AHFS Class:

• Chemotherapy antidotes/protectants 91:04.12

Generic Name(s):

• Leucovorin Calcium

Leucovorin calcium is the calcium salt of folinic acid, an active metabolite of folic acid.

Prevention and Treatment of Toxicity Associated with Folic Acid Antagonists

Leucovorin is used as an antidote to diminish the toxicity and counteract the effect of unintentional overdosage of folic acid antagonists, such as methotrexate, trimethoprim, and pyrimethamine. Leucovorin also is used in conjunction with these folic acid antagonists for the prevention and treatment of undesired hematopoietic effects of the drugs. When used in the treatment of accidental overdosage of folic acid antagonists, leucovorin therapy should be initiated as soon as possible since the effectiveness of leucovorin in counteracting hematologic toxicity diminishes as the time period between antifolate (e.g., methotrexate) administration and leucovorin rescue increases.

Methotrexate Toxicity

Leucovorin rescue has been administered in conjunction with high-dose methotrexate therapy in an effort to control the duration of exposure of sensitive cells to methotrexate. This regimen has been more effective than methotrexate alone in inducing and maintaining remissions in osteogenic sarcoma, head and neck cancer, refractory acute leukemia, and lung carcinoma; the superiority of this combination in other neoplastic diseases has not been demonstrated. Generally, leucovorin should not be administered simultaneously with systemic methotrexate because the therapeutic effect as well as the toxicity of the antimetabolite may be nullified; however, leucovorin can generally be administered 6-24 hours after methotrexate infusion. When methotrexate is administered by intra-arterial (regional perfusion) or intrathecal injection, leucovorin can be given IM, IV, or orally concomitantly to offset systemic methotrexate toxicity without abolishing the local activity of the antineoplastic drug.

Leucovorin has been used in conjunction with methotrexate in the treatment of psoriasis; however, results have been conflicting. Some investigators reported small doses of leucovorin increased the number, size, and activity of psoriasiform lesions when administered orally 24-72 hours after oral methotrexate. Other investigators have found leucovorin to decrease the adverse effects of methotrexate without decreasing the effects of the antimetabolite when leucovorin was administered IM 2 hours after IM methotrexate.

Trimetrexate Glucuronate Toxicity

Leucovorin is administered concomitantly with trimetrexate glucuronate and continued for 72 hours after the last dose to prevent potentially serious or life-threatening toxicities (e.g., bone marrow suppression) associated with the drug.160

Pyrimethamine Toxicity

Protozoa are unable to utilize leucovorin, apparently because they require p -aminobenzoic acid (PABA) for biosynthesis of an active cofactor. For this reason, therapeutic doses of leucovorin have been administered at the same time as pyrimethamine to decrease the hematologic toxicity of pyrimethamine in the treatment of toxoplasmosis, Pneumocystis carinii pneumonia, or Plasmodium falciparum malaria, without nullifying the effect of pyrimethamine on the parasite.

Trimethoprim Toxicity

Leucovorin has been used to antagonize the hematologic toxicity of trimethoprim without interfering with the drug's antibacterial effectiveness.

Megaloblastic Anemia

Leucovorin is used in the treatment of folate deficient megaloblastic anemias of infancy, pregnancy, sprue, and nutritional deficiencies when oral folic acid therapy is not feasible. However, since the ability to convert folic acid to tetrahydrofolic acid is not impaired in these anemias, leucovorin has no advantage over folic acid injection.

In contrast to folic acid, leucovorin is also effective in the treatment of megaloblastic anemia produced by congenital dihydrofolate reductase deficiency. Leucovorin is not effective in and should not be used for the treatment of pernicious anemia and other megaloblastic anemias secondary to lack of vitamin B₁₂.101,102,106 (See Cautions: Precautions and Contraindications.)

Combined Therapy with Fluorouracil for Advanced Colorectal Carcinoma

Leucovorin calcium is used to potentiate the antineoplastic activity of, and thus improve response to, fluorouracil in the palliative treatment of advanced colorectal carcinoma.102,107,108,112,114,115,116,117,118,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,144,146,151,153,154,155,158 Leucovorin calcium is designated an orphan drug by the US Food and Drug Administration (FDA) for such use.164 Such combined therapy is employed in an attempt to prolong survival relative to fluorouracil alone in patients with advanced disease.102,108,112,114,116,118,124,125,126,127,128,129,131,140,146,153,154,155 In vitro studies119,120,121,122,123,146 and clinical evidence102,114,115,116,117,118,126,129,130,131,132,133,134 have shown that the cytotoxicity of fluorouracil may be enhanced by leucovorin; it appears that elevated intracellular concentrations of reduced folates (e.g., leucovorin) may stabilize the covalent ternary complex formed by fluorodeoxyuridylic acid, 5,10-methylenetetrahydrofolate, and thymidylate synthase, enhancing inhibition of this enzyme and thereby increasing the efficacy of fluorouracil.102,119,128,141,144,146,147,148,149,150

Analysis of pooled data144 from several randomized studies107,118,133,134,138,142,158 in patients with advanced colorectal carcinoma indicates that combined therapy with IV fluorouracil and IV leucovorin calcium produces higher objective response rates (i.e., tumor responses) than does IV fluorouracil alone.144 However, despite the superiority in objective tumor response with combined therapy, overall survival rates were not improved appreciably compared with fluorouracil alone.144 In this analysis, overall objective response rates were about 23% for combined fluorouracil and leucovorin therapy and 11% for fluorouracil alone, with only 3 and 2.6%, respectively, exhibiting complete responses;144 median durations of survival were 11.5 months for combined therapy and 11 months for fluorouracil alone.144 It remains unclear why the higher response rate did not result in improved survival with combination therapy.144 It was suggested that the low rates of response, particularly complete responses, for such advanced disease observed both in patients receiving combined therapy and in those receiving monotherapy may have been insufficient to affect overall survival.144 In addition, the large number of nonresponders to fluorouracil alone who subsequently received combined therapy may have obscured any potential difference in survival; however, a survival benefit also was not apparent when trials with crossovers were excluded.144 While it remains to be established, the possibility exists that survival differences may be more apparent with less advanced stages of disease.144

Combination therapy in randomized studies in patients with advanced colorectal carcinoma consisted of regimens in which courses of IV fluorouracil and IV leucovorin calcium therapy were repeated at approximately monthly intervals102,116,126,129,130,131,132,133,134,138,142,144 and those in which courses were repeated weekly.114,118,126,136,142,144 The approximately monthly regimens included 5-day courses of fluorouracil 370 mg/m² and leucovorin calcium 200 or 500 mg/m² daily, fluorouracil 425 mg/m² and leucovorin calcium 20 mg/m² daily, or fluorouracil 400 mg/m² and leucovorin calcium 200 mg/m² daily, repeated at intervals of 4-5 weeks.102,107,116,126,129,130,131,132,133,134,138,142,144 Weekly dosage schedules of the combination included 600 mg/m² of fluorouracil and 25, 200, or 500 mg/m² of leucovorin administered once weekly, usually for 6 weeks.114,118,126,136,142,144,158 Fluorouracil alone was administered in various dosage regimens, including 5-day courses of 370, 400, or 500 mg/m² or 13.5 mg/kg daily, repeated at intervals of 4-5 weeks.102,116,126,129,130,131,132,133,134,138,142,144 Other dosage regimens of IV fluorouracil without leucovorin (i.e., fluorouracil 12 mg/kg daily for 5 days [total daily dosage did not exceed 800 mg] followed by fluorouracil 15 mg/kg once weekly, with dosage being increased by 10% weekly until dose-limiting toxicity or the desired degree of myelosuppression occurred) or 600 mg every 7 days also were used.102,126,134,144

While analysis of almost all individual randomized studies in patients with advanced disease also failed to reveal a survival benefit,144 a tendency toward improved survival was observed with combined fluorouracil and leucovorin therapy in a few of these studies;102,116,126,130,131,132 however, this tendency may be lost with continued follow-up.126,135 In one study (the NCCTG/Mayo Clinic Trial) in which patients were followed for a median of 21 months (range: 14—41 months), improved survival was associated with combined regimens of fluorouracil and either high- (200 mg/m² daily for 5 days) or low- (20 mg/m² daily for 5 days) dose leucovorin;102,126,131,144 however, the survival benefit was limited to those with nonmeasurable disease.131,144,156 In this study, no advantage was apparent for the high-dose leucovorin regimen,131 but study and analysis of possible dose-response differences are continuing.144

IV fluorouracil also has been used in combination with orally administered leucovorin in a limited number of patients with advanced colorectal carcinoma.126

The combination of fluorouracil and leucovorin with methotrexate or cisplatin also is being studied in the treatment of advanced colorectal carcinoma.102,109,110,111,113,131,132 In patients with advanced colorectal carcinoma, combined therapy with fluorouracil and leucovorin was associated with higher objective response rates and longer median durations of survival than therapy with sequential methotrexate, fluorouracil, and leucovorin;102 objective response rates were 31-33% and median durations of survival were 402-418 days in patients receiving combined therapy with fluorouracil and leucovorin compared with objective response rates of 4% and a median duration of survival of 223 days in patients receiving sequential methotrexate, fluorouracil, and leucovorin therapy.102

In addition to possible therapeutic potentiation, leucovorin may potentiate the risk of fluorouracil-induced toxicity (especially GI toxicity, including diarrhea, nausea, stomatitis, and vomiting, and, to a lesser degree, myelosuppression).102,114,116,126,129,130,131,132,133,134,143,145,151 A syndrome characterized by progression from mild to severe GI symptoms and rarely to potentially fatal enterocolitis has been reported in several studies of patients with advanced colorectal carcinoma receiving combined therapy with the drugs; in these studies, adverse GI effects (e.g., severe diarrhea, stomatitis) were the dose-limiting toxicity.114,115,129,130,131,145,151 (See Cautions: GI Effects, in Fluorouracil 10:00). Limited data suggest that once-weekly administration of fluorouracil plus leucovorin may be associated with a higher risk of developing serious adverse GI effects than 5-day regimens administered at approximately monthly intervals.102,114,126,143 Severe diarrhea appears to be the dose-limiting toxicity associated with once-weekly administration of the combination,114,126,156 while diarrhea and/or mucositis appear to be the dose-limiting toxicities associated with the 5-day regimens.126,131,156 Combined therapy with fluorouracil and leucovorin should not be initiated or continued in patients with symptomatic GI toxicity until such symptoms have completely resolved.102,114,126 Close monitoring is particularly important in patients who develop diarrhea with such combined therapy since rapid clinical deterioration and death can occur.102,143,155 Death secondary to severe enterocolitis, diarrhea, and dehydration has occurred in geriatric patients receiving the combination.102,143

Reconstitution and Administration

Leucovorin calcium is administered orally or by IM or IV injection. The drug should be given parenterally rather than orally in patients with GI toxicity, nausea, or vomiting and when individual doses greater than 25 mg are to be administered.101 Parenteral administration generally is preferred when leucovorin is administered following chemotherapy with a folic acid antagonist and there is a possibility that the patient may vomit and not absorb oral leucovorin.101,102,106 Leucovorin calcium should not be administered intrathecally.102

Leucovorin calcium powder for injection should be reconstituted by adding 5 or 10 mL of sterile water for injection or bacteriostatic water for injection containing benzyl alcohol to a vial labeled as containing 50 or 100 mg of leucovorin, respectively; the resultant solutions contain 10 mg/mL. Leucovorin calcium vials of the powder for injection labeled as containing 350 mg of leucovorin should be reconstituted by adding 17 mL of sterile water for injection or bacteriostatic water for injection containing benzyl alcohol to the vial; the resultant solution contains 20 mg/mL. When parenteral doses greater than 10 mg/m² are necessary, leucovorin calcium powder for injection reconstituted with sterile water for injection should be used; leucovorin calcium powder for injection reconstituted with bacteriostatic water containing benzyl alcohol should be used only when parenteral doses of 10 mg/m² or lower are required.102,106 Since parenteral leucovorin calcium doses exceeding 10 mg/m² are used in combination with fluorouracil for the treatment of advanced colorectal carcinoma, leucovorin calcium powder for injection (reconstituted with sterile water for injection ) should be used for this indication.102 When leucovorin is administered by IV infusion, the infusion rate should not exceed 16 mL (160 mg of leucovorin) per minute because of the calcium concentration of the solution.102,106

Dosage

Dosage of leucovorin calcium is expressed in terms of leucovorin.

Prevention and Treatment of Hematologic Toxicity Associated with Folic Acid Antagonists

As an antidote for inadvertent overdosage of folic acid antagonists, the manufacturers recommend that leucovorin be administered IM or IV in amounts equal to the weight of the antagonist given, as soon as the overdosage is detected and preferably within the first hour. When large doses or overdoses of methotrexate are given, leucovorin can be administered by IV infusion in doses up to 75 mg within 12 hours, followed by 12 mg IM every 6 hours for 4 doses. When average doses of methotrexate appear to have an adverse effect, 6-12 mg of leucovorin may be given IM every 6 hours for 4 doses. Prompt administration of leucovorin calcium is essential.

Methotrexate Toxicity

As part of a high-dose methotrexate regimen in cancer chemotherapy, leucovorin rescue therapy must begin within 24 hours of methotrexate administration. Dosage of leucovorin is approximately twice that of levoleucovorin (the active levorotatory [ l ] isomer).162 (See Levoleucovorin Calcium 92:12.)

The manufacturers of leucovorin calcium state that a typical leucovorin rescue dosage schedule is 10 mg/m² usually administered parenterally followed by 10 mg/m² orally (if there is adequate GI function) every 6 hours until the serum methotrexate concentration has declined to less than 10^-8 M . If at 24 hours following methotrexate administration the patient's serum creatinine has increased to 50% or more above the serum creatinine prior to methotrexate or the serum methotrexate concentration is greater than 5 × 10^-6 M , or if at 48 hours following methotrexate administration the serum methotrexate concentration is greater than 9 × 10^-7 M , leucovorin dosage should be increased immediately to 100 mg/m² every 3 hours until the serum methotrexate concentration is less than 10^-8 M . Use of high-dose methotrexate and leucovorin rescue therapy in treating certain cancers is an evolving science, and the optimum dosage and sequence of methotrexate and leucovorin calcium have not been established. Patients should not be given such therapy unless a specific formal protocol is being followed; the clinician should consult published protocols for the dosage of leucovorin calcium and the duration of methotrexate therapy before leucovorin calcium is administered.

In one study utilizing methotrexate in the treatment of psoriasis, the toxic effects of methotrexate were usually overcome by 4-8 mg of leucovorin administered IM 2 hours after IM methotrexate.

Trimetrexate Glucuronate Toxicity

The usual leucovorin dosage for the prevention of potentially serious and life-threatening toxicities in immunocompromised patients receiving trimetrexate glucuronate for the treatment of Pneumocystis carinii pneumonia is 20 mg/m² every 6 hours (total daily dose of 80 mg/m²).160,161 Leucovorin may be administered orally or IV (over 5-10 minutes) in these patients; if leucovorin is administered orally, the calculated dose should be rounded up to the next 25-mg increment.160 Leucovorin should be continued for at least 72 hours after the last trimetrexate dose.160 For the treatment of moderate to severe Pneumocystis carinii pneumonia in adults, the usual dosage of trimetrexate is 45 mg/m² given once daily.160 The recommended course of trimetrexate therapy is 21 days and that of leucovorin is 24 days.160

Dosage of trimetrexate and leucovorin must be adjusted according to the hematologic tolerance of the patient.160 For patients with neutrophil counts exceeding 1000/ mm³ and platelet counts exceeding 75,000/ mm³ (grade 1 toxicity), the usual dosages of trimetrexate and leucovorin can be used.160 For those with neutrophil counts of 750-1000/ mm³ and platelet counts of 50,000-75,000/ mm³ (grade 2 toxicity), the usual trimetrexate dosage should be used but leucovorin dosage should be increased to 40 mg/m² every 6 hours.160 Trimetrexate dosage should be reduced to 22 mg/ mm² once daily and leucovorin dosage should be increased to 40 mg/m² every 6 hours for neutrophil and platelet counts of 500-749 and 25,000-49,999 per mm³ (grade 3 toxicity), respectively.160 When using these dosage guidelines, dosage should be modified based on the worst of the two blood cell counts.160 For patients with lower neutrophil or platelet counts (grade 4 toxicity), leucovorin dosage should be increased to 40 mg/m² every 6 hours, and trimetrexate therapy should be discontinued if such changes occur prior to day 10 of therapy, continuing the higher dosage of leucovorin for an additional 72 hours.160 If such low counts develop during days 10-21 of trimetrexate therapy, the drug may be withheld up to 96 hours to permit recovery of the blood count(s) to a minimum of grade 3 toxicity before reinstituting trimetrexate; dosage should be adjusted according to the grade of hematologic toxicity achieved at the time of recovery.160 If hematologic toxicity does not improve to a minimum of grade 3 toxicity after 96 hours, trimetrexate therapy should be discontinued; leucovorin should be continued at the higher dosage for 72 hours after the last dose of trimetrexate.160

Pyrimethamine Toxicity

The dosage of leucovorin necessary to prevent hematologic toxicity associated with pyrimethamine varies depending on the dosage of the folic acid antagonist and the clinical status of the patient.159

In adults or children receiving pyrimethamine in a dosage of 25-100 mg daily or 1-2 mg/kg daily for the treatment of toxoplasmosis, some clinicians suggest that 10-25 mg of leucovorin be administered with each dose of pyrimethamine.161

When a regimen containing pyrimethamine (50 or 75 mg once weekly) and dapsone is used for the prevention of initial episodes ( primary prophylaxis ) of P. carinii pneumonia or Toxoplasma gondii infections or prevention of recurrence ( chronic maintenance therapy of secondary prophylaxis ) of P. carinii pneumonia in adults or adolescents with human immunodeficiency virus (HIV) infection, some clinicians recommend that oral leucovorin be administered concomitantly in a dosage of 25 mg once weekly.105,161 If adults or adolescents are receiving a regimen that contains a higher dosage of pyrimethamine (25-50 mg once daily) with clindamycin or sulfadiazine for secondary prophylaxis of toxoplasmosis, the dosage of leucovorin necessary to prevent hematologic toxicity may range from 10-25 mg once daily.105 When a regimen containing pyrimethamine 25 mg once daily and atovaquone is used for primary or secondary prophylaxis against toxoplasmosis in adults and adolescents with HIV infection, some clinicians recommend that oral leucovorin be administered concomitantly in a dosage of 10 mg daily.105

In HIV-infected children receiving a regimen that contains pyrimethamine (1 mg/kg once daily) with dapsone or clindamycin for primary or secondary prophylaxis , respectively, of toxoplasmosis, some clinicians recommend a leucovorin dosage of 5 mg once every 3 days.105

Megaloblastic Anemia

In the treatment of folate deficient megaloblastic anemias, up to 1 mg of leucovorin may be given IM daily. Although doses of 10 mg daily have been recommended in the past, the manufacturers state there is no evidence that IM doses greater than 1 mg daily are more effective. The duration of leucovorin therapy for megaloblastic anemia depends on the hematologic response to the drug, as evidenced in both peripheral blood and bone marrow. In general, patient response to therapy depends on the degree and nature of the folate deficiency, but once proper corrective measures are undertaken, deficient patients will generally respond rapidly. During the first 24 hours of treatment, the patient experiences an improved sense of well-being; the bone marrow begins to become normoblastic within 48 hours. Reticulocytosis generally begins within 2-5 days after the start of therapy.

In the treatment of megaloblastic anemia resulting from a congenital deficiency of dihydrofolate reductase, 3-6 mg of leucovorin has been given IM daily.

Combined Therapy with Fluorouracil for Advanced Colorectal Carcinoma

For potentiation of the antineoplastic effects of fluorouracil in the palliative treatment of advanced colorectal carcinoma, optimum dosage of leucovorin has not been clearly established.102,126,144 Current evidence indicates that an IV leucovorin dose of 20 mg/m² followed by an IV fluorouracil dose of 425 mg/m² can be used.102,126,130,131,132,144 Alternatively, a leucovorin dose of 200 mg/m² administered by slow IV injection (over a minimum of 3 minutes) followed by an IV fluorouracil dose of 370 mg/m² can be used,102,116,126,130,131,132,144,156 but there currently is no evidence of superiority with this leucovorin dosage.131 Either selected 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 subsided.102,126 Dosage of fluorouracil in subsequent courses of therapy should be adjusted according to patient tolerance of the prior treatment course;102 dosage of leucovorin in subsequent courses generally is not adjusted according to toxicity.102 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.102,126,133 If no toxicity occurs, fluorouracil dosage may be increased by 10%.102 Other combination dosage regimens also have been used.114,118,126,133,134,136,142,144,158 (See Uses: Combined Therapy with Fluorouracil for Advanced Colorectal Carcinoma.)

Adverse Effects

Leucovorin appears to be nontoxic in therapeutic doses, although thrombocytosis has been reported in patients receiving leucovorin during intra-arterial infusion of methotrexate. In addition, hypersensitivity reactions, including anaphylactoid reactions and urticaria, have been reported with both oral and parenteral use of leucovorin. While leucovorin can potentiate the toxic effects of fluorouracil, potentially resulting in increased severity and frequency of certain effects, the observed toxicity is that generally associated with fluorouracil. (See Uses: Combined Therapy with Fluorouracil for Advanced Colorectal Carcinoma and also see the Cautions section in the monograph on Fluorouracil 10:00.)

Precautions and Contraindications

Since allergic reactions have been reported following oral and parenteral administration of folic acid, the possibility of allergic reactions to leucovorin should be considered.

There is a potential danger in administering leucovorin to patients with undiagnosed anemia, as leucovorin may obscure the diagnosis of pernicious anemia by alleviating hematologic manifestations of the disease while allowing neurologic complications to progress. This may result in severe nervous system damage before the correct diagnosis is made. Adequate doses of vitamin B₁₂ may prevent, halt, or improve neurologic changes caused by pernicious anemia.

When leucovorin rescue is used in conjunction with high-dose methotrexate therapy, the drugs should be administered only by physicians experienced in cancer chemotherapy, in centers where facilities for measuring blood methotrexate concentrations are available. Leucovorin is usually effective in counteracting severe methotrexate toxicity in these regimens, but toxic reactions to methotrexate may occur despite leucovorin therapy, especially when the half-life of methotrexate is increased (e.g., renal dysfunction). Therefore, it is extremely important that leucovorin be administered until the blood concentration of methotrexate declines to nontoxic concentrations.

Since leucovorin calcium enhances the toxicity of fluorouracil, adjunctive therapy with leucovorin calcium and fluorouracil should be given only by, or under the supervision of, physicians experienced in cancer chemotherapy and in the use of antimetabolites.102 Hematologic indices (complete blood cell counts with differential, and quantitative platelet count) should be performed before each course of therapy with fluorouracil and leucovorin and repeated weekly during the first 2 courses of therapy and once during each subsequent course of therapy (when anticipated leukocyte nadir occurs).102 Determinations of serum electrolyte concentrations and liver function tests should be performed before each course of therapy for the first 3 courses of therapy and then prior to each other course of therapy.102 Dosage of fluorouracil should be reduced in patients who experienced moderate or severe hematologic or GI toxicity.102 (See Dosage and Administration: Dosage.) Therapy should be interrupted until the leukocyte count is 4000/mm³ and the platelet count is 130,000/mm³.102 If these counts do not increase to these levels within 2 weeks, therapy should be discontinued.102 Patients should be followed up with physical examinations before each course of therapy, and appropriate radiographic examinations should be performed as needed.102 Therapy should be discontinued if there is clear evidence of tumor progression.102

There is some evidence to suggest that the risk of fluorouracil-induced GI toxicity may be increased in patients receiving leucovorin concomitantly with the drug. Death secondary to severe enterocolitis, diarrhea, and dehydration has occurred in geriatric patients receiving the drugs concomitantly. Concomitant granulocytopenia and fever were present in some but not all cases. (See Cautions: GI Effects, in Fluorouracil 10:00.) Combined leucovorin and fluorouracil therapy should be used with extreme caution in geriatric or debilitated patients since such patients are more likely to develop serious toxicity from fluorouracil.102,143

Pregnancy and Lactation

Pregnancy

Animal reproduction studies have not been performed with leucovorin. It is also not known whether leucovorin can cause fetal harm when administered to pregnant women. Leucovorin should be used during pregnancy only when clearly needed.

Lactation

Since it is not known if leucovorin is distributed into milk, the drug should be used with caution in nursing women.

Pharmacology

Leucovorin is a derivative of tetrahydrofolic acid, the reduced form of folic acid, which is involved as a cofactor for 1-carbon transfer reactions in the biosynthesis of purines and pyrimidines of nucleic acids. Impairment of thymidylate synthesis in patients with folic acid deficiency is thought to account for the defective DNA synthesis that leads to megaloblast formation and megaloblastic and macrocytic anemias. Because of its ready conversion to other tetrahydrofolic acid derivatives, leucovorin is a potent antidote for both the hematopoietic and reticuloendothelial toxic effects of folic acid antagonists (e.g., methotrexate, pyrimethamine, trimethoprim). It is postulated that in some cancers leucovorin enters and “rescues” normal cells from the toxic effects of folic acid antagonists, in preference to tumor cells, because of a difference in membrane transport mechanisms; this principle is the basis of high-dose methotrexate therapy with “leucovorin rescue.”

Pharmacokinetics

Absorption and Distribution

In vivo, leucovorin calcium is rapidly and extensively converted to other tetrahydrofolic acid derivatives including 5-methyl tetrahydrofolate, which is the major transport and storage form of folate in the body.

Normal total serum folate concentrations have been reported to range from 0.005-0.015 mcg/mL. Folate is actively concentrated in CSF, and normal CSF concentrations are reported to be about 0.016-0.021 mcg/mL. Normal erythrocyte folate concentrations range from 0.175-0.316 mcg/mL. In general, serum folate concentrations less than 0.005 mcg/mL indicate folate deficiency and concentrations less than 0.002 mcg/mL usually result in megaloblastic anemia. Following IM administration of a 15-mg (7.5 mg/m²) dose in healthy men, mean peak serum folate concentrations of 0.241 mcg/mL occur within about 40 minutes. Following oral administration of a 15-mg (7.5 mg/m²) dose in healthy men, mean peak serum folate concentrations of 0.268 mcg/mL occur within about 1.72 hours. Areas under the serum folate concentration-time curves (AUCs) are reported to be about 8% less following IM injection in the gluteal region than in the deltoid region and about 12% less following IM injection in the gluteal region than following IV or oral administration.

Tetrahydrofolic acid and its derivatives are distributed to all body tissues; the liver contains about one-half of total body folate stores. In a small number of patients, biliary concentration of folates was about 4.5 times the plasma folate concentration after oral administration of a 2-mg dose of leucovorin; this is believed to represent the hepatic folate pool rather than excretion of the administered dose.

Elimination

Leucovorin is excreted in urine, mainly as 10-formyl tetrahydrofolate and 5,10-methenyl tetrahydrofolate. There is some evidence that 5-methyl tetrahydrofolate may be conserved by the kidneys in preference to 5-formyl tetrahydrofolate (leucovorin). Loss of folate in the urine becomes approximately logarithmic as the amount of leucovorin administered exceeds 1 mg.

Chemistry and Stability

Chemistry

Leucovorin calcium is the calcium salt of folinic acid, an active metabolite of folic acid. Leucovorin consists of equal amounts of d - and l -isomers; the l -isomer (levoleucovorin) is the pharmacologically active isomer.162,163 (See Levoleucovorin Calcium 92:12.) Leucovorin calcium occurs as a yellowish white or yellow, odorless powder and has solubilities of more than 500 mg/mL in water and less than 1 mg/mL in alcohol. The pK_as of leucovorin are 3.1, 4.8, and 10.4.

Stability

Leucovorin calcium powder for injection and tablets should be stored at 15-30°C and protected from light.101

When leucovorin calcium powder for injection is reconstituted as directed, resultant solutions should be used immediately when reconstituted with sterile water for injection or within 7 days when reconstituted with bacteriostatic water for injection containing benzyl alcohol.102

Leucovorin calcium solutions that have been admixed with 10% dextrose injection, 10% dextrose and 0.9% sodium chloride injection, Ringer's injection, or lactated Ringer's injection are stable for 24 hours when stored at room temperature protected from light.103 Although some former manufacturers of leucovorin calcium powder for injection have recommended that reconstituted solutions of the drug be protected from light,106 there is evidence that solutions of the drug are not adversely affected by exposure to room light.103,104 Reconstituted solutions of leucovorin calcium that have been further diluted with 50 mL of 5% dextrose injection and stored in Viaflex^® or glass containers unprotected from light retain at least 90% potency for 24 hours at room temperature.104

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.

Only references cited for selected revisions after 1984 are available electronically.

101. Immunex. Leucovorin calcium tablets prescribing information. Seattle, WA; 1994 May.

102. Immunex. Leucovorin calcium for injection prescribing information. Seattle, WA; 1994 May.

103. Engel SI (Lederle Laboratories, Pearl River, NY): personal communication; 1987 Jun.

104. Benvenuto JA, Anderson RW, Kerkof K et al. Stability and compatibility of antitumor agents in glass and plastic containers. Am J Hosp Pharm . 1981; 38:1914-8. [PubMed 7325172]

105. US Public Health Service (USPHS) and Infectious Diseases Society of America (IDSA) Prevention of Opportunistic Infections Working Group. 2001 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons with human immunodeficiency virus. From HIV/AIDS Treatment Information Services (ATIS) website ([Web]) [Fulltext MMWR]

106. Quad Pharmaceuticals. Leucovorin calcium for injection prescribing information. Indianapolis, IN; 1987 Mar.

107. Machover D, Schwarzenberg L, Goldschmidt E et al. Treatment of advanced colorectal and gastric adenocarcinomas with 5-FU combined with high-dose folinic acid: a pilot study. Cancer Treat Rep . 1982; 66:1803-7. [PubMed 6982099]

108. Budd GT, Fleming TR, Bukowski RM et al. 5-fluorouracil and folinic acid in the treatment of metastatic colorectal cancer: a randomized comparison: a Southwest Oncology Group study. J Clin Oncol . 1987; 5:272-7. [PubMed 3543246]

109. Panasci L, Ford J, Margolese R. A phase II study of sequential methotrexate and fluorouracil in advanced colorectal cancer. Cancer Chemother Pharmacol . 1985; 15:164-6. [PubMed 4017165]

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