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
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Safety and efficacy of levoleucovorin rescue were evaluated in an analysis of data from 2 open-label studies and other unpublished trials in a limited number of patients (6-21 years of age) with osteogenic sarcoma.1, 2, 3, 17 Of the 16 patients evaluated, 13 received levoleucovorin 7.5 mg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
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
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
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
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
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
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.)
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
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
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
Allergic reactions have been reported in patients receiving levoleucovorin.1
Category C.1 (See Users Guide.)
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
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
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 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.)
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
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
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
Levoleucovorin potentiates the toxicity of fluorouracil.1, 9 (See Toxicity Potentiation with Concomitant Therapy under Cautions: Warnings/Precautions.)
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
High dosages of racemic leucovorin may reduce the efficacy of intrathecally administered methotrexate.10007
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
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.
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.
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]
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]
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