Version May 2024
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).
Off- label dosing/combination: 200 mg/m2 on day 1 (in combination with fluorouracil, oxaliplatin, and irinotecan [FOLFOXIRI regimen]) every 2 weeks until disease progression, unacceptable toxicity, or up to a maximum of 12 cycles (Falcone 2007).
High-dose methotrexate rescue: IV: Usual dose: 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 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.
Clinically important but less severe impaired methotrexate elimination or renal impairment (less severe than as described above): Extend levoleucovorin treatment for an additional 24 hours (total of 14 doses over 84 hours) in subsequent treatment cycles.
Delayed methotrexate elimination due to third space fluid accumulation (eg, ascites, pleural effusion), renal insufficiency, or inadequate hydration: May require higher levoleucovorin doses or prolonged administration.
Impaired methotrexate elimination or folic acid antagonist overdose:
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); then continue levoleucovorin (at the 50 mg/m2 dose) until the methotrexate level is <0.05 micromolar (5 x 10-8 M). Maintain hydration (aggressive [3 L/day]) and urinary alkalinization (urinary pH ≥7 with sodium bicarbonate).
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); then continue levoleucovorin (at the 50 mg/m2 dose) until the methotrexate level is <0.05 micromolar (5 x 10-8 M). Maintain hydration (aggressive [3 L/day]) and urinary alkalinization (urinary pH ≥7 with sodium bicarbonate).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no initial dosage adjustments provided in the manufacturer's labeling; in patients with impaired methotrexate elimination, adjust levoleucovorin dose based on methotrexate levels.
There are no dosage adjustments provided in the manufacturer's labeling.
Refer to adult dosing.
(For additional information see "LEVOleucovorin: Pediatric drug information")
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. In trials, the youngest reported patients were 4 to 6 years of age (Goorin 1995; Jaffe 1993). Hydration (aggressive) and urinary alkalinization (with sodium bicarbonate; goal urine pH ≥7) should also be maintained. 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 beginning 24 hours after the start of the methotrexate infusion.
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.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Children and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling.
Children and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported with levoleucovorin either as a part of combination chemotherapy or following chemotherapy.
>10%:
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%)
Nervous system: Fatigue (≤29%), malaise (≤29%)
Neuromuscular & skeletal: Asthenia (≤29%)
1% to 10%:
Gastrointestinal: Dysgeusia (6%), dyspepsia (6%), neutropenic typhlitis (6%)
Nervous system: Confusion (6%), neuropathy (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
Severe hypersensitivity to leucovorin products, folinic acid, folic acid, or any component of the formulation.
Concerns related to adverse effects:
• GI toxicity: Levoleucovorin and leucovorin calcium enhance the toxicity of fluorouracil. The typical fluorouracil GI toxicities (eg, diarrhea, stomatitis) may be more common and may be of greater severity or longer duration with fluorouracil and levoleucovorin combination therapy. Deaths due to severe enterocolitis, diarrhea, and dehydration have occurred in elderly patients receiving weekly leucovorin calcium in combination with fluorouracil. Monitor for GI toxicities. Symptoms of GI toxicity should be completely resolved prior to initial or continued treatment. Rapid deterioration may occur in patients with diarrhea; monitor until resolved.
• Hypersensitivity: Hypersensitivity reactions have been reported with leucovorin calcium. In a small series of confirmed hypersensitivity/infusion reactions to leucovorin calcium (when used as a part of combination chemotherapy regimens), reactions also occurred with subsequent rechallenge with levoleucovorin (Ureña-Tavera 2015).
• Seizure/syncope: Seizures and/or syncope have been reported with leucovorin calcium, generally in patients with CNS metastases or other underlying risk factors.
Special populations:
• HIV patients: Concomitant use of leucovorin calcium and sulfamethoxazole-trimethoprim for the acute treatment of pneumocystis jirovecii pneumonia in patients with HIV infection has been associated with increased rates of treatment failure and morbidity; may also occur with levoleucovorin.
Dosage form specific issues:
• Calcium content: Some levoleucovorin products contain calcium. Do not exceed an infusion rate of 160 mg/minute for products containing calcium.
Other warnings/precautions:
• Administration: For IV administration only; do not administer intrathecally.
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:
Generic: 50 mg (1 ea)
Solution Reconstituted, Intravenous [preservative free]:
Khapzory: 175 mg (1 ea); 300 mg (1 ea [DSC])
Generic: 50 mg (1 ea)
Yes
Solution (LEVOleucovorin Calcium PF Intravenous)
175 mg/17.5ml (per mL): $7.54 - $8.45
250 mg/25 mL (per mL): $7.82 - $8.26
Solution (reconstituted) (Khapzory Intravenous)
175 mg (per each): $931.06
Solution (reconstituted) (LEVOleucovorin Calcium Intravenous)
50 mg (per each): $60.00 - $218.88
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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; Falcone 2007; Tournigand 2006).
Parenteral: IV: For IV administration only; do not administer intrathecally. Administer by slow IV push or infusion over at least 3 minutes, not to exceed 160 mg/minute (due to calcium content).
Colorectal cancer, metastatic: Treatment of adults with advanced, metastatic colorectal cancer (in combination with fluorouracil).
Folic acid antagonist overdose: Antidote to diminish toxicity associated with overdosage of folic acid antagonists in adult and pediatric patients.
High-dose methotrexate rescue: Rescue agent after high-dose methotrexate therapy in adult and pediatric patients with osteosarcoma.
Impaired methotrexate elimination: Antidote to diminish toxicity associated with impaired methotrexate elimination in adult and pediatric patients.
Limitations of use: Levoleucovorin is not indicated for pernicious anemia or megaloblastic anemias secondary to the lack of vitamin B12 (due to the risk of progressive neurologic manifestations despite hematologic remission).
LEVOleucovorin may be confused with leucovorin calcium, Leukeran, Leukine
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Fluorouracil Products: Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of Fluorouracil Products. Risk C: Monitor therapy
Fosphenytoin: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of Fosphenytoin. Risk C: 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. Risk D: Consider therapy modification
PHENobarbital: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of PHENobarbital. Risk C: Monitor therapy
Phenytoin: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of Phenytoin. Risk C: 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). Risk C: Monitor therapy
Raltitrexed: Leucovorin Calcium-Levoleucovorin may diminish the therapeutic effect of Raltitrexed. Risk X: Avoid combination
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. Risk X: Avoid combination
Information related to levoleucovorin use in pregnancy is limited. Levoleucovorin is administered in combination with either methotrexate or fluorouracil; also refer to the Methotrexate or Fluorouracil monographs for additional information.
It is not known if levoleucovorin is present in breast milk.
Levoleucovorin is administered in combination with either methotrexate or fluorouracil; also refer to Methotrexate or Fluorouracil monographs for additional information.
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 (until resolution) and stomatitis.
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.
Distribution: Small quantities of systemically administered leucovorin enter the cerebrospinal fluid, primarily as the major metabolite 5-methyl-tetrahydrofolate.
Metabolism: Converted to the active reduced form of folate, 5-methyl-tetrahydrofolate (5-methyl-THF; active).
Half-life elimination: Total-tetrahydrofolate: 5.1 hours; (6S)-5-methyl-5,6,7,8-tetrahydrofolate: 6.8 hours.
Time to peak, serum: IV (healthy volunteers; 15 mg dose): 0.9 hours.
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