and morbidity.

Seizures and/or syncope reported rarely, usually following concomitant therapy with fluoropyrimidines; most commonly reported in cancer patients with CNS metastases or other predisposing factors.

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether distributed into milk; discontinue nursing or drug.

Pediatric Use

Safety and efficacy have been evaluated in 16 patients 6–21 years of age. The manufacturer makes no specific recommendations regarding use in pediatric patients.

Possible decreased anticonvulsant effect in pediatric patients receiving anticonvulsant therapy concomitantly with large amounts of folic acid; possible increased frequency of seizures in susceptible patients. (See Specific Drugs under Interactions.)

Geriatric Use

Patients with osteosarcoma: Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.

Patients with advanced colorectal cancer: No overall differences in adverse effects observed relative to younger adults; however, death due to severe enterocolitis, diarrhea, and dehydration reported in geriatric patients receiving weekly racemic leucovorin and fluorouracil therapy.

Renal Impairment

Possible delayed methotrexate elimination; higher dosages and extended duration of therapy may be required. (See Dosage and Administration: Special Populations.)

Common Adverse Effects

Levoleucovorin rescue following high-dose methotrexate: Vomiting, stomatitis, nausea.

Levoleucovorin in combination with fluorouracil: Diarrhea, nausea, stomatitis, vomiting, asthenia/fatigue/malaise, anorexia/decreased appetite, dermatitis, alopecia.

Drug Interactions

Specific Drugs

LEVOleucovorin Pharmacokinetics

Absorption

Bioavailability

Peak serum concentrations of active metabolite 5-methyltetrahydrofolic acid (5-methyl-THF) attained in an average 0.9 hours.

Equipotent doses of IV levoleucovorin and IV racemic leucovorin result in similar systemic exposures to the l-isomer of leucovorin and to 5-methyl-THF.

Distribution

Extent

Levoleucovorin is actively and passively transported across cell membranes.

Small amounts of 5-methyl-THF distributed into CSF.

Elimination

Metabolism

Metabolized to 5-methyl-THF, the primary circulating form of active reduced folate. Levoleucovorin and 5-methyl-THF are polyglutamated intracellularly by folylpolyglutamate synthetase.

Elimination Route

Excreted in urine as unchanged drug and metabolites.

Half-life

5.1 and 6.8 hours for THF and 5-methyl-THF, respectively.

Stability

Storage

Parenteral

Powder for Injection

25°C (may be exposed to 15–30°C). Protect from light.

Following reconstitution or further dilution in 0.9% sodium chloride injection, solutions may be stored up to 12 hours at room temperature.

Following dilution in 5% dextrose injection, solutions may be stored for up to 4 hours at room temperature.

Injection

2–8°C. Protect from light.

Following dilution in 0.9% sodium chloride injection or 5% dextrose injection, solutions may be stored for up to 4 hours at room temperature.

Compatibility

Parenteral

Solution Compatibility1 17

Drug Compatibility

Actions

• The pharmacologically active levorotatory (l) isomer of racemic d,l-leucovorin. Constitutes approximately 50% of racemic leucovorin; exerts effects at half the dose of racemic leucovorin.

• A reduced derivative of folic acid; does not require reduction by dihydrofolate reductase to participate in reactions utilizing folates.

• Counteracts the therapeutic and toxic effects (e.g., hematologic toxicity) of folic acid antagonists (e.g., methotrexate); no effect on other established toxicities of methotrexate resulting from drug and/or metabolite precipitation in kidneys (e.g., nephrotoxicity).

• Enhances therapeutic and toxic effects of fluoropyrimidines (e.g., fluorouracil) by stabilizing binding of fluorouracil metabolite (5-fluoro-2′-deoxyuridine 5′-monophosphate [FdUMP]) to thymidylate synthase (enzyme responsible for DNA repair and replication), thus enhancing inhibition of this enzyme.

Advice to Patients

• Risk of diarrhea, vomiting, stomatitis, and nausea.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., renal impairment).

• Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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