Fusilev

Generic Name: Levoleucovorin Calcium
Class: Antidotes
VA Class: VT102
Chemical Name: (6S)-N-{4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl] amino]benzoyl}-L-glutamate pentahydrate
Molecular Formula: C₂₀H₂₁CaN₇O₇ • 5H₂O

Introduction

Folic acid derivative; active levorotatory (l) isomer of racemic leucovorin.^{1 2 3 4 5 7 10 17}

Uses for Fusilev

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).^{1 2 3 6 17}

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).^{1 6 17}

Colorectal Cancer

Has been studied for treatment of advanced-stage colorectal cancer† in combination with fluorouracil, with or without other agents (i.e., irinotecan, oxaliplatin)†.^{10001 10002 10003 10004 10005 10006} However, use in such combination regimens not fully established.¹⁹

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.¹

AHFS Off-label Use Determinations for Oncology

Off-label Use (condition and patient population)	Regimen	Strength of Evidence; Strength of Study End Point(s)	Grade of Recommendation	Disclosure Information	AHFS Publication Date
First-line therapy for advanced-stage colorectal cancer	Levoleucovorin 100 mg/m2 as an IV injection, followed by fluorouracil 400 mg/m2 as a 2-hour IV infusion; both drugs given daily on days 1–5 with dosage adjustments, as needed, for response and/or toxicity.10001 Cycle repeated every 4 weeks	High quality (see Clinical Trial Summary) End point: Survival	Not fully established	No conflicts of interest were disclosed during this review.	August 2008
First-line therapy for advanced-stage colorectal cancer	Levoleucovorin 100 mg/m2 as an IV injection, followed by fluorouracil 370 mg/m2 by IV injection; both drugs given daily on days 1–5 with dosage adjustments, as needed, for response and/or toxicity.10002 Cycle repeated at 4 and 8 weeks, then every 5 weeks thereafter	High quality (see Clinical Trial Summary) End point: Survival	Not fully established	No conflicts of interest were disclosed during this review.	August 2008
First-line therapy for advanced-stage colorectal cancer	Biweekly or Simplified LV5FU2 (sLV5FU2)10003 Levoleucovorin 200 mg/m2 as a 2-hour IV infusion on day 1; followed by fluorouracil 400 mg/m2 as an IV injection on day 1, then 1500 mg/m2/day as a continuous IV infusion over 23 hours on days 1 and 2 (a total of 3000 mg/m2 by continuous IV infusion over 46 hours) with dosage adjustments, as needed, for response and/or toxicity. Cycle repeated every 2 weeks	Low quality (see Clinical Trial Summary)	Not fully established	No conflicts of interest were disclosed during this review.	August 2008
First-line therapy for advanced-stage colorectal cancer	FOLFOX4 Regimen10003 Oxaliplatin 85 mg/m2 as a 2-hour infusion on day 1; levoleucovorin 100 mg/m2 as a 2-hour IV infusion on days 1 and 2; followed by fluorouracil 400 mg/m2 as an IV injection, on days 1 and 2, then 600 mg/m2 /day as a continuous IV infusion on days 1 and 2 (a total of 1200 mg/m2 by continuous IV infusion over 44 hours) with dosage adjustments, as needed, for response and/or toxicity. Cycle repeated every 2 weeks	Low quality (see Clinical Trial Summary)	Not fully established	No conflicts of interest were disclosed during this review.	August 2008
First-line therapy for advanced-stage colorectal cancer	FOLFOX6 Regimen10004 Levoleucovorin 200 mg/m2 as a 2-hour IV infusion on day 1; oxaliplatin 100 mg/m2 as a 2-hour IV infusion on day 1; followed by fluorouracil 400 mg/m2 as an IV injection on day 1, then 1200 mg/m2/day as a continuous IV infusion over 23 hours on days 1 and 2 (a total of 2400 mg/m2 by continuous IV infusion over 46 hours) with dosage adjustments, as needed, for response and/or toxicity. Cycle repeated every 2 weeks	Low quality (see Clinical Trial Summary)	Not fully established	No conflicts of interest were disclosed during this review.	August 2008
First-line therapy for advanced-stage colorectal cancer	Modified FOLFOX6 (or modified de Gramont) Regimen10005 10006 Levoleucovorin 175 mg as a 2-hour IV infusion; oxaliplatin 85 mg/m2 as a 2-hour IV infusion on day 1; followed by fluorouracil 400 mg/m2 as an IV injection on day 1, then 1200 mg/m2/day as a continuous IV infusion over 23 hours on days 1 and 2 (a total of 2400 mg/m2 by continuous IV infusion over 46 hours) with dosage adjustments, as needed, for response and/or toxicity. Cycle repeated every 2 weeks	Low quality (see Clinical Trial Summary)	Not fully established	No conflicts of interest were disclosed during this review.	August 2008
First-line therapy for advanced-stage colorectal cancer	FOLFOX7 Regimen10003 Levoleucovorin 200 mg/m2 as a 2-hour IV infusion on day 1; oxaliplatin 130 mg/m2 as a 2-hour infusion on day 1; followed by fluorouracil 1200 mg/m2/day as a continuous IV infusion over 23 hours on days 1 and 2 (a total of 2400 mg/m2 by continuous IV infusion over 46 hours) with dosage adjustments, as needed, for response and/or toxicity. Cycle repeated every 2 weeks	Low quality (see Clinical Trial Summary)	Not fully established	No conflicts of interest were disclosed during this review.	August 2008
First-line therapy for advanced-stage colorectal cancer	FOLFIRI Regimen10004 Levoleucovorin 200 mg/m2 as a 2-hour IV infusion on day 1; irinotecan 180 mg/m2 as a 90 minute infusion on day 1; followed by fluorouracil 400 mg/m2 as an IV injection, then 1200 mg/m2/day as a continuous IV infusion over 23 hours on days 1 and 2 (a total of 2400 mg/m2 by continuous IV infusion over 46 hours) with dosage adjustments, as needed, for response and/or toxicity. Cycle repeated every 2 weeks	Low quality (see Clinical Trial Summary)	Not fully established	No conflicts of interest were disclosed during this review.	August 2008

Clinical Trial Summary

Levoleucovorin and Fluorouracil as first-line therapy for advanced-stage (metastatic) colorectal cancer

Levoleucovorin [(l)–leucovorin] was compared with racemic leucovorin ([d,l]–leucovorin), in combination with fluorouracil in a phase 3, open-label, randomized study (n=248) to determine if a twofold increase in leucovorin dose would result in differences in overall response rate, toxicity, and survival for patients with metastatic and/or recurrent colorectal cancer.¹⁰⁰⁰¹

• 
  

  Patients were randomized to receive either levoleucovorin or racemic leucovorin, both dosed at 100 mg/m² and administered as an IV injection. The fluorouracil regimen was identical in both treatment groups.

  
  


• 
  

  A slight improvement in overall response rates was reported for the levoleucovorin arm compared with the racemic leucovorin group (overall response rate: 32 versus 25%; complete response + partial response: 5 + 27% versus 3 + 21%, respectively).

  
  


• 
  

  The discontinuance rates were similar (34% for both groups); severe adverse events were reported as 18% in the racemic leucovorin group compared with 13% in the levoleucovorin group. An increase in granulocytopenia (all grades) and grade III/IV leukopenia and diarrhea was reported in the racemic leucovorin group compared with levoleucovorin (increases with racemic leucovorin compared with levoleucovorin were granulocytopenia (all grades): 16%; grade III/IV granulocytopenia: 6%; grade III/IV leukopenia: 5%; grade III/IV diarrhea: 3%). The incidence of both grade I/II stomatitis and diarrhea was similar for both groups.

  
  


• 
  

  An improvement in time-to-progression was reported with the levoleucovorin group (8 versus 6.25 months [p=0.0505]); also no statistically significant difference was observed between the two treatment groups in overall survival (14.5 versus 15 months [p=0.28]), 1-year survival (58.3 versus 60.6% [p=0.72]), or estimated 2-year survival (15.3 versus 23% [p=0.16]).

  
  

A second phase 3, open-label, randomized study (n=926) evaluated equipotent doses of levoleucovorin compared with racemic leucovorin, administered either orally or IV in patients with advanced-stage (i.e., unresectable) colorectal cancer.¹⁰⁰⁰²

• 
  

  The study was designed to determine if the use of levoleucovorin would result in enhanced fluorouracil modulation, reflected as an improvement either in response rate or overall survival. The study was powered to detect a 25% reduction in mortality in the experimental arm (i.e., levoleucovorin) compared with racemic leucovorin.

  
  


• 
  

  Patients were randomized to one of the following three treatment arms: levoleucovorin 100 mg/m² given as an IV injection, oral racemic leucovorin 125 mg/m² given at hours 0, 1, 2, and 3, or racemic leucovorin 200 mg/m² given by IV injection. The fluorouracil regimen was identical in all three treatment groups.

  
  


• 
  

  A small increase in stomatitis and sepsis was reported in the IV racemic leucovorin group compared with the IV levoleucovorin group (increases in the racemic leucovorin group relative to levoleucovorin were: stomatitis: grade III/IV 3 and 2.6%, respectively; sepsis: grade III/IV: 2.3 and 0.6%, respectively). A variable pattern was reported for diarrhea, with a 2.7% increase and a 4% decrease in grade III and grade IV events, respectively in the IV racemic leucovorin arm. Three infection-related fatalities each were reported in the IV levoleucovorin and IV racemic leucovorin arms.

  
  


• 
  

  The overall response rate reported was not statistically different between the three groups (28, 34 and 34% for IV levoleucovorin, and oral and IV leucovorin, respectively [p=0.31]); 1-year survival was approximately 40% for all treatment groups based on Kaplan-Meier survival curve estimates.

  
  

In a third study, either IV levoleucovorin or racemic leucovorin, in combination with fluorouracil (administered as a continuous IV infusion) were used as part of the simplified de Gramont regimen (i.e., sLVFU2) as one of the treatment regimens in the OPTIMOX1 protocol (a study that evaluated alternative dosing sequences and regimens to reduce the incidence of oxaliplatin-induced sensory neuropathy).¹⁰⁰⁰³

• 
  

  Patients received either IV levoleucovorin or racemic leucovorin; however, no information is provided in the methodology section indicating the rationale for selection between the levoleucovorin or racemic leucovorin regimens.

  
  


• 
  

  The results, reported as both response and toxicity rates, reflected the different treatment sequence schedules; however, neither the response nor toxicity data are specifically described for the different leucovorin formulations.

  
  

Levoleucovorin with FOLFOX and FOLFIRI regimens as first-line therapy for advanced-stage colorectal cancer.

Randomized studies evaluating different schedules of various FOLFOX regimens (i.e., FOLFOX6, modified FOLFOX6, and FOLFOX7), as well as the FOLFIRI regimen, have reported using either IV levoleucovorin or racemic leucovorin for patients enrolled in these studies.^{10003 10004 10005}

• 
  

  Patients received either IV levoleucovorin or IV racemic leucovorin; however, no information is provided in the methodology section indicating the rationale for the selection of either the levoleucovorin or racemic leucovorin regimen.

  
  


• 
  

  The results, reported as both response and toxicity rates, reflected the different treatment sequence schedules; however, neither the response nor toxicity data is specifically described for the different leucovorin formulations.

  
  

The FOCUS (fluorouracil, oxaliplatin, and CPT11–Use and Sequencing) study, conducted by the United Kingdom Medical Research Council (MRC), used levoleucovorin (levofolinate) exclusively, as part of the fluorouracil, irinotecan, and oxaliplatin-based regimens in this protocol.¹⁰⁰⁰⁶ The safety and response data reported in this study reflect the various chemotherapy sequences and combinations, administered either as first or second-line therapy for poor prognosis colorectal cancer patients; however, the specific effects attributed to levoleucovorin are not fully characterized.

Discussion

Background

The use of leucovorin to enhance the cytotoxic effects of fluorouracil is a recognized treatment for advanced-stage colorectal cancer.¹⁰⁰⁰⁷ Racemic leucovorin (containing a mixture of both the levo [l] and dextro [d] stereroisomers), administered either orally or as IV infusion, is the formulation that has been used in the US since 1952.¹⁰⁰⁰⁸ It is recognized that the l-isomer (levoleucovorin) is the biologically active form of leucovorin and exhibits a different pharmacokinetic profile to that of the d-isomer, characterized by enhanced absorption following oral administration, a more rapid metabolism or transformation to the active 5-methyltetrahydrofolate (5-MTHF) metabolite, and a reduced fraction excreted by renal elimination.¹⁰⁰⁰⁹ Despite the long-term use of the racemic leucovorin formulation, concerns have been raised about the potential effects of the d-isomer on the absorption and disposition of the l-isomer.¹⁰⁰⁰⁹ Proposed pharmacokinetic interactions between the two isomers include competitive inhibition of the intracellular transport process, inhibition of polyglutamation, and changes in plasma protein binding, thereby modifying the renal clearance or filtration of the l-isomer, resulting in increased renal elimination of the active metabolite.¹⁰⁰⁰⁹ However, pharmacokinetic data from small clinical studies conducted in both healthy volunteers and cancer patients have failed to confirm the adverse effects of the d-isomer on the biologically active moiety when the oral racemic leucovorin formulation is used.^{10009 10010}

Administration of racemic leucovorin by the IV route bypasses the first-pass metabolism and saturable oral absorption—two stereoselective processes resulting in enhanced bioavailability of the d-isomer. Therefore, administration of high doses may result in elevated serum concentrations of the d-isomer, thereby modifying the activity of the l-isomer.¹⁰⁰⁰⁹ Data from two studies, conducted with both healthy volunteers and colorectal cancer patients, showed no inhibitory effects on the l-isomer pharmacokinetic profile when IV racemic leucovorin was given either prior to or concurrently with an equipotent dose of IV levoleucovorin.^{10011 10012} However, a cross-study analysis performed on a small number of colorectal cancer patients receiving equipotent IV doses of levoleucovorin reported higher levels of the parent compound and lower levels of the active metabolite (5-MTHF) with levoleucovorin compared with the racemic leucovorin formulation.¹⁰⁰¹³ Another small study characterized the potential pharmacokinetic interactions at a cellular level for both the levo- and racemic leucovorin forms by evaluating tumor concentrations of both isomers in liver metastases in patients with colorectal cancer.¹⁰⁰¹⁴ These investigators reported higher tumor-to-serum ratios in patients receiving levoleucovorin compared with the racemic leucovorin form, suggesting a possible inhibitory effect of the d-isomer in preventing adequate cellular uptake of the active l-isomer in tumors. The clinical significance of the results described in these in vitro studies is not fully known.

Summary

Levoleucovorin is currently FDA-approved for use after high-dose methotrexate therapy in patients with osteosarcoma, and to diminish the toxicity and counteract the effects of impaired methotrexate elimination or inadvertent overdose of folic acid antagonists.¹⁰⁰⁰⁷ The approved dosage for this indication is 7.5 mg (as a fixed dose) every 6 hours for a total of 10 doses, starting 24 hours after the beginning of the methotrexate infusion. The dosages proposed with the off-label fluorouracil-containing regimens in adults with metastatic colorectal cancer range from 100 to 200 mg/m² for each dose.^{10001 10002 10003 10004 10005 10006} These doses reflect a 50% reduction of the racemic leucovorin dose based on data from a bioequivalence study confirming similar serum concentrations of both 5-MTHF and total tetrahydrofolate following either an oral or IV dose.¹⁰⁰¹⁵

Results from the randomized studies revealed a slight reduction in grade III/IV toxicity (i.e., diarrhea, stomatitis, leukopenia, and sepsis-related events) with levoleucovorin compared with the racemic leucovorin formulation. In one study it was concluded that there were no differences in toxicity between levoleucovorin and racemic leucovorin when used with fluororuracil; however, in another study the investigators reported an increase in granulocytopenia with racemic leucovorin, but acknowledged that due to the lack of complications (e.g., febrile/neutropenic events) and the low incidence of granulocytopenia overall for the study population, the observed increase may be of limited significance.^{10001 10002} Levoleucovorin has been used as part of an oxaliplatin- or irinotecan-containing regimen (i.e., FOLFOX or FOLFIRI); however, data are not available from randomized studies directly comparing safety and efficacy with racemic leucovorin.^{10003 10004 10005 10006} Published data describing the use of levoleucovorin as part of a fluorouracil-based regimen (i.e., FOLFOX or FOLFIRI) with bevacizumab are not available; therefore, the safety profile has not been fully established for use with such combinations.

Given the lack of established difference in either the safety or efficacy profile of the levoleucovorin-fluorouracil regimens relative to the racemic leucovorin-fluorouracil regimens, as well as the lack of consistent pharmacokinetic data demonstrating an adverse effect of the racemic leucovorin formulation on the pharmacokinetics and biologic effects of the l-isomer, the clinicial benefit of using levoleucovorin in combination with fluorouracil for the treatment of advanced-stage colorectal cancer is not fully established.

Fusilev 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.¹ Monitor S_cr and methotrexate concentrations at least once daily.¹

  
  


• 
  

  Maintain adequate hydration (3 L daily) and administer sodium bicarbonate to maintain urinary pH at ≥7 during therapy.¹

  
  


• 
  

  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^-8M) and renal failure has resolved.¹

  
  

Administration

IV Administration

Administer by IV injection;¹ has been administered by IV infusion in various published studies.¹⁷

Use strict aseptic technique since drug product contains no preservatives.¹

Do not admix or infuse concomitantly with other drugs.^{1 17}

Do not administer intrathecally.¹

Reconstitution

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.¹

Use of sodium chloride containing preservatives (e.g., benzyl alcohol) not studied.¹ Use of solutions other than 0.9% sodium chloride to reconstitute levoleucovorin not recommended.¹

Levoleucovorin solution may be administered following reconstitution or may be diluted.¹⁷

Dilution

Immediately following reconstitution, may be further diluted in an appropriate volume of 0.9% sodium chloride injection or 5% dextrose injection to yield a concentration of 0.5–5 mg/mL.¹

Rate of Administration

Administer by IV injection at a rate not >16 mL (160 mg of levoleucovorin) per minute.^{1 17} (See Rate of Administration under Cautions.)

Dosage

Available as levoleucovorin calcium; dosage expressed in terms of levoleucovorin.¹

Levoleucovorin is dosed at one-half the usual dosage of racemic leucovorin.^{1 2}

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;^{1 17} however, safety and efficacy of levoleucovorin have been evaluated in 16 patients 6–21 years of age.¹

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.¹

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.¹

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^-5M] at 24 hours, 1 micromolar [10^-6M] at 48 hours, and 0.2 micromolar [2 × 10^-7M]) at 72 hours after administration).¹

Continue therapy and maintain adequate hydration and urinary alkalinization (pH ≥7) until methotrexate concentration declines to <0.05 micromolar (5 × 10^-8M).¹

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.¹

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

Table 1. Guidelines for Levoleucovorin Dosage Adjustment in Patients with Delayed Late Methotrexate Elimination

Serum Methotrexate Concentration	Leucovorin Dosage Adjustment
>0.2 micromolar (2 × 10-7M) at 72 hours and >0.05 micromolar (5 × 10-8M) at 96 hours following methotrexate administration	Continue levoleucovorin 7.5 mg IV every 6 hours until methotrexate concentration declines to <0.05 micromolar (5 × 10-8M)1

Table 2. Guidelines for Levoleucovorin Dosage Adjustment in Patients with Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury

Serum Methotrexate and/or Scr Concentration	Leucovorin Dosage Adjustment and Monitoring
Methotrexate concentration ≥50 micromolar (5 × 10-5M) at 24 hours or ≥5 micromolar (5 × 10-6M) at 48 hours after methotrexate administration, or a ≥100% increase in Scr at 24 hours after methotrexate administration (e.g., an increase from 0.5 to 1 mg/dL or more)	Levoleucovorin 75 mg IV every 3 hours until methotrexate concentration declines to <1 micromolar (10-6M), then levoleucovorin 7.5 mg IV every 3 hours until methotrexate concentration declines to <0.05 micromolar (5 × 10-8M)1 If renal failure develops, monitor fluid and electrolyte status until methotrexate concentration declines to <0.05 micromolar (5 × 10-8M) and renal failure has resolved1

Methotrexate Overdosage

IV

7.5 mg (approximately 5 mg/m²) every 6 hours until serum methotrexate concentration declines to <0.01 micromolar (10^-8M); initiate administration as soon as possible after overdosage and within 24 hours following methotrexate administration if delayed elimination is detected.¹

If 24-hour S_cr increases 50% over baseline, 24-hour methotrexate concentration is >5 micromolar (5×10^-6M), or 48-hour methotrexate concentration is >0.9 micromolar (9 × 10^-7M), increase dosage immediately to 50 mg/m² IV every 3 hours until serum methotrexate concentration declines to <0.01 micromolar (10^-8M).¹

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.¹

Cautions for Fusilev

Contraindications

• 
  

  Known hypersensitivity to folic acid or folinic acid.¹

  
  

Warnings/Precautions

Warnings/Precautions

Rate of Administration

Injection rate should not exceed 16 mL (160 mg of levoleucovorin) per minute because of the calcium concentration (4.26 mg Ca⁺⁺ per 64 mg of levoleucovorin calcium pentahydrate) of the solution.^{1 17}

Toxicity Potentiation with Concomitant Therapy

Possible potentiation of fluorouracil toxicity.¹ Deaths from severe enterocolitis, diarrhea, and dehydration reported in geriatric patients receiving weekly racemic leucovorin concomitantly with fluorouracil.^{1 9}

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.^{1 17 18}

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether distributed into milk.¹ Use with caution.¹

Pediatric Use

Safety and efficacy have been evaluated in 16 patients 6–21 years of age.¹ The manufacturer makes no specific recommendations regarding use in pediatric patients.^{1 17}

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.¹ (See Specific Drugs under Interactions.)

Geriatric Use

Insufficient experience in patients ≥65 years of age for treatment of osteosarcoma to determine whether geriatric patients respond differently than younger adults.¹ Death secondary to severe enterocolitis, diarrhea, and dehydration reported in geriatric patients receiving weekly racemic leucovorin concomitantly with fluorouracil.¹

Renal Impairment

Possible delayed methotrexate elimination; higher dosages and extended duration of therapy may be required.¹ (See Dosage and Administration: Special Populations.)

Common Adverse Effects

Vomiting, stomatitis, nausea.¹

Interactions for Fusilev

Specific Drugs

Drug	Interaction	Comments
Anticonvulsants (phenobarbital, phenytoin, primidone)	Decreased anticonvulsant effect if used concomitantly with large amounts of folic acid; possible increased frequency of seizures in susceptible pediatric patients1 13 14 16 Possible increased hepatic metabolism and decreased plasma phenytoin concentrations based on studies in rats12	Use concomitantly with caution1 15
Co-trimoxazole	Increased rates of treatment failure and morbidity observed in HIV-infected patients receiving combination therapy with leucovorin for treatment of P. jiroveci pneumonia1 17 18
Fluorouracil	Possible potentiation of fluorouracil antineoplastic activity and toxicity1
Methotrexate, intrathecal	Possible decreased methotrexate efficacy if used concomitantly with high doses of leucovorina

Fusilev Pharmacokinetics

Absorption

Bioavailability

Peak serum concentrations of active metabolite 5-methyltetrahydrofolic acid (5-methyl-THF) attained in an average 0.9 hours.¹

Distribution

Extent

Levoleucovorin is actively and passively transported across cell membranes.¹

Small amounts of 5-methyl-THF distributed into CSF.¹

Elimination

Metabolism

Metabolized to 5-methyl-THF, the primary circulating form of active reduced folate.^{1 7 8 10} Levoleucovorin and 5-methyl-THF are polyglutamated intracellularly by folylpolyglutamate synthetase.¹

Elimination Route

Excreted in urine as unchanged drug and metabolites.^{10 17}

Half-life

5.1 and 6.8 hours for THF and 5-methyl-THF, respectively.¹

Stability

Storage

Parenteral

Powder for Injection

25°C (may be exposed to 15–30°C).¹ Protect from light.¹

Following reconstitution or further dilution in 0.9% sodium chloride injection, solutions may be stored up to 12 hours at room temperature.¹

Following dilution in 5% dextrose injection, solutions may be stored for up to 4 hours at room temperature.¹

ActionsActions

• 
  

  The pharmacologically active levorotatory (l) isomer of racemic d,l-leucovorin.^{1 2 3 4 5 7 10} Constitutes approximately 50% of racemic leucovorin.^{1 2 3 5 7 8 10 17}

  
  


• 
  

  A reduced derivative of folic acid; does not require reduction by dihydrofolate reductase to participate in reactions utilizing folates.¹

  
  


• 
  

  Counteracts the therapeutic and toxic effects (e.g., hematologic toxicity) of folic acid antagonists (e.g., methotrexate);^{1 2} exerts such effects at half the dose of racemic leucovorin.⁴ No effect on other established toxicities of methotrexate resulting from drug and/or metabolite precipitation in kidneys (e.g., nephrotoxicity).¹

  
  


• 
  

  Enhances therapeutic and toxic effects of fluoropyrimidines (e.g., fluorouracil) by stabilizing binding of fluorouracil metabolite (fluorodeoxyridylic acid) to thymidylate synthase (enzyme responsible for DNA repair and replication), thus enhancing inhibition of this enzyme.^a

  
  

Advice to Patients

• 
  

  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).¹

  
  


• 
  

  Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed.¹

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

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

Levoleucovorin Calcium

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection	50 mg (of levoleucovorin)	Fusilev	Spectrum

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions May 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Spectrum Pharmaceuticals, Inc. Fusilev (levoleucovorin calcium) powder for injection prescribing information. Irvine, CA; 2008 Jul.

2. Goorin A, Strother D, Poplack D et al. Safety and efficacy of l-leucovorin rescue following high-dose methotrexate for osteosarcoma. Med Pediatr Oncol. 1995; 24:362-7. [PubMed 7715542]

3. Jaffe N, Jorgensen K, Robertson R et al. Substitution of l-leucovorin for d,l-leucovorin in the rescue from high-dose methotrexate treatment in patients with osteosarcoma. Anticancer Drugs. 1993; 4:559-64. [PubMed 8292813]

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