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LEVOleucovorin

Medically reviewed by Drugs.com. Last updated on Feb 4, 2019.

Pronunciation

See also: Xeloda

(lee voe loo koe VOR in)

Index Terms

  • 6S-leucovorin
  • Calcium Levoleucovorin
  • L-leucovorin
  • Levo-folinic Acid
  • Levo-leucovorin
  • Levoleucovorin Calcium Pentahydrate
  • S-leucovorin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous [preservative free]:

Generic: 175 mg/17.5 mL (17.5 mL); 250 mg/25 mL (25 mL)

Solution Reconstituted, Intravenous:

Fusilev: 50 mg (1 ea)

Generic: 50 mg (1 ea)

Solution Reconstituted, Intravenous [preservative free]:

Khapzory: 175 mg (1 ea); 300 mg (1 ea)

Generic: 175 mg (1 ea [DSC])

Brand Names: U.S.

  • Fusilev
  • Khapzory

Pharmacologic Category

  • Antidote
  • Chemotherapy Modulating Agent
  • Rescue Agent (Chemotherapy)

Pharmacology

Levoleucovorin counteracts the toxic (and therapeutic) effects of folic acid antagonists (eg, methotrexate) which act by inhibiting dihydrofolate reductase. Levoleucovorin is the levo isomeric and pharmacologic active form of leucovorin (levoleucovorin does not require reduction by dihydrofolate reductase). A reduced derivative of folic acid, leucovorin supplies the necessary cofactor blocked by methotrexate.

Leucovorin enhances the activity (and toxicity) of fluorouracil by stabilizing the binding of 5-fluoro-2’-deoxyuridine-5’-monophosphate (FdUMP; a fluorouracil metabolite) to thymidylate synthetase resulting in inhibition of this enzyme.

Metabolism

Converted to the active reduced form of folate, 5-methyl-tetrahydrofolate (5-methyl-THF; active)

Time to Peak

Serum: IV (healthy volunteers; 15 mg dose): 0.9 hours

Half-Life Elimination

Total-tetrahydrofolate: 5.1 hours; (6)-5-methyl-5,6,7,8-tetrahydrofolate: 6.8 hours

Use: Labeled Indications

Colorectal cancer, metastatic: Treatment of advanced, metastatic colorectal cancer (in combination with fluorouracil)

Folic acid antagonist overdose: Antidote to diminish toxicity in inadvertent overdosage of folic acid antagonists

High-dose methotrexate rescue: Rescue agent after high-dose methotrexate therapy in osteosarcoma treatment

Impaired methotrexate elimination: Antidote to diminish toxicity and counteract effects of impaired methotrexate elimination

Limitations of use: Levoleucovorin is not indicated for the treatment of pernicious anemia or megaloblastic anemias secondary to the lack of vitamin B12 (due to the risk of progressive neurologic manifestations despite hematologic remission).

Contraindications

Severe hypersensitivity or previous allergic reaction to leucovorin products, folinic acid, folic acid, or any component of the formulation.

Dosing: Adult

Note: Levoleucovorin, when substituted in place of leucovorin calcium (the racemic form), is dosed at one-half the usual dose of leucovorin calcium:

Colorectal cancer, metastatic: IV: The following regimens have been used (in combination with fluorouracil; fluorouracil doses may need to be adjusted for toxicity; no adjustment is required for the levoleucovorin dose):

100 mg/m2/day over at least 3 minutes (followed by fluorouracil 370 mg/m2/day) for 5 days every 4 weeks for 2 cycles, then every 4 to 5 weeks depending on recovery from toxicities, or

10 mg/m2/day (followed by fluorouracil 425 mg/m2/day) for 5 days every 4 weeks for 2 cycles, then every 4 to 5 weeks depending on recovery from toxicities, or

Substitution dosing: Levoleucovorin, when substituted in place of leucovorin calcium within a chemotherapy regimen, is dosed at one-half the usual dose of leucovorin calcium (Goldberg 1997; Kovoor 2009)

High-dose methotrexate rescue: IV: Usual dose: 7.5 mg (~5 mg/m2) every 6 hours for 10 doses, beginning 24 hours after the start of the methotrexate infusion (based on a methotrexate dose of 12 g/m2 IV over 4 hours). Levoleucovorin (and hydration and urinary alkalinization to pH ≥7) should be continued and/or adjusted until the methotrexate level is <0.05 micromolar (5 x 10-8 M) as follows:

Normal methotrexate elimination (serum methotrexate levels ~10 micromolar at 24 hours post administration, 1 micromolar at 48 hours and <0.2 micromolar at 72 hours post infusion): 7.5 mg IV every 6 hours for 10 doses

Delayed late methotrexate elimination (serum methotrexate levels >0.2 micromolar at 72 hours and >0.05 micromolar at 96 hours post methotrexate infusion): Continue 7.5 mg IV every 6 hours until methotrexate level is <0.05 micromolar

Delayed early methotrexate elimination and/or evidence of acute renal injury (serum methotrexate level ≥50 micromolar at 24 hours, ≥5 micromolar at 48 hours or a doubling or more of the serum creatinine level at 24 hours post methotrexate infusion [likely to develop reversible renal failure]): 75 mg IV every 3 hours until methotrexate level is <1 micromolar, followed by 7.5 mg IV every 3 hours until methotrexate level is <0.05 micromolar

Significant clinical toxicity in the presence of impaired methotrexate elimination or renal impairment (as described above): Extend levoleucovorin treatment for an additional 24 hours (total of 14 doses) in subsequent treatment cycles.

Delayed methotrexate elimination due to third space fluid accumulation, renal insufficiency, or inadequate hydration: May require higher levoleucovorin doses or prolonged administration.

Folic acid antagonist overdose: IV: 7.5 mg (~5 mg/m2) every 6 hours; continue until the methotrexate level is <0.05 micromolar (5 x 10-8 M). Initiate treatment as soon as possible after methotrexate overdose. Monitor serum creatinine and methotrexate levels at least every 24 hours. Increase the levoleucovorin dose to 50 mg/m2 IV every 3 hours if the 24-hour serum creatinine has increased 50% over baseline, or if the 24 hour methotrexate level is >5 micromolar (5 x 10-6 M), or if the 48-hour methotrexate level is >0.9 micromolar (9 x 10-7 M); continue levoleucovorin until the methotrexate level is <0.05 micromolar (5 x 10-8 M). Hydration (aggressive [3 L/day]) and urinary alkalinization (urinary pH ≥7 with sodium bicarbonate) should also be maintained.

Impaired methotrexate elimination: IV: 7.5 mg (~5 mg/m2) every 6 hours; continue until the methotrexate level is <0.05 micromolar (5 x 10-8 M). Initiate treatment within 24 hours of methotrexate administration if elimination is impaired. Monitor serum creatinine and methotrexate levels at least every 24 hours. Increase the levoleucovorin dose to 50 mg/m2 IV every 3 hours if the 24-hour serum creatinine has increased 50% over baseline, or if the 24-hour methotrexate level is >5 micromolar (5 x 10-6 M), or if the 48-hour methotrexate level is >0.9 micromolar (9 x 10-7 M); continue levoleucovorin until the methotrexate level is <0.05 micromolar (5 x 10-8 M). Hydration (aggressive [3 L/day]) and urinary alkalinization (urinary pH ≥7 with sodium bicarbonate) should also be maintained.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Levoleucovorin, when substituted in place of leucovorin calcium (the racemic form), is dosed at one-half the usual dose of leucovorin calcium.

High-dose methotrexate rescue: Children and Adolescents: IV: 7.5 mg (~5 mg/m2) every 6 hours, beginning 24 hours after the start of the methotrexate infusion (based on a methotrexate dose of 12 g/m2 IV over 4 hours). Levoleucovorin (and hydration and urinary alkalinization) should be continued and/or adjusted until the methotrexate level is <0.05 micromolar (5 x 10-8 M). In trials, the youngest reported patients were 4 to 6 years of age (Goorin, 1995; Jaffe, 1993). The dosage and frequency should be determined based on methotrexate elimination and serum level:

Normal methotrexate elimination (serum methotrexate levels ~10 micromolar at 24 hours post administration, 1 micromolar at 48 hours, and <0.2 micromolar at 72 hours post infusion): 7.5 mg IV every 6 hours for 10 doses

Delayed late methotrexate elimination (serum methotrexate levels >0.2 micromolar at 72 hours and >0.05 micromolar at 96 hours post-methotrexate infusion): Continue 7.5 mg IV every 6 hours until methotrexate level is <0.05 micromolar

Delayed early methotrexate elimination and/or evidence of acute renal injury (serum methotrexate level ≥50 micromolar at 24 hours, ≥5 micromolar at 48 hours, or a doubling or more of the serum creatinine level at 24 hours post-methotrexate infusion): 75 mg IV every 3 hours until methotrexate level is <1 micromolar, followed by 7.5 mg IV every 3 hours until methotrexate level is <0.05 micromolar

Significant clinical toxicity in the presence of less severe abnormalities in methotrexate elimination or renal function (as described above): Extend levoleucovorin treatment for an additional 24 hours (total of 14 doses) in subsequent treatment cycles.

Delayed methotrexate elimination due to third space fluid accumulation, renal insufficiency, or inadequate hydration: May require higher levoleucovorin doses or prolonged administration.

Methotrexate overdose (inadvertent): Children and Adolescents: 7.5 mg (~5 mg/m2) every 6 hours; continue until the methotrexate level is <0.01 micromolar (10-8 M). Initiate treatment as soon as possible after methotrexate overdose. Increase the levoleucovorin dose to 50 mg/m2 IV every 3 hours if the 24 hour serum creatinine has increased 50% over baseline, or if the 24-hour methotrexate level is >5 micromolar (5 x 10-6 M), or if the 48-hour methotrexate level is >0.9 micromolar (9 x 10-7 M); continue levoleucovorin until the methotrexate level is <0.01 micromolar (10-8 M). Hydration (aggressive) and urinary alkalinization (with sodium bicarbonate; goal urine pH ≥7) should also be maintained.

Reconstitution

Preparation instructions vary based on manufacturer; also refer to prescribing information.

Lyophilized powder: Reconstitute the 50 mg vial with 5.3 mL NS (preservative free) to a concentration of 10 mg/mL. Reconstitute 175 mg vial with 17.7 mL NS (preservative free) to a concentration of 10 mg/mL. Reconstitute the 175 and 300 mg vials (Khapzory brand) with 3.6 and 6.2 mL NS (preservative free), respectively, to a concentration of 50 mg/mL. Do not use if solution appears cloudy or contains a precipitate. May further dilute for infusion in NS or D5W to a final concentration of 0.5 to 5 mg/mL.

Injection solution: May further dilute for infusion in NS or D5W to a concentration of 0.5 mg/mL.

Do not prepare with other products in the same admixture; may cause precipitation.

Administration

IV: For IV administration only; do not administer intrathecally. Administer by slow IV push or infusion over at least 3 minutes. Do not exceed 160 mg/minute for products containing calcium.

For colorectal cancer: Levoleucovorin has also been administered (off-label administration rate) as IV infusion over 2 hours (Comella 2000; Tournigand 2006).

Storage

Storage times may vary based on manufacturer and/or product; refer to manufacturer’s labeling.

Lyophilized powder: Prior to reconstitution, store intact vials at 25°C (77°F); excursions permitted from 15°C to 30°C (59°F to 86°F). Protect from light. Initial reconstituted solution in the vial should be used immediately or stored for up to 24 hours (depending on manufacturer) at room temperature. Solutions further diluted for infusion in NS are stable for 12 to 24 hours (depending on manufacturer) at room temperature. Solutions further diluted for infusion in D5W are stable for 4 or 12 hours (depending on manufacturer) at room temperature. Protect reconstituted solutions and solutions diluted for infusion from light.

Injection solution: Store intact vials between 2°C and 8°C (36°F and 46°F). Protect from light. Store in carton until contents are used. Solutions further diluted for infusion in NS or D5W are stable for up to 4 hours at room temperature.

Drug Interactions

Capecitabine: Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of Capecitabine. Monitor therapy

Floxuridine: Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of Floxuridine. Monitor therapy

Fluorouracil (Systemic): Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of Fluorouracil (Systemic). This effect is associated with the ability of leucovorin or levoleucovorin to enhance the anticancer effects of fluorouracil. Monitor therapy

Fluorouracil (Topical): Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of Fluorouracil (Topical). Monitor therapy

Fosphenytoin: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of Fosphenytoin. Monitor therapy

Glucarpidase: May decrease serum concentrations of the active metabolite(s) of Leucovorin Calcium-Levoleucovorin. Specifically, 6S-5-methyltetrahydrofolateconcentrations may be reduced. Glucarpidase may decrease the serum concentration of Leucovorin Calcium-Levoleucovorin. Management: Avoid leucovorin administration within 2 hours of glucarpidase dosing. Continue to administer the pre-glucarpidase leucovorin dose for at least the first 48 hours after glucarpidase administration, and dose based on methotrexate concentration thereafter. Consider therapy modification

PHENobarbital: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of PHENobarbital. Monitor therapy

Phenytoin: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of Phenytoin. Monitor therapy

Primidone: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of Primidone. Additionally, leucovorin/levoleucovorin may decrease concentrations of active metabolites of primidone (e.g., phenobarbital). Monitor therapy

Raltitrexed: Leucovorin Calcium-Levoleucovorin may diminish the therapeutic effect of Raltitrexed. Avoid combination

Tegafur: Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of Tegafur. This effect is associated with the ability of leucovorin or levoleucovorin to enhance the anticancer effects of fluorouracil. Monitor therapy

Trimethoprim: Leucovorin Calcium-Levoleucovorin may diminish the therapeutic effect of Trimethoprim. Management: Avoid concurrent use of leucovorin or levoleucovorin with trimethoprim (plus sulfamethoxazole) for Pneumocystis jirovecii pneumonia. If trimethoprim is used for another indication, monitor closely for reduced efficacy. Avoid combination

Adverse Reactions

Adverse reactions reported with levoleucovorin either as a part of combination chemotherapy or following chemotherapy.

>10%:

Central nervous system: Fatigue (≤29%), malaise (≤29%)

Dermatologic: Dermatitis (6% to 29%), alopecia (26%)

Gastrointestinal: Stomatitis (38% to 72%; grades ≥3: 6% to 12%), diarrhea (6% to 70%), nausea (19% to 62%), vomiting (38% to 40%), anorexia (≤24%), decreased appetite (≤24%), abdominal pain (≤14%)

Neuromuscular & skeletal: Asthenia (≤29%)

1% to 10%:

Central nervous system: Confusion (6%), neuropathy (6%)

Gastrointestinal: Dysgeusia (6%), dyspepsia (6%), typhlitis (6%)

Renal: Renal insufficiency (6%)

Respiratory: Dyspnea (6%)

<1%, postmarketing, and/or case reports: Disruption of body temperature regulation, hypersensitivity reaction, pruritus, rigors, skin rash

Warnings/Precautions

Concerns related to adverse effects:

• Gastrointestinal toxicity: Levoleucovorin and leucovorin calcium enhance the toxicity of fluorouracil. Deaths due to severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin calcium in combination with fluorouracil. Levoleucovorin is indicated in combination with fluorouracil for the treatment of colorectal cancer; when administered together, the fluorouracil dose is reduced (compared to fluorouracil dosing without levoleucovorin). The typical fluorouracil gastrointestinal toxicities (eg, diarrhea, stomatitis) may be more common and may be of greater severity or longer duration with fluorouracil and levoleucovorin combination therapy. Symptoms of gastrointestinal toxicity should be completely resolved prior to treatment (initial or repeat).

• Seizure/syncope: Seizures and/or syncope have been reported with leucovorin calcium; generally in patients with CNS metastases or other underlying risk factors.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• HIV patients: Concomitant use of leucovorin calcium and sulfamethoxazole-trimethoprim for the acute treatment of pneumocystis jirovecii pneumonia (PCP) in patients with HIV infection has been associated with increased rates of treatment failure and morbidity; may also occur with levoleucovorin.

Other warnings/precautions:

• Administration: For IV administration only; do not administer intrathecally.

Monitoring Parameters

High-dose methotrexate therapy, impaired methotrexate elimination, or methotrexate overdose (inadvertent): Serum methotrexate and creatinine levels at least every 24 hours. Monitor urine pH. Monitor fluid and electrolyte status in patients with delayed methotrexate elimination (likely to experience renal toxicity). For colorectal cancer, monitor for diarrhea and stomatitis.

Pregnancy Considerations

Levoleucovorin is the levo isomeric form of racemic leucovorin, a biologically active form of folic acid. Adequate amounts of folic acid are recommended during pregnancy. Refer to Folic Acid monograph. Levoleucovorin is administered in combination with either methotrexate or fluorouracil; also refer to Methotrexate or Fluorouracil monographs. Information related to the treatment of colorectal cancer in pregnancy is limited (Rogers 2016).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, diarrhea, change in taste, loss of strength and energy, hair loss, or lack of appetite. Have patient report immediately to prescriber mouth irritation, mouth sores, severe abdominal pain, bloody stools, shortness of breath, confusion, burning or numbness feeling, urinary retention, or change in amount of urine passed (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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