Introduction ⬇
AHFS Class:
- Chemotherapy antidotes/protectants 91:04.12
Generic Name(s):
Levoleucovorin calcium, the levorotatory ( l ) isomer of racemic d,l -leucovorin, is one of several active, chemically reduced derivatives of folic acid.1,2,3,4,5,7,10,17
Uses ⬆ ⬇
Toxicity Associated with Folic Acid Antagonists 
Levoleucovorin calcium rescue is used after high-dose methotrexate therapy (to control the duration of exposure of sensitive cells to methotrexate for treatment of osteosarcoma.1,2,3,17 Levoleucovorin also is used as an 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.1,17 Levoleucovorin is designated an orphan drug by the US Food and Drug Administration (FDA) for these uses.6,17
Safety and efficacy of levoleucovorin rescue were evaluated in an analysis of data from 2 open-label studies and other unpublished trials in a limited number of patients (6-21 years of age) with osteogenic sarcoma.1,2,3,17 Of the 16 patients evaluated, 13 received levoleucovorin 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate (12 g/m2 IV over 4 hours), and 3 received levoleucovorin 7.5 mg every 3 hours for 18 doses beginning 12 hours after completion of methotrexate (12.5 g/m2 IV over 6 hours).1 Patients received a mean of 18.2 doses of levoleucovorin and a mean total dose of 350 mg per methotrexate course.1 Efficacy of levoleucovorin was determined by comparing its ability to prevent methotrexate-related toxicity with that of racemic leucovorin.2,3 In the first open-label study, 3 patients receiving a total of 22 courses of levoleucovorin following high-dose methotrexate therapy experienced fewer serious adverse events (0% of the 22 courses) compared with 6 historical control patients receiving a total of 24 courses of racemic leucovorin (10% of the 24 courses).3,17 In the second open-label study in which 15 patients received a total of 90 courses of levoleucovorin, severe adverse events were reported in 4% of the 90 courses. 2,17 However, it should be noted that interpretation of these results is limited by the statistical limitations of the studies (e.g., small sample size, reliance on retrospective review of records for historical control data).2,3
Although levoleucovorin may ameliorate the hematologic toxicity associated with high-dose methotrexate, the drug has no effect on other established toxicities of methotrexate such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney.1
Colorectal Cancer
Combined Therapy with Fluorouracil for Advanced-stage Colorectal Cancer
Levoleucovorin calcium is used in combination with fluorouracil for the palliative treatment of advanced-stage colorectal cancer.1 Use of levoleucovorin calcium in combination with fluorouracil and other agents (i.e., irinotecan, oxaliplatin)† also has been studied for the treatment of advanced-stage colorectal cancer†;10003,10004,10005,10006 however, use of levoleucovorin in regimens containing fluorouracil and either irinotecan or oxaliplatin currently is not fully established for this indication because of inadequate data and/or experience.19
Levoleucovorin and Fluorouracil
The current indication for use of levoleucovorin in combination with fluorouracil for the palliative treatment of advanced-stage colorectal cancer is based principally on the results of a phase 3, open-label, randomized study.1,10002 In this study, 926 patients with advanced-stage (i.e., unresectable) colorectal cancer were randomized to receive levoleucovorin 100 mg/m2 by IV injection, racemic leucovorin 125 mg/m2 orally at 1-hour intervals for 4 doses, or racemic leucovorin 200 mg/m2 by IV injection;1,10002 fluorouracil (370 mg/m2 given as an IV injection) was administered immediately following the IV dose of leucovorin or levoleucovorin or 1 hour after the fourth oral dose of leucovorin.10002 The drugs were administered daily on days 1-5 of the treatment cycle, with dosages adjusted as needed based on toxicity and response; treatment cycles were repeated at 4 and 8 weeks and every 5 weeks thereafter until disease progression or unacceptable toxicity occurred.1,10002 Overall response rates for the 3 groups did not differ significantly; 1-year survival was approximately 40% for all treatment groups.1,10002 There were no substantial differences in toxicity between levoleucovorin and racemic leucovorin when used in conjunction with fluorouracil.1,10002
In a second phase 3, open-label, randomized trial in 248 patients with metastatic and/or recurrent colorectal cancer, levoleucovorin was compared with racemic leucovorin to determine if a twofold increase in leucovorin dosage (given as levoleucovorin) would result in differences in overall response rate, toxicity, and survival.10001 Patients received either levoleucovorin (100 mg/m2) or racemic leucovorin (100 mg/m2) by IV injection, followed immediately by fluorouracil (400 mg/m2 as a 2-hour IV infusion), on days 1-5 of each 4-week treatment cycle, with dosages adjusted as needed based on toxicity and response.10001 A slight improvement in overall response rate was reported for levoleucovorin/fluorouracil compared with racemic leucovorin/fluorouracil; the overall response rate was 32% (5% complete and 27% partial responses) for patients receiving levoleucovorin/fluorouracil compared with 25% (3% complete and 21% partial responses) for those receiving racemic leucovorin/fluorouracil.10001 Median time to progression was 8 or 6.25 months with levoleucovorin/fluorouracil or racemic leucovorin/fluorouracil treatment, respectively; overall survival (14.5 versus 15 months), 1-year survival (58.3 versus 60.6%), and estimated 2-year survival (15.3 versus 23%) for patients receiving racemic leucovorin/fluorouracil or levoleucovorin/fluorouracil, respectively, did not differ significantly.10001 The discontinuance rates were similar (34%) for both groups.10001 Severe adverse events were slightly more common in patients receiving racemic leucovorin/fluorouracil compared with those receiving levoleucovorin/fluorouracil (18 versus 13%).19,10001 Increased incidences of granulocytopenia (all grades; 39 versus 21%), grade 3 or 4 granulocytopenia (8 versus 2%), grade 3 or 4 leukopenia (5 versus 0%), and grade 3 or 4 diarrhea (10 versus 7%) were reported with racemic leucovorin/fluorouracil compared with levoleucovorin/fluorouracil treatment;18,10001 however, the investigators acknowledged that the increased incidence of granulocytopenia observed with racemic leucovorin/fluorouracil treatment may be of limited clinical importance based on a lack of complications (e.g., febrile/neutropenic events) and the low incidence of granulocytopenia overall for the study population.19 The incidences of grade 1 or 2 stomatitis and diarrhea were similar for both groups.10001
In a third study (OPTIMOX1; a study that evaluated alternative dosing sequences and regimens as a means for reducing the incidence of oxaliplatin-induced sensory neuropathy), one of the treatment regimens, the simplified de Gramont regimen, consisted of IV levoleucovorin or racemic leucovorin in combination with fluorouracil (as a continuous IV infusion).19,10003 However, neither response nor toxicity results based on the leucovorin formulation used have been reported to date.10003
Levoleucovorin/Fluorouracil in Combination with Other Agents
Levoleucovorin has been used as a component of irinotecan/fluorouracil/levoleucovorin (FOLFIRI) or oxaliplatin/fluorouracil/levoleucovorin (FOLFOX) regimens for treatment of advanced-stage colorectal cancer;10003,10004,10005,10006 however, data are not available from randomized studies directly comparing safety and efficacy of levoleucovorin versus racemic leucovorin in such regimens.19 Randomized studies evaluating different schedules of various FOLFOX regimens (i.e., FOLFOX4, FOLFOX6, modified FOLFOX6, FOLFOX7), as well as the FOLFIRI regimen, have allowed use of either IV levoleucovorin or racemic leucovorin in these regimens,10003,10004,10005 although the basis for selection of one leucovorin formulation over the other is unclear.18,10003,10004,10005 Available response and toxicity data from these studies reflect the treatment schedules and sequences evaluated; analyses based on the leucovorin formulation used have not been reported.19,10003,10004,10005
In the FOCUS (Fluorouracil, Oxaliplatin, and CPT11[ irinotecan]-Use and Sequencing) study in patients with poor-prognosis, advanced-stage colorectal cancer, levoleucovorin was used exclusively as the leucovorin component of the fluorouracil-, irinotecan-, and oxaliplatin-based regimens evaluated for first- or second-line therapy.10006 Safety and response data have been reported from this study for the various chemotherapy sequences and combinations studied; however, the specific effects attributable to levoleucovorin have not been fully characterized.19,10006
Data are not available from randomized studies directly comparing safety and efficacy of levoleucovorin and racemic leucovorin in combination with fluorouracil and either irinotecan or oxaliplatin in patients with advanced-stage colorectal cancer.19 Published data describing the use of levoleucovorin as a component of combination therapy with a fluorouracil-based regimen (i.e., FOLFOX or FOLFIRI) and bevacizumab are not available; therefore, the safety of levoleucovorin in such combination regimens has not been fully established.19
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 cancera | 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 Regimen 10003 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 Regimen 10004 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) Regimen 1000510006 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 Regimen 10003 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 Regimen 10004 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 |
aOn April 29, 2011, FDA approved labeling of levoleucovorin calcium (levoleucovorin 100 mg/m2 in combination with fluorouracil 370 mg/m2 or levoleucovorin 10 mg/m2 in combination with fluorouracil 425 mg/m2) for the palliative treatment of advanced-stage colorectal cancer.
23Clinical 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.
(Addendum: On April 29, 2011, FDA approved labeling of levoleucovorin calcium [levoleucovorin 100 mg/m2 in combination with fluorouracil 370 mg/m2 or levoleucovorin 10 mg/m2 in combination with fluorouracil 425 mg/m2] for the palliative treatment of advanced-stage colorectal cancer.)23
Dosage and Administration ⬆ ⬇
Reconstitution and Administration
Levoleucovorin calcium is administered by IV administration; the drug should not be administered intrathecally.1 When administered by IV injection, the injection rate should not exceed 160 mg of levoleucovorin per minute (16 mL per minute as a 10-mg/mL solution) because of the calcium concentration (4.26 mg Ca++ per 64 mg of levoleucovorin calcium pentahydrate) of the solution.1,17 Levoleucovorin has been administered by IV infusion in various published studies.17
Levoleucovorin calcium is commercially available as a powder for injection and as an injection solution.1 Strict aseptic technique must be observed since the drug contains no preservative.1
Levoleucovorin calcium powder for injection is reconstituted by adding 5.3 mL of 0.9% sodium chloride injection to a vial labeled as containing 50 mg of levoleucovorin to provide a solution containing 10 mg/mL.1 The manufacturer states that reconstitution with sodium chloride solutions containing preservatives (e.g., benzyl alcohol) has not been studied and is not recommended.1 Following reconstitution, levoleucovorin solution may be administered by IV injection or further diluted, immediately, 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 Following reconstitution or further dilution using 0.9% sodium chloride injection, levoleucovorin is stable for up to 12 hours when stored at room temperature.1 Following dilution in 5% dextrose injection, the drug is stable for up to 4 hours when stored at room temperature.1
The commercially available levoleucovorin 10-mg/mL injection 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 mg/mL.1 Following dilution in 0.9% sodium chloride injection or 5% dextrose injection, the drug is stable for up to 4 hours when stored at room temperature.1
Reconstituted and diluted solutions of levoleucovorin should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit; the solutions should not be used if cloudiness or a precipitate is observed.1
Because of the risk of precipitation,11 levoleucovorin should not be combined with other agents in the same admixture.1,17
Dosage
Levoleucovorin is commercially available as the calcium pentahydrate; dosage of the drug is expressed in terms of levoleucovorin (i.e., 64 mg of levoleucovorin calcium pentahydrate is equivalent to 50 mg of levoleucovorin).1
Levoleucovorin is dosed at one-half the usual dosage of racemic leucovorin.1,2 (See Description.) 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 (See Uses: Toxicity Associated with Folic Acid Antagonists.)
Toxicity Associated with Folic Acid Antagonists
Rescue after High-dose Methotrexate Therapy
Dosage recommendations for levoleucovorin are based on a methotrexate dosage of 12 g/m2 administered by IV infusion over 4 hours; the prescribing information for methotrexate should be consulted for additional information.1 Dosage and duration of levoleucovorin rescue therapy should be adjusted based on the elimination pattern of methotrexate and the patient's renal function (see Table 1).1,17
Serum creatinine and methotrexate concentrations should be monitored at least once daily.1 Levoleucovorin therapy should be continued, and adequate hydration and urinary alkalinization (pH of 7 or greater) maintained, until serum methotrexate concentration declines to less than 0.05 micromolar (5 × 10-8 M ).1 Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure; therefore, fluid and electrolyte status also should be closely monitored in such patients until serum methotrexate concentration declines to less than 0.05 micromolar (5 × 10-8 M ) and renal failure has resolved.1
Table 1. Guidelines for Levoleucovorin Dosage Adjustment in Patients with Normal or Delayed Methotrexate Elimination1
Clinical Situation | Serum Methotrexate Concentrationa | Levoleucovorin Dosage and Monitoring |
|---|
Normal methotrexate eliminationb | Approximately 10 micromolar (10-5 M ) at 24 hours, 1 micromolar (10-6 M ) at 48 hours, and less than 0.2 micromolar (2 x 10-7 M ) at 72 hours after methotrexate administration | 7.5 mg (approximately 5 mg/m2) IV every 6 hours for 60 hours (10 doses), starting at 24 hours after initiation of methotrexate infusionb |
Delayed late methotrexate elimination | Greater than 0.2 micromolar (2 x 10-7 M ) at 72 hours and greater than 0.05 micromolar (5 x 10-8 M ) at 96 hours after methotrexate administration | Continue levoleucovorin 7.5 mg IV every 6 hours until methotrexate concentration declines to less than 0.05 micromolar (5 x 10-8 M ) |
Delayed early methotrexate elimination and/or evidence of acute renal injury | 50 micromolar (5 x 10-5 M ) or greater at 24 hours or 5 micromolar (5 x 10-6 M ) or greater at 48 hours after methotrexate administration, or a 100% or greater increase in serum creatinine concentration at 24 hours after methotrexate administration (e.g., an increase from 0.5 to 1 mg/dL or more) | 75 mg IV every 3 hours until methotrexate concentration declines to less than 1 micromolar (10-6 M ), then 7.5 mg IV every 3 hours until methotrexate concentration declines to less than 0.05 micromolar (5 x 10-8 M ) |
aThe possibility that the patient is receiving other drugs that interact with methotrexate (e.g., by decreasing methotrexate elimination, binding to serum albumin) should always be considered when laboratory abnormalities or clinical toxicities are observed.1
bIn patients with mild abnormalities in methotrexate elimination or renal function who experience clinically important toxicity, levoleucovorin rescue should be extended for an additional 24 hours (i.e., 14 doses over 84 hours) for subsequent methotrexate courses.1
Methotrexate Overdosage
Levoleucovorin rescue should begin as soon as possible following unintentional overdosage and within 24 hours of methotrexate administration if delayed elimination is detected; delayed administration of levoleucovorin may reduce its effectiveness in counteracting toxicity associated with folic acid antagonists.1
The usual levoleucovorin dosage for management of methotrexate overdosage is 7.5 mg (approximately 5 mg/m2) IV every 6 hours until serum methotrexate concentration declines to less than 0.01 micromolar (10-8 M ).1 Serum creatinine and serum methotrexate concentrations should be determined at 24-hour intervals.1 If the 24-hour serum creatinine concentration increases 50% over baseline, the 24-hour methotrexate concentration is greater than 5 micromolar (5 x 10-6 M ), or the 48-hour methotrexate concentration is greater than 0.9 micromolar (9 x 10-7 M ), levoleucovorin dosage should be increased to 50 mg/m2 IV every 3 hours until serum methotrexate concentration declines to less than 0.01 micromolar (10-8 M ).1 Hydration (3 L daily) and urinary alkalinization with sodium bicarbonate (to maintain a urinary pH of 7 or greater) should be employed concomitantly.1
Colorectal Cancer
Combined Therapy with Fluorouracil for Advanced-stage Colorectal Cancer
Regimens of levoleucovorin and fluorouracil that historically have been used for the palliative treatment of advanced-stage colorectal cancer include a levoleucovorin dose of 100 mg/m2 administered by slow IV injection (over a minimum of 3 minutes) followed by an IV fluorouracil dose of 370 mg/m2, or a levoleucovorin dose of 10 mg/m2 administered by IV injection followed by an IV fluorouracil dose of 425 mg/m2.1 Either regimen is administered daily for 5 days and may be repeated at 4-week intervals for 2 additional courses; thereafter, the regimen may be repeated at intervals of 4-5 weeks provided toxicity from the previous course of combined therapy has resolved completely.1
Dosage of fluorouracil in subsequent courses of therapy should be adjusted according to patient tolerance of the prior treatment course; dosage of levoleucovorin in subsequent courses is not adjusted because of toxicity.1 Daily fluorouracil dosage generally is reduced by 20% in patients who experienced moderate hematologic or GI toxicity in the prior course and by 30% in those patients who experienced severe toxicity.1 If no toxicity occurs, fluorouracil dosage may be increased by 10%.1
Other levoleucovorin and fluorouracil dosage regimens also have been used.10001 (See Levoleucovorin and Fluorouracil under Colorectal Cancer: Combined Therapy with Fluorouracil for Advanced-stage Colorectal Cancer, in Uses.)
Special Populations
Patients with Delayed Methotrexate Elimination
Higher dosages and extended duration of levoleucovorin 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 ⬆ ⬇
Contraindications
Pernicious anemia or other megaloblastic anemias secondary to lack of vitamin B12; such use may obscure the diagnosis of pernicious anemia by alleviating hematologic manifestations while allowing neurologic complications to progress.1,17
Hypersensitivity to folic acid or folinic acid.1
Warnings/Precautions
Rate of Administration
The injection rate should not exceed 160 mg of levoleucovorin per minute (16 mL per minute as a 10-mg/mL solution) because of the calcium concentration of the solution.1
Toxicity Potentiation with Concomitant Therapy
Levoleucovorin potentiates the toxicity of fluorouracil; therefore, fluorouracil dosage must be reduced when levoleucovorin is used concomitantly in the treatment of advanced-stage colorectal cancer.1 Although toxicities in patients receiving levoleucovorin in combination with fluorouracil are qualitatively similar to those in patients receiving fluorouracil alone, GI toxicities (particularly stomatitis and diarrhea) occur more frequently and may be more severe or prolonged in patients receiving combined therapy.1 Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in geriatric patients receiving weekly racemic leucovorin concomitantly with fluorouracil.1,9 In addition, in a study evaluating higher weekly dosages of fluorouracil and racemic leucovorin, an increased risk of severe GI toxicity was observed in geriatric and/or debilitated patients.1
In several clinical trials in patients with advanced-stage colorectal cancer, treatment-related toxicity occurred more frequently in patients receiving a low dose of racemic leucovorin (20 mg/m2) in combination with fluorouracil (425 mg/m2) than in patients receiving a higher dose of racemic leucovorin (200 mg/m2) in combination with fluorouracil (370 mg/m2).1 In one study, 20% of patients receiving fluorouracil in combination with racemic leucovorin 20 mg/m2 experienced toxicity (primarily GI toxicity) requiring hospitalization, compared with 7% of those receiving fluorouracil alone or in combination with racemic leucovorin 200 mg/m2.1 In another study, 11% of patients receiving fluorouracil in combination with racemic leucovorin 20 mg/m2 required hospitalization for treatment-related toxicity, compared with 3% of those receiving fluorouracil in combination with racemic leucovorin 200 mg/m2.1
Combined therapy with fluorouracil and levoleucovorin should not be initiated or continued in patients with symptomatic GI toxicity until such symptoms have resolved completely.1 Patients who develop diarrhea should be monitored with particular care until the diarrhea has resolved, since rapid clinical deterioration and death can occur.1 (See Cautions: Precautions and Contraindications, in Leucovorin Calcium 92:12.)
Concomitant use of racemic leucovorin with co-trimoxazole for treatment of Pneumocystis jiroveci (formerly P. carinii ) pneumonia in patients with HIV infection has been associated with increased rates of treatment failure and morbidity.1,17,18
Seizures and/or syncope have occurred rarely in cancer patients receiving racemic leucovorin, usually in conjunction with fluoropyrimidine therapy; cases have occurred most commonly in patients with other predisposing factors (e.g., CNS metastasis).1 A causal relationship to racemic leucovorin has not been fully established.1
Sensitivity Reactions
Allergic reactions have been reported in patients receiving levoleucovorin.1
Specific Populations
Pregnancy
Category C.1 (See Users Guide.)
Lactation
It is not known whether levoleucovorin is distributed into milk; because of the potential for serious adverse reactions to levoleucovorin in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1
Pediatric Use
Safety and efficacy of levoleucovorin have been evaluated in 16 patients 6-21 years of age.1 (See Uses: Toxicity Associated with Folic Acid Antagonists.) The manufacturer makes no specific recommendations regarding use in pediatric patients.1,17
Geriatric Use
Clinical studies of levoleucovorin in the treatment of osteosarcoma did not include patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.1
In a clinical trial evaluating levoleucovorin in combination with fluorouracil for the treatment of advanced-stage colorectal cancer, adverse reactions were consistent with known toxicities of fluorouracil; no overall differences in adverse effects were observed between geriatric patients (65 years of age or older) and younger adults.1 However, deaths from severe enterocolitis, diarrhea, and dehydration have been reported in geriatric patients receiving weekly racemic leucovorin concomitantly with fluorouracil.1 (See Cautions: Precautions and Contraindications, in Leucovorin Calcium 92:12.)
Renal Impairment
Renal impairment may cause delayed methotrexate elimination; higher dosages and extended duration of levoleucovorin therapy may be required in patients with renal impairment.1 (See Dosage and Administration: Special Populations.)
Common Adverse Effects
Adverse effects reported in more than 15% of patients receiving levoleucovorin rescue following high-dose methotrexate therapy include vomiting, stomatitis, and nausea.1 Less frequently reported adverse effects, occurring in less than 10% of patients, include diarrhea, dyspepsia, typhlitis, dyspnea, dermatitis, confusion, neuropathy, abnormal renal function, and taste perversion.1
Adverse effects reported in more than 50% of patients with advanced-stage colorectal cancer receiving levoleucovorin in combination with fluorouracil include diarrhea, nausea, and stomatitis.1 Other frequently reported adverse effects, occurring in 20-40% of patients, include vomiting, asthenia/fatigue/malaise, anorexia/decreased appetite, dermatitis, and alopecia.1 The incidence of adverse effects is similar to that reported in patients receiving an equipotent dosage of racemic leucovorin in combination with fluorouracil.1
Drug Interactions ⬆ ⬇
Anticonvulsants
Folic acid in large amounts may counteract the anticonvulsant effect of phenobarbital, phenytoin, and primidone and increase the frequency of seizures in susceptible children.1,13,14,16 Racemic leucovorin has been shown to increase hepatic metabolism and decrease plasma concentrations of phenytoin in rats.12 Therefore, caution is advised when levoleucovorin is used concomitantly with anticonvulsants.1,15
Co-trimoxazole
Concomitant use of racemic leucovorin with co-trimoxazole for treatment of Pneumocystis jiroveci (formerly P. carinii ) pneumonia in patients with HIV infection has been associated with increased rates of treatment failure and morbidity.1,17,18
Fluorouracil
Levoleucovorin potentiates the toxicity of fluorouracil.1,9 (See Toxicity Potentiation with Concomitant Therapy under Cautions: Warnings/Precautions.)
Glucarpidase
In patients receiving high-dose methotrexate therapy with leucovorin rescue, administration of glucarpidase (an enzyme that converts methotrexate to inactive metabolites) 2 hours before a racemic leucovorin dose reduced systemic exposure and peak plasma concentrations of leucovorin and its active metabolite, 5-methyltetrahydrofolate.21 Similar effects would be expected with levoleucovorin.22 In addition, methotrexate concentrations measured by immunoassay within 48 hours following glucarpidase administration are unreliable.21 Racemic leucovorin or levoleucovorin should not be administered within 2 hours before or after glucarpidase administration.21,22 Dosage adjustment of the continuing racemic leucovorin or levoleucovorin regimen is not necessary since dosage is based on the patient's methotrexate concentration prior to glucarpidase administration.21,22 During the first 48 hours after glucarpidase administration, racemic leucovorin or levoleucovorin should be administered at the same dosage administered prior to glucarpidase administration; beyond 48 hours, dosage should be based on the measured methotrexate concentration.21,22 Therapy with racemic leucovorin or levoleucovorin should be continued until the methotrexate concentration has been maintained below the threshold for such treatment for at least 3 days.21,22
Methotrexate
High dosages of racemic leucovorin may reduce the efficacy of intrathecally administered methotrexate.10007
Other Information ⬆ ⬇
Description
Levoleucovorin is the levorotatory ( l ) isomer of racemic d,l -leucovorin.1,2,3,4,5,7,10 Levoleucovorin is the pharmacologically active isomer and constitutes approximately 50% of racemic leucovorin; therefore, the effects of levoleucovorin are observed at half the dose of racemic leucovorin.1,2,3,4,5,7,8,10 17 Because levoleucovorin is a reduced derivative of folic acid and does not require reduction by dihydrofolate reductase to participate in reactions utilizing folates, the drug counteracts the therapeutic and toxic effects of folic acid antagonists (e.g., methotrexate).1,2 The drug also enhances the efficacy and toxicity of fluoropyrimidines (e.g., fluorouracil) by stabilizing binding of the fluorouracil metabolite 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) to thymidylate synthase (an enzyme responsible for DNA repair and replication), thus enhancing inhibition of this enzyme.1
Levoleucovorin is actively and passively transported across cell membranes.1 In vivo, levoleucovorin is converted to 5-methyltetrahydrofolic acid (5-methyl-THF), the primary circulating form of active reduced folate.1,7,8,10 Levoleucovorin and 5-methyl-THF are polyglutamated intracellularly by the enzyme folylpolyglutamate synthetase.1 Folylpolyglutamates are active and participate in numerous biochemical pathways that require reduced folate.1,10
Following IV administration of a single 15-mg dose of levoleucovorin in healthy male volunteers, peak serum concentrations of (6 S )-5-methyl-5,6,7,8-tetrahydrofolate (the l -isomer of 5-methyl-THF)17 were reached within 0.9 hours.1 The mean terminal half-life of total tetrahydrofolate and (6 S )-5-methyl-5,6,7,8-tetrahydrofolate were 5.1 and 6.8 hours, respectively.1 Levoleucovorin and its metabolites are excreted in urine.10,17
Data from several crossover studies in healthy individuals and patients with colorectal cancer have shown no substantial differences in exposure to the l -isomer of leucovorin or to 5-methyltetrahydrofolate regardless of whether IV racemic leucovorin or an equipotent dose of IV levoleucovorin is administered.1,10011,10012
Advice to Patients
Risk of diarrhea, vomiting, stomatitis, and nausea.1
Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed.1
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 informing patients of other important precautionary information.1 (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.
LEVOleucovorin Calcium
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|
Parenteral | For injection, for IV use | 50 mg (of levoleucovorin) | Fusilev® | Spectrum |
| Injection, for IV use | 10 mg (of levoleucovorin) per mL (175 and 250 mg) | Fusilev® | Spectrum |
Copyright ⬆ ⬇
AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions May 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 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 and injection solution prescribing information. Irvine, CA; 2011 Apr.
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]
4. Zittoun J. Pharmacokinetics and in vitro studies of l-leucovorin. Comparison with the d and d,l-leucovorin. Ann Oncol . 1993; 4 Suppl 2:1-5. [PubMed 8353099]
5. Zittoun J, Marquet J, Pilorget JJ et al. Comparative effect of 6S, 6R and 6RS leucovorin on methotrexate rescue and on modulation of 5-fluorouracil. Br J Cancer . 1991; 63:885-8. [PubMed 2069845][PubMedCentral]
6. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to May 16, 2008. Rockville, MD; from FDA website. [Web]
7. Zittoun J, Tonelli AP, Marquet J et al. Pharmacokinetic comparison of leucovorin and levoleucovorin. Eur J Clin Pharmacol . 1993; 44:569-73. [PubMed 8405015]
8. Etienne MC, Thyss A, Bertrand Y et al. l-folinic acid versus d,l-folinic acid in rescue of high-dose methotrexate therapy in children. J Natl Cancer Inst . 1992; 84:1190-5. [PubMed 1635087]
9. Meropol NJ, Petrelli NJ, Rustum YM et al. A phase II and pharmacokinetic study of 6S-leucovorin plus 5-fluorouracil in patient with colorectal carcinoma. Invest New Drugs . 1995; 13:149-55. [PubMed 8617578]
10. DeVito JM, Kozloski GD, Tonelli AP et al. Bioequivalence of oral and injectable levoleucovorin and leucovorin. Clin Pharm . 1993; 12:293-9. [PubMed 8458180]
11. Trissel LA, Martinez JF, Xu QA. Incompatibility of fluorouracil with leucovorin calcium or levoleucovorin calcium. Am J Health Syst Pharm . 1995; 52:710-5. [PubMed 7627739]
12. Yamasaki D, Tsujimoto M, Ohdo S et al. Possible mechanisms for the pharmacokinetic interaction between phenytoin and folinate in rats. Ther Drug Monit . 2007; 29:404-11. [PubMed 17667793]
13. Lewis DP, Van Dyke DC, Willhite LA et al. Phenytoin-folic acid interaction. Ann Pharmacother . 1995 Jul-Aug; 29:726-35.
14. Steinweg DL, Bentley ML. Seizures following reduction in phenytoin level after orally administered folic acid. Neurology . 2005; 64:1982. [PubMed 15955964]
15. Tidwell BH, Cleary JD. Comment: leucovorin-phenytoin: a drug-drug interaction?. Ann Pharmacother . 1995; 29:1303-4. [PubMed 8672847]
16. Seligmann H, Potasman I, Weller B et al. Phenytoin-folic acid interaction: a lesson to be learned. Clin Neuropharmacol . 1999 Sep-Oct; 22:268-72.
17. Spectrum Pharmaceuticals, Irvine, CA: Personal communication.
18. Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis . 1994; 170:912-7. [PubMed 7930736]
19. Levoleucovorin Final Determination. Published August 2008. [Web]
21. BTG International Inc. Voraxaze® (glucarpidase) for injection prescribing information. West Conshohocken, PA; 2012 Jan
22. BTG International Inc. West Conshohocken, PA: Personal communication.
23. Justice RL. Fusilier® (levoleucovorin): FDA supplement approval. NDA number: 020140/5-002. Silver Spring, MD: US Food and Drug Administration. From FDA website. Accessed 2012 Aug 29.
10001. Scheithauer W, Kornek G, Marczell A et al. Fluorouracil plus racemic leucovorin versus fluorouracil combined with the pure l-isomer of leucovorin for the treatment of advanced colorectal cancer: a randomized phase III study. J Clin Oncol . 1997; 15:908-14. [PubMed 9060527]
10002. Goldberg RM, Hatfield AK, Kahn M et al. Prospectively randomized North Central Cancer Treatment Group trial of intensive-course fluorouracil combined with the l-isomer of intravenous leucovorin, oral leucovorin, or intravenous leucovorin for the treatment of advanced colorectal cancer. J Clin Oncol . 1997; 15:3320-9. [PubMed 9363861]
10003. Tournigand C, Cervantes A, Figer A et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol . 2006; 24:394-400. [PubMed 16421419]
10004. Tournigand C, André T, Achille E et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol . 2004; 22:229-37. [PubMed 14657227]
10005. Cheeseman SL, Joel SP, Chester JD et al. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer . 2002; 87:393-9. [PubMed 12177775][PubMedCentral]
10006. Seymour MT, Maughan TS, Ledermann JA et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet . 2007; 370:143-52. [PubMed 17630037]
10007. Bedford Laboratories. Leucovorin calcium for injection prescribing information. Bedford, OH; 2008 Sep.
10008. Spectrum Pharmaceuticals, Inc. Fusilev® (levoleucovorin calcium) powder for injection prescribing information. Irvine, CA; 2008.
10009. Zittoun J, Tonelli AP, Marquet J et al. Pharmacokinetic comparison of leucovorin and levoleucovorin. Eur J Clin Pharmacol . 1993; 44:569-73. [PubMed 8405015]
10010. Etienne MC, Thyss A, Bertrand Y et al. l-folinic acid versus d,l-folinic acid in rescue of high-dose methotrexate therapy in children. J Natl Cancer Inst . 1992; 84:1190-5. [PubMed 1635087]
10011. Schalhorn A, Kuhl M, Heil K et al. Comparative pharmacokinetics of d,l-folinic acid and of the pure l-folinic acid. Proceedings of ASCO. 1990; 9:66. Abstract No. 253.
10012. Meropol NJ, Petrelli NJ, Rustum YM et al. A phase II and pharmacokinetic study of 6S-leucovorin plus 5-fluorouracil in patient with colorectal carcinoma. Invest New Drugs . 1995; 13:149-55. [PubMed 8617578]
10013. Rustum YM, Zhang ZG, Frank C et al. Pharmacokinetics of the biologically active isomer, 6S-leucovorin in patients with advanced colorectal cancer. Proceedings of American Association for Cancer Research. 1991; 32:174. Abstract No. 1037.
10014. Schuller J, Czejka M, Pietrzak C et al. Serum and tissue levels of l-folinic acid (fa) after IV bolus of either racemic (d,l) fa or pure l-entantiomer (l-fa). Proceedings of ASCO. 1996: 15:175. Abstract No. 353.
10015. DeVito JM, Kozloski GD, Tonelli AP et al. Bioequivalence of oral and injectable levoleucovorin and leucovorin. Clin Pharm . 1993; 12:293-9. [PubMed 8458180]