{"id":"levoleucovorin","rwe":[{"pmid":"20301716","year":"1993","title":"Hereditary Folate Malabsorption.","finding":"","journal":"","studyType":"Clinical Study"},{"pmid":"41010482","year":"2025","title":"Vitamins, Vascular Health and Disease.","finding":"","journal":"Nutrients","studyType":"Clinical Study"},{"pmid":"40856428","year":"2025","title":"Electronic Patient-Reported Outcome Quality of Life Score in Japanese Patients With Pancreatic Cancer on Second-Line Chemotherapy: A Multicenter Observational Study.","finding":"","journal":"Cancer medicine","studyType":"Clinical Study"},{"pmid":"37247353","year":"2006","title":"Leucovorin.","finding":"","journal":"","studyType":"Clinical Study"},{"pmid":"39987459","year":"2025","title":"NALIRIFOX in Japanese treatment-naïve patients with metastatic pancreatic adenocarcinoma: an open-label, phase II trial design.","finding":"","journal":"Future oncology (London, England)","studyType":"Clinical Study"}],"_fda":{"id":"17100790-fb82-43cd-80eb-b3e73d918bbd","set_id":"059a3306-6207-497f-a947-33198f18761f","openfda":{"unii":["778XL6VBS8"],"route":["INTRAVENOUS"],"rxcui":["1720765","1720773"],"spl_id":["17100790-fb82-43cd-80eb-b3e73d918bbd"],"brand_name":["Levoleucovorin"],"spl_set_id":["059a3306-6207-497f-a947-33198f18761f"],"package_ndc":["71288-105-18","71288-105-25"],"product_ndc":["71288-105"],"generic_name":["LEVOLEUCOVORIN CALCIUM"],"product_type":["HUMAN PRESCRIPTION DRUG"],"substance_name":["LEVOLEUCOVORIN CALCIUM"],"manufacturer_name":["Meitheal Pharmaceuticals Inc."],"application_number":["ANDA211002"],"is_original_packager":[true]},"version":"9","pregnancy":["8.1 Pregnancy Risk Summary There are limited data with levoleucovorin use in pregnant women. Animal reproduction studies have not been conducted with levoleucovorin. Levoleucovorin is administered in combination with methotrexate or fluorouracil, which can cause embryo-fetal harm. Refer to methotrexate and fluorouracil prescribing information for additional information. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively."],"overdosage":["2.4 Recommended Dosage for Overdosage of Folic Acid Antagonists or Impaired Methotrexate Elimination Start levoleucovorin injection as soon as possible after an overdosage of methotrexate or within 24 hours of methotrexate administration when methotrexate elimination is impaired. As the time interval between methotrexate administration and levoleucovorin injection increases, the effectiveness of levoleucovorin injection to diminish methotrexate toxicity may decrease. Administer levoleucovorin injection 7.5 mg (approximately 5 mg/m 2 ) by intravenous infusion every 6 hours until the serum methotrexate level is less than 5 x 10 -8 M (0.05 micromolar). Monitor serum creatinine and methotrexate levels at least every 24 hours. Increase the dosage of levoleucovorin injection to 50 mg/m 2 intravenously every 3 hours and continue levoleucovorin injection at this dosage until the methotrexate level is less than 5 x 10 -8 M for the following: if serum creatinine at 24-hours increases 50% or more compared to baseline if the methotrexate level at 24-hours is greater than 5 x 10 -6 M if the methotrexate level at 48-hours is greater than 9 x 10 -7 M, Continue concomitant hydration (3 L per day) and urinary alkalinization with sodium bicarbonate. Adjust the sodium bicarbonate dose to maintain urine pH at 7 or greater."],"description":["11 DESCRIPTION Levoleucovorin is a folate analog and the pharmacologically active levo-isomer of d,l -leucovorin. The chemical name of levoleucovorin calcium is calcium (6 S )-N-{4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl] amino]benzoyl}- L -glutamate mixed hydrates. The molecular formula is C 20 H 21 CaN 7 O 7 ● nH 2 O (n = 3 to 6) and the molecular weight is 565.6 to 619.6. The molecular structure is: Levoleucovorin Injection, for intravenous use is supplied as a sterile colorless to yellow, clear solution of either 175 mg levoleucovorin in 17.5 mL or 250 mg levoleucovorin in 25 mL per single-dose vial. Each mL contains 10 mg levoleucovorin (equivalent to 10.8 mg levoleucovorin calcium, on anhydrous basis) and 8.3 mg sodium chloride. Sodium hydroxide is used for pH adjustment to pH 8.0 (6.5 to 8.5). molecular structure"],"how_supplied":["16 HOW SUPPLIED/STORAGE AND HANDLING Levoleucovorin Injection is a sterile colorless to yellow, clear solution in a single-dose vial, and is supplied as follows: NDC Levoleucovorin Injection (10 mg per mL) Package Factor 71288- 105 -18 175 mg per 17.5 mL Single-Dose Vial 1 vial per carton 71288- 105 -25 250 mg per 25 mL Single-Dose Vial 1 vial per carton Store refrigerated between 2° and 8°C (36° and 46°F). Protect from light. Store in carton until contents are used. Discard unused portion. Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex. meitheal ® Mfd. for Meitheal Pharmaceuticals Chicago, IL 60631 (USA) ©2023 Meitheal Pharmaceuticals Inc. Mfd. by Kindos Pharmaceuticals Co., Ltd. Chengdu, China 611731 Revised: August 2023"],"geriatric_use":["8.5 Geriatric Use Clinical studies of levoleucovorin in the treatment of osteosarcoma did not include patients aged 65 and over to determine whether they respond differently from younger patients. In the NCCTG clinical trial of levoleucovorin in combination with fluorouracil for the treatment of metastatic colorectal cancer, no overall differences in safety or effectiveness were observed between patients age 65 years and older and younger patients."],"pediatric_use":["8.4 Pediatric Use The safety and effectiveness of levoleucovorin have been established in pediatric patients for rescue after high-dose methotrexate therapy in osteosarcoma and diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination. Use of levoleucovorin in pediatric patients is supported by open-label clinical trial data in 16 pediatric patients 6 years of age and older, with additional supporting evidence from literature [see Clinical Studies ( 14.1 )]. The safety and effectiveness of levoleucovorin have not been established for the treatment of pediatric patients with advanced metastatic colorectal cancer."],"effective_time":"20230801","clinical_studies":["14 CLINICAL STUDIES 14.1 Rescue after High-Dose Methotrexate Therapy in Patients with Osteosarcoma The efficacy of levoleucovorin rescue following high-dose methotrexate was evaluated in 16 patients aged 6 to 21 years who received 58 courses of therapy for osteogenic sarcoma. High-dose methotrexate was one component of several different combination chemotherapy regimens evaluated across several trials. Methotrexate 12 grams/m 2 as an intravenous infusion over 4 hours was administered to 13 patients, who received levoleucovorin 7.5 mg by intravenous infusion every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate. Three patients received methotrexate 12.5 grams/m 2 intravenously over 6 hours, followed by levoleucovorin 7.5 mg by intravenous infusion every 3 hours for 18 doses beginning 12 hours after completion of methotrexate. The mean number of levoleucovorin doses per course was 18.2 and the mean total dose per course was 350 mg. The efficacy of levoleucovorin rescue following high-dose methotrexate was based on the adverse reaction profile [see Adverse Reactions ( 6.1 )]. 14.2 Metastatic Colorectal Cancer In a randomized clinical study conducted by Mayo Clinic and North Central Cancer Treatment Group (NCCTG) in patients with metastatic colorectal cancer comparing d,l -leucovorin 200 mg/m 2 and fluorouracil 370 mg/m 2 versus d,l -leucovorin 20 mg/m 2 and fluorouracil 425 mg/m 2 versus fluorouracil 500 mg/m 2 , with all drugs administered by intravenous infusion daily for 5 days every 28 to 35 days, response rates were 26% (p=0.04 versus fluorouracil alone), 43% (p=0.001 versus fluorouracil alone) and 10%, respectively. Respective median survival times were 12.2 months (p=0.037), 12 months (p=0.050), and 7.7 months. The low dose d,l -leucovorin regimen was associated with a statistically significant improvement in weight gain of more than 5%, relief of symptoms, and improvement in performance status. The high dose d,l -leucovorin regimen was associated with a statistically significant improvement in performance status and trended toward improvement in weight gain and in relief of symptoms but these were not statistically significant. In a second randomized clinical study conducted by Mayo Clinic and NCCTG, the fluorouracil alone arm was replaced by a regimen of sequentially administered methotrexate, fluorouracil, and d,l -leucovorin. Response rates with d,l -leucovorin 200 mg/m 2 and fluorouracil 370 mg/m 2 versus d,l -leucovorin 20 mg/m 2 and fluorouracil 425 mg/m 2 versus sequential methotrexate and fluorouracil and d,l -leucovorin were respectively 31% (p≤0.01), 42% (p≤0.01), and 14%. Respective median survival times were 12.7 months (p≤0.04), 12.7 months (p≤0.01), and 8.4 months. There was no statistically significant difference in weight gain of more than 5% or in improvement in performance status was seen between the treatment arms. A randomized controlled trial conducted by NCCTG in patients with metastatic colorectal cancer failed to show superiority of a regimen of fluorouracil + levoleucovorin to fluorouracil + d,l -leucovorin in overall survival. Patients were randomized to fluorouracil 370 mg/m 2 intravenously and levoleucovorin 100 mg/m 2 intravenously, both daily for 5 days, or to fluorouracil 370 mg/m 2 intravenously and d,l -leucovorin 200 mg/m 2 intravenously, both daily for 5 days. Treatment was repeated week 4 and week 8, and then every 5 weeks until disease progression or unacceptable toxicity."],"pharmacokinetics":["12.3 Pharmacokinetics The pharmacokinetics of levoleucovorin after intravenous administration of a 15 mg dose was studied in healthy subjects. The mean maximum serum total tetrahydrofolate (total-THF) concentrations was 1722 ng/mL (CV 39%) and the mean maximum serum (6S)-5-methyl-5,6,7,8-tetrahydrofolate concentrations was 275 ng/mL (CV 18%) observed around 0.9 hours post injection. Distribution Exploratory studies show that small quantities of systemically administered leucovorin enter the cerebrospinal fluid (CSF), primarily as its major metabolite 5-methyltetrahydrofolate (5-MTHFA). In humans, the CSF levels of 5-MTHFA remain 1-3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. Elimination The mean terminal half-life was 5.1 hours for total-THF and 6.8 hours for (6S)-5-methyl-5,6,7,8-tetrahydrofolate. Drug Interaction Studies The mean dose-normalized steady-state plasma concentrations for both levoleucovorin and 5-methyl-THF were comparable whether fluorouracil (370 mg/m 2 /day as an intravenous bolus) was given in combination with levoleucovorin (250 mg/m 2 and 1000 mg/m 2 as a continuous intravenous infusion for 5.5 days) or with d,l -leucovorin (500 mg/m 2 as a continuous intravenous infusion for 5.5 days)."],"adverse_reactions":["6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypercalcemia [see Warnings and Precautions ( 5.1 )] Increased gastrointestinal toxicities with fluorouracil [see Warnings and Precautions ( 5.2 )] The most common adverse reactions (≥20%) in patients receiving high-dose methotrexate therapy with levoleucovorin rescue are stomatitis and vomiting. ( 6.1 ) The most common adverse reactions (>50%) in patients receiving levoleucovorin in combination with fluorouracil for metastatic colorectal cancer are stomatitis, diarrhea, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals Inc. at 1-844-824-8426 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. High-Dose Methotrexate Therapy Table 2 presents the frequency of adverse reactions which occurred during the administration of 58 courses of high-dose methotrexate 12 grams/m 2 followed by levoleucovorin rescue for osteosarcoma in 16 patients aged 6 to 21 years. Most patients received levoleucovorin 7.5 mg every 6 hours for 60 hours or longer, beginning 24 hours after completion of methotrexate administration. Table 2 Adverse Reactions with High-Dose Methotrexate Therapy Adverse Reactions Levoleucovorin Injection n = 16 All Grades (%) Grades 3-4 (%) Gastrointestinal Stomatitis 38 6 Vomiting 38 0 Nausea 19 0 Diarrhea 6 0 Dyspepsia 6 0 Typhlitis 6 6 Respiratory Dyspnea 6 0 Skin and Appendages Dermatitis 6 0 Other Confusion 6 0 Neuropathy 6 0 Renal function abnormal 6 0 Taste perversion 6 0 Combination with Fluorouracil in Colorectal Cancer Table 3 presents the frequency of adverse reaction which occurred in 2 arms of a randomized controlled trial conducted by the North Central Cancer Treatment Group (NCCTG) in patients with metastatic colorectal cancer. The trial failed to show superior overall survival with fluorouracil + levoleucovorin compared to fluorouracil + d,l -leucovorin. Patients were randomized to fluorouracil 370 mg/m 2 intravenously and levoleucovorin 100 mg/m 2 intravenously, both daily for 5 days, or to fluorouracil 370 mg/m 2 intravenously and d,l -leucovorin 200 mg/m 2 intravenously, both daily for 5 days. Treatment was repeated week 4 and week 8, and then every 5 weeks until disease progression or unacceptable toxicity. Table 3 Adverse Reactions Occurring in ≥ 10% of Patients in Either Arm 1 Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness Adverse Reaction Levoleucovorin/fluorouracil n=318 d,l -Leucovorin/fluorouracil n=307 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Gastrointestinal Disorders Stomatitis 72 12 72 14 Diarrhea 70 19 65 17 Nausea 62 8 61 8 Vomiting 40 5 37 6 Abdominal Pain 1 14 3 19 3 General Disorders Asthenia/Fatigue/Malaise 29 5 32 11 Skin Disorders Dermatitis 29 1 28 1 Alopecia 26 0.3 28 1 Metabolism and Nutrition Anorexia/Decreased Appetite 24 4 25 2 6.2 Postmarketing Experience The following adverse reaction have been identified during postapproval use of levoleucovorin products. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Dermatologic: pruritus, rash Respiratory: dyspnea Other: temperature change, rigors, allergic reactions"],"contraindications":["4 CONTRAINDICATIONS Levoleucovorin is contraindicated in patients who have had severe hypersensitivity to leucovorin products, folic acid or folinic acid [see Adverse Reactions ( 6.2 )] . Patients who have had severe hypersensitivity reactions to leucovorin products, folic acid or folinic acid. ( 4 )"],"description_table":["
"],"drug_interactions":["7 DRUG INTERACTIONS 7.1 Effects of Leucovorin Products on Other Drugs Antiepileptic Drugs Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone and increase the frequency of seizures in susceptible children. It is not known whether folinic acid has the same effects; however, both folic and folinic acids share some common metabolic pathways. Monitor patients taking folinic acid in combination with antiepileptic drugs. Fluorouracil Leucovorin products increase the toxicity of fluorouracil. Do not initiate or continue therapy with levoleucovorin and fluorouracil in patients with symptoms of gastrointestinal toxicity until those symptoms have resolved. Monitor patients with diarrhea until the diarrhea has resolved, as rapid deterioration leading to death can occur [see Warnings and Precautions ( 5.2 )]. Trimethoprim-Sulfamethoxazole The concomitant use of d,l -leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis jiroveci pneumonia in patients with HIV infection was associated with increased rates of treatment failure and morbidity in a placebo-controlled study [see Warnings and Precautions ( 5.3 )] ."],"how_supplied_table":["
NDCLevoleucovorin Injection (10 mg per mL)Package Factor
71288-105-18175 mg per 17.5 mL Single-Dose Vial1 vial per carton
71288-105-25250 mg per 25 mL Single-Dose Vial1 vial per carton
"],"mechanism_of_action":["12.1 Mechanism of Action High-Dose Methotrexate Therapy Levoleucovorin is the pharmacologically active isomer of 5-formyl tetrahydrofolic acid. Levoleucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “one-carbon” moieties. Administration of levoleucovorin counteracts the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. Combination with Fluorouracil in Colorectal Cancer Levoleucovorin enhances the therapeutic and toxic effects of fluorouracil. Fluorouracil is metabolized to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which binds to and inhibits thymidylate synthase (an enzyme important in DNA repair and replication). Levoleucovorin is converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of FdUMP to thymidylate synthase and thereby enhancing the inhibition of thymidylate synthase."],"clinical_pharmacology":["12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action High-Dose Methotrexate Therapy Levoleucovorin is the pharmacologically active isomer of 5-formyl tetrahydrofolic acid. Levoleucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “one-carbon” moieties. Administration of levoleucovorin counteracts the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. Combination with Fluorouracil in Colorectal Cancer Levoleucovorin enhances the therapeutic and toxic effects of fluorouracil. Fluorouracil is metabolized to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which binds to and inhibits thymidylate synthase (an enzyme important in DNA repair and replication). Levoleucovorin is converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of FdUMP to thymidylate synthase and thereby enhancing the inhibition of thymidylate synthase. 12.3 Pharmacokinetics The pharmacokinetics of levoleucovorin after intravenous administration of a 15 mg dose was studied in healthy subjects. The mean maximum serum total tetrahydrofolate (total-THF) concentrations was 1722 ng/mL (CV 39%) and the mean maximum serum (6S)-5-methyl-5,6,7,8-tetrahydrofolate concentrations was 275 ng/mL (CV 18%) observed around 0.9 hours post injection. Distribution Exploratory studies show that small quantities of systemically administered leucovorin enter the cerebrospinal fluid (CSF), primarily as its major metabolite 5-methyltetrahydrofolate (5-MTHFA). In humans, the CSF levels of 5-MTHFA remain 1-3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. Elimination The mean terminal half-life was 5.1 hours for total-THF and 6.8 hours for (6S)-5-methyl-5,6,7,8-tetrahydrofolate. Drug Interaction Studies The mean dose-normalized steady-state plasma concentrations for both levoleucovorin and 5-methyl-THF were comparable whether fluorouracil (370 mg/m 2 /day as an intravenous bolus) was given in combination with levoleucovorin (250 mg/m 2 and 1000 mg/m 2 as a continuous intravenous infusion for 5.5 days) or with d,l -leucovorin (500 mg/m 2 as a continuous intravenous infusion for 5.5 days)."],"indications_and_usage":["1 INDICATIONS AND USAGE Levoleucovorin Injection is indicated for: rescue after high-dose methotrexate therapy in adult and pediatric patients with osteosarcoma. diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination in adult and pediatric patients. the treatment of adults with metastatic colorectal cancer in combination with fluorouracil. Limitations of Use Levoleucovorin Injection is not indicated for pernicious anemia and megaloblastic anemia secondary to the lack of vitamin B 12 , because of the risk of progression of neurologic manifestations despite hematologic remission. Levoleucovorin Injection is a folate analog indicated for: Rescue after high-dose methotrexate therapy in adult and pediatric patients with osteosarcoma. ( 1 ) Diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination in adult and pediatric patients. ( 1 ) Treatment of adults with metastatic colorectal cancer in combination with fluorouracil. ( 1 ) Limitations of Use Levoleucovorin Injection is not indicated for the treatment of pernicious anemia and megaloblastic anemia secondary to lack of vitamin B 12 , because of the risk of progression of neurologic manifestations despite hematologic remission. ( 1 )"],"warnings_and_cautions":["5 WARNINGS AND PRECAUTIONS Hypercalcemia: Due to calcium content, inject no more than 16 mL (160 mg) of levoleucovorin solution intravenously per minute. ( 5.1 ) Increased Gastrointestinal Toxicities with Fluorouracil : Do not initiate or continue therapy with levoleucovorin and fluorouracil in patients with symptoms of gastrointestinal toxicity until symptoms have resolved. Monitor patients with diarrhea until it has resolved as rapid deterioration leading to death can occur. ( 5.2 , 7 ) Drug Interaction with Trimethoprim-Sulfamethoxazole : Increased rates of treatment failure and morbidity with concomitant use of d,l- leucovorin with trimethoprim-sulfamethoxazole for Pneumocystis jiroveci pneumonia in patients with HIV. ( 5.3 ) 5.1 Hypercalcemia Because of the calcium content of the levoleucovorin solution, inject no more than 16 mL (160 mg of levoleucovorin) intravenously per minute. 5.2 Increased Gastrointestinal Toxicities with Fluorouracil Leucovorin products increase the toxicities of fluorouracil [see Drug Interactions ( 7 )] . Gastrointestinal toxicities, including stomatitis and diarrhea, occur more commonly and may be of greater severity and of prolonged duration. Deaths from severe enterocolitis, diarrhea, and dehydration have occurred in elderly patients receiving weekly d,l- leucovorin and fluorouracil. Monitor patients for gastrointestinal toxicities. Do not initiate or continue therapy with levoleucovorin and fluorouracil in patients with symptoms of gastrointestinal toxicity until those symptoms have resolved. Monitor patients with diarrhea until resolved, as rapid deterioration leading to death can occur. 5.3 Drug Interaction with Trimethoprim-Sulfamethoxazole The concomitant use of d,l- leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis jiroveci pneumonia in patients with HIV infection was associated with increased rates of treatment failure and morbidity [see Drug Interactions ( 7 )] ."],"nonclinical_toxicology":["13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been conducted to evaluate the potential of levoleucovorin for carcinogenesis, mutagenesis and impairment of fertility."],"adverse_reactions_table":["
Table 2 Adverse Reactions with High-Dose Methotrexate Therapy
Adverse ReactionsLevoleucovorin Injection n = 16
All Grades (%)Grades 3-4 (%)
Gastrointestinal
Stomatitis 38 6
Vomiting 38 0
Nausea 19 0
Diarrhea 6 0
Dyspepsia 6 0
Typhlitis 6 6
Respiratory
Dyspnea 6 0
Skin and Appendages
Dermatitis 6 0
Other
Confusion 6 0
Neuropathy 6 0
Renal function abnormal 6 0
Taste perversion 6 0
","
Table 3 Adverse Reactions Occurring in ≥ 10% of Patients in Either Arm
1Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness
Adverse Reaction Levoleucovorin/fluorouracil n=318d,l-Leucovorin/fluorouracil n=307
Grades 1-4 (%)Grades 3-4 (%)Grades 1-4 (%)Grades 3-4 (%)
Gastrointestinal Disorders
Stomatitis 72 12 72 14
Diarrhea 70 19 65 17
Nausea 62 8 61 8
Vomiting 40 5 37 6
Abdominal Pain114 3 19 3
General Disorders
Asthenia/Fatigue/Malaise 29 5 32 11
Skin Disorders
Dermatitis 29 1 28 1
Alopecia 26 0.3 28 1
Metabolism and Nutrition
Anorexia/Decreased Appetite 24 4 25 2
"],"dosage_and_administration":["2 DOSAGE AND ADMINISTRATION For intravenous administration only. Do not administer intrathecally. ( 2.1 ) Rescue After High-Dose Methotrexate Therapy Rescue recommendations are based on methotrexate dose of 12 grams/m 2 administered by intravenous infusion over 4 hours. Initiate rescue at a dose of 7.5 mg (approximately 5 mg/m 2 ) every 6 hours, 24 hours after the beginning of methotrexate infusion. ( 2.3 ) Continue until the methotrexate level is below 5 x 10 -8 M (0.05 micromolar). Adjust dose if necessary based on methotrexate elimination; refer to Full Prescribing Information. ( 2.3 ) Overdosage of Folic Acid Antagonists or Impaired Methotrexate Elimination Start as soon as possible after methotrexate overdosage or within 24 hours of delayed methotrexate elimination. ( 2.4 ) Administer levoleucovorin injection 7.5 mg (approximately 5 mg/m 2 ) intravenously every 6 hours until methotrexate level is less than 5 x 10 -8 M (0.05 micromolar). ( 2.4 ) Metastatic Colorectal Cancer in Combination with Fluorouracil The following regimens have been used for the treatment of colorectal cancer: Levoleucovorin injection 100 mg/m 2 by intravenous injection over a minimum of 3 minutes, followed by fluorouracil 370 mg/m 2 once daily for 5 consecutive days. ( 2.5 ) Levoleucovorin injection 10 mg/m 2 by intravenous injection followed by fluorouracil 425 mg/m 2 once daily for 5 consecutive days. ( 2.5 ) Administer fluorouracil and levoleucovorin injection separately to avoid the formation of precipitate. The above five-day courses may be repeated every 4 weeks for 2 courses, then every 4 to 5 weeks, if the patient has recovered from toxicity from the prior course. Do not adjust levoleucovorin injection dosage for toxicity. ( 2.5 ) 2.1 Important Use Information Levoleucovorin injection is indicated for intravenous administration only . Do not administer intrathecally . 2.2 Co-administration of Levoleucovorin Injection with Other Agents Due to the risk of precipitation, do not co-administer levoleucovorin injection with other agents in the same admixture. 2.3 Recommended Dosage for Rescue After High-Dose Methotrexate Therapy The recommended dosage for levoleucovorin injection is based on a methotrexate dose of 12 grams/m 2 administered by intravenous infusion over 4 hours. Twenty-four hours after starting the methotrexate infusion, initiate levoleucovorin injection at a dose of 7.5 mg (approximately 5 mg/m 2 ) as an intravenous infusion every 6 hours. Monitor serum creatinine and methotrexate levels at least once daily. Continue levoleucovorin injection administration, hydration, and urinary alkalinization (pH of 7 or greater) until the methotrexate level is below 5 x 10 -8 M (0.05 micromolar). Adjust the levoleucovorin injection dose or extend the duration as recommended in Table 1 . Table 1 Recommended Dosage for Levoleucovorin Injection based on Serum Methotrexate and Creatinine Levels * These patients are likely to develop reversible renal failure. In addition to appropriate levoleucovorin injection therapy, continue hydration and urinary alkalinization and monitor fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. Clinical Situation Laboratory Findings Recommendation Normal Methotrexate Elimination Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours. Administer 7.5 mg by intravenous infusion every 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion). Delayed Late Methotrexate Elimination Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration. Continue 7.5 mg by intravenous infusion every 6 hours until methotrexate level is less than 0.05 micromolar. Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury* Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration OR 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more). Administer 75 mg by intravenous infusion every 3 hours until methotrexate level is less than 1 micromolar; then 7.5 mg by intravenous infusion every 3 hours until methotrexate level is less than 0.05 micromolar. Impaired Methotrexate Elimination or Renal Impairment Decreased methotrexate elimination or renal impairment which are clinically important but less severe than the abnormalities described in Table 1 can occur following methotrexate administration. If toxicity associated with methotrexate is observed, in subsequent courses extend levoleucovorin injection rescue for an additional 24 hours (total of 14 doses over 84 hours). Third-Space Fluid Collection and Other Causes of Delayed Methotrexate Elimination Accumulation in a third space fluid collection (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration can delay methotrexate elimination. Under such circumstances, higher doses of levoleucovorin injection or prolonged administration may be indicated. 2.4 Recommended Dosage for Overdosage of Folic Acid Antagonists or Impaired Methotrexate Elimination Start levoleucovorin injection as soon as possible after an overdosage of methotrexate or within 24 hours of methotrexate administration when methotrexate elimination is impaired. As the time interval between methotrexate administration and levoleucovorin injection increases, the effectiveness of levoleucovorin injection to diminish methotrexate toxicity may decrease. Administer levoleucovorin injection 7.5 mg (approximately 5 mg/m 2 ) by intravenous infusion every 6 hours until the serum methotrexate level is less than 5 x 10 -8 M (0.05 micromolar). Monitor serum creatinine and methotrexate levels at least every 24 hours. Increase the dosage of levoleucovorin injection to 50 mg/m 2 intravenously every 3 hours and continue levoleucovorin injection at this dosage until the methotrexate level is less than 5 x 10 -8 M for the following: if serum creatinine at 24-hours increases 50% or more compared to baseline if the methotrexate level at 24-hours is greater than 5 x 10 -6 M if the methotrexate level at 48-hours is greater than 9 x 10 -7 M, Continue concomitant hydration (3 L per day) and urinary alkalinization with sodium bicarbonate. Adjust the sodium bicarbonate dose to maintain urine pH at 7 or greater. 2.5 Dosage in Combination with Fluorouracil for Metastatic Colorectal Cancer The following regimens have been used for the treatment of colorectal cancer: Levoleucovorin injection 100 mg/m 2 by intravenous injection over a minimum of 3 minutes, followed by fluorouracil at 370 mg/m 2 by intravenous injection, once daily for 5 consecutive days. Levoleucovorin injection 10 mg/m 2 by intravenous injection, followed by fluorouracil 425 mg/m 2 by intravenous injection, once daily for 5 consecutive days. Administer fluorouracil and levoleucovorin injection separately to avoid the formation of a precipitate. This five-day course may be repeated every 4 weeks for 2 courses, then every 4 to 5 weeks, if the patient has recovered from the toxicity from the prior course. Do not adjust levoleucovorin injection dosage for toxicity. Refer to fluorouracil prescribing information for information on fluorouracil dosage and dosage modifications for adverse reactions. 2.6 Preparation for Administration Levoleucovorin Injection Levoleucovorin contains no preservative. Observe strict aseptic technique during reconstitution of the drug product. Discard unused portion. Levoleucovorin solutions may be further diluted to concentrations of 0.5 mg per mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Do not store the product diluted using 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP for more than 4 hours at room temperature. Visually inspect the diluted solution for particulate matter and discoloration prior to administration. Do not use if cloudiness or precipitate is observed. Inject no more than 16 mL of levoleucovorin injection (160 mg of levoleucovorin) intravenously per minute, because of the calcium content of the levoleucovorin solution."],"spl_product_data_elements":["Levoleucovorin levoleucovorin calcium levoleucovorin calcium levoleucovorin sodium chloride water sodium hydroxide"],"dosage_forms_and_strengths":["3 DOSAGE FORMS AND STRENGTHS Injection: 175 mg per 17.5 mL (10 mg per mL) or 250 mg per 25 mL (10 mg per mL) of levoleucovorin sterile colorless to yellow, clear solution in a single-dose vial. Injection: 175 mg per 17.5 mL (10 mg per mL) or 250 mg per 25 mL (10 mg per mL) in a single-dose vial ( 3 )"],"use_in_specific_populations":["8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are limited data with levoleucovorin use in pregnant women. Animal reproduction studies have not been conducted with levoleucovorin. Levoleucovorin is administered in combination with methotrexate or fluorouracil, which can cause embryo-fetal harm. Refer to methotrexate and fluorouracil prescribing information for additional information. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 8.2 Lactation Risk Summary There are no data on the presence of levoleucovorin in human milk or its effects on the breastfed infant or on milk production. Levoleucovorin is administered in combination with methotrexate or fluorouracil. Refer to methotrexate and fluorouracil prescribing information for additional information. 8.4 Pediatric Use The safety and effectiveness of levoleucovorin have been established in pediatric patients for rescue after high-dose methotrexate therapy in osteosarcoma and diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination. Use of levoleucovorin in pediatric patients is supported by open-label clinical trial data in 16 pediatric patients 6 years of age and older, with additional supporting evidence from literature [see Clinical Studies ( 14.1 )]. The safety and effectiveness of levoleucovorin have not been established for the treatment of pediatric patients with advanced metastatic colorectal cancer. 8.5 Geriatric Use Clinical studies of levoleucovorin in the treatment of osteosarcoma did not include patients aged 65 and over to determine whether they respond differently from younger patients. In the NCCTG clinical trial of levoleucovorin in combination with fluorouracil for the treatment of metastatic colorectal cancer, no overall differences in safety or effectiveness were observed between patients age 65 years and older and younger patients."],"dosage_and_administration_table":["
Table 1 Recommended Dosage for Levoleucovorin Injection based on Serum Methotrexate and Creatinine Levels
* These patients are likely to develop reversible renal failure. In addition to appropriate levoleucovorin injection therapy, continue hydration and urinary alkalinization and monitor fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved.
Clinical SituationLaboratory FindingsRecommendation
Normal Methotrexate Elimination Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours. Administer 7.5 mg by intravenous infusion every 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion).
Delayed Late Methotrexate Elimination Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration. Continue 7.5 mg by intravenous infusion every 6 hours until methotrexate level is less than 0.05 micromolar.
Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury* Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration OR 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more). Administer 75 mg by intravenous infusion every 3 hours until methotrexate level is less than 1 micromolar; then 7.5 mg by intravenous infusion every 3 hours until methotrexate level is less than 0.05 micromolar.
"],"package_label_principal_display_panel":["PRINCIPAL DISPLAY PANEL – Levoleucovorin Injection, USP 175 mg per 17.5 mL Vial Label NDC 71288- 105 -18 Rx only Levoleucovorin Injection 175 mg per 17.5 mL (10 mg per mL) present as levoleucovorin calcium 17.5 mL Single-Dose Vial Discard unused portion For Intravenous Use PRINCIPAL DISPLAY PANEL – Levoleucovorin Injection, USP 175 mg per 17.5 mL Vial Label","PRINCIPAL DISPLAY PANEL – Levoleucovorin Injection, USP 175 mg per 17.5 mL Carton NDC 71288- 105 -18 Levoleucovorin Injection 175 mg per 17.5 mL (10 mg per mL) present as levoleucovorin calcium 1 x 17.5 mL Single-Dose Vial Discard unused portion For Intravenous Use PRINCIPAL DISPLAY PANEL – Levoleucovorin Injection, USP 175 mg per 17.5 mL Carton","PRINCIPAL DISPLAY PANEL – Levoleucovorin Injection, USP 250 mg per 25 mL Vial Label NDC 71288- 105 -25 Rx only Levoleucovorin Injection 250 mg per 25 mL (10 mg per mL) present as levoleucovorin calcium 25 mL Single-Dose Vial Discard unused portion For Intravenous Use PRINCIPAL DISPLAY PANEL – Levoleucovorin Injection, USP 250 mg per 25 mL Vial Label","PRINCIPAL DISPLAY PANEL – Levoleucovorin Injection, USP 250 mg per 25 mL Carton NDC 71288- 105 -25 Levoleucovorin Injection 250 mg per 25 mL (10 mg per mL) present as levoleucovorin calcium 1 x 25 mL Single-Dose Vial Discard unused portion For Intravenous Use PRINCIPAL DISPLAY PANEL – Levoleucovorin Injection, USP 250 mg per 25 mL Carton"],"carcinogenesis_and_mutagenesis_and_impairment_of_fertility":["13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been conducted to evaluate the potential of levoleucovorin for carcinogenesis, mutagenesis and impairment of fertility."]},"tags":[{"label":"Folate Analog","category":"class"},{"label":"Small Molecule","category":"modality"},{"label":"V03AF04","category":"atc"},{"label":"Oral","category":"route"},{"label":"Intravenous","category":"route"},{"label":"Capsule","category":"form"},{"label":"Injection","category":"form"},{"label":"Active","category":"status"},{"label":"Adjunct to Fluorouracil Treatment of Colorectal Cancer","category":"indication"},{"label":"Bone Marrow Suppression due to Folic Acid Antagonism","category":"indication"},{"label":"Folic acid deficiency","category":"indication"},{"label":"Malignant tumor of stomach","category":"indication"},{"label":"Megaloblastic anemia","category":"indication"},{"label":"Methotrexate Toxicity","category":"indication"},{"label":"Acrotech Biopharma","category":"company"},{"label":"Approved 2000s","category":"decade"},{"label":"Antidotes","category":"pharmacology"},{"label":"Protective Agents","category":"pharmacology"}],"phase":"marketed","safety":{"boxedWarnings":[],"safetySignals":[{"date":"","signal":"OFF LABEL USE","source":"FDA FAERS","actionTaken":"265 reports"},{"date":"","signal":"NAUSEA","source":"FDA FAERS","actionTaken":"260 reports"},{"date":"","signal":"NEUTROPENIA","source":"FDA FAERS","actionTaken":"239 reports"},{"date":"","signal":"DIARRHOEA","source":"FDA FAERS","actionTaken":"237 reports"},{"date":"","signal":"DECREASED APPETITE","source":"FDA FAERS","actionTaken":"177 reports"},{"date":"","signal":"VOMITING","source":"FDA FAERS","actionTaken":"157 reports"},{"date":"","signal":"NEUROPATHY PERIPHERAL","source":"FDA FAERS","actionTaken":"147 reports"},{"date":"","signal":"MALIGNANT NEOPLASM PROGRESSION","source":"FDA FAERS","actionTaken":"143 reports"},{"date":"","signal":"PYREXIA","source":"FDA FAERS","actionTaken":"135 reports"},{"date":"","signal":"ASTHENIA","source":"FDA FAERS","actionTaken":"126 reports"}],"commonSideEffects":[{"effect":"Diarrhea","drugRate":"≥20%","severity":"common","_validated":true},{"effect":"Polycythemia vera","drugRate":"≥20%","severity":"serious","_validated":true},{"effect":"Itching","drugRate":"≥20%","severity":"common","_validated":true},{"effect":"Transitory exanthema","drugRate":"≥20%","severity":"common","_validated":true},{"effect":"Feeling of swelling of entire body","drugRate":"≥20%","severity":"common","_validated":true}],"specialPopulations":{"Lactation":"There are no data on the presence of levoleucovorin in human milk or its effects on the breastfed infant or on milk production. Levoleucovorin is administered in combination with methotrexate or fluorouracil. Refer to methotrexate and fluorouracil prescribing information for additional information.","Pregnancy":"There are limited data with levoleucovorin use in pregnant women. Animal reproduction studies have not been conducted with levoleucovorin. Levoleucovorin is administered in combination with methotrexate or fluorouracil, which can cause embryo-fetal harm. Refer to methotrexate and fluorouracil prescribing information for additional information. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.","Geriatric use":"Clinical studies of levoleucovorin injection in the treatment of osteosarcoma did not include subjects aged 65 and over to determine whether they respond differently from younger subjects. In the NCCTG clinical trial of levoleucovorin injection in combination with 5-FU in advanced colorectal cancer, adverse reactions were consistent with 5-FU related toxicity and were similar for patients age 65 and older and for patients younger than age 65.","Paediatric use":"The safety and effectiveness of levoleucovorin have been established in pediatric patients for rescue after high-dose methotrexate therapy in osteosarcoma and diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination. Use of levoleucovorin in pediatric patients is supported by open-label clinical trial data in 16 pediatric patients years of age and older, with additional supporting evidence from literature [see Clinical Studies 14.1)]. The safety and effectiveness of levoleucovorin have not been established for pediatric patients younger than 2 years of age."}},"trials":[],"aliases":[],"company":"Acrotech Biopharma","patents":[{"applNo":"N211226","source":"FDA Orange Book","status":"Active","expires":"Mar 25, 2039","useCode":"","territory":"US","drugProduct":true,"patentNumber":"11541012","drugSubstance":false}],"pricing":[],"_sources":{"trials":{"url":"https://clinicaltrials.gov/search?intr=levoleucovorin","method":"api_direct","source":"ClinicalTrials.gov","rawText":"","confidence":1,"sourceType":"ctgov","retrievedAt":"2026-04-19T23:43:10.306213+00:00"},"patents":{"url":"","method":"deterministic","source":"FDA Orange Book","rawText":"","confidence":1,"sourceType":"fda_orange_book","retrievedAt":"2026-04-19T23:43:10.304167+00:00"},"timeline":{"url":"https://en.wikipedia.org/wiki/Levoleucovorin","method":"deterministic","source":"Wikipedia","rawText":"","confidence":0.8,"sourceType":"wikipedia","retrievedAt":"2026-04-19T23:43:18.549489+00:00"},"regulatory.ca":{"url":"","method":"api_direct","source":"Health Canada DPD","rawText":"","confidence":1,"sourceType":"health_canada_dpd","retrievedAt":"2026-04-19T23:43:17.190941+00:00"},"regulatory.us":{"url":"","method":"api_direct","source":"FDA Drugs@FDA","rawText":"","confidence":1,"sourceType":"fda_drugsfda","retrievedAt":"2026-04-19T23:43:08.882270+00:00"},"publicationCount":{"url":"https://pubmed.ncbi.nlm.nih.gov/?term=levoleucovorin","method":"api_direct","source":"PubMed/NCBI","rawText":"","confidence":1,"sourceType":"pubmed","retrievedAt":"2026-04-19T23:43:17.977627+00:00"},"administration.route":{"url":"","method":"deterministic","source":"FDA Label","rawText":"","confidence":1,"sourceType":"fda_label","retrievedAt":"2026-04-19T23:43:07.683743+00:00"},"safety.boxedWarnings":{"url":"","method":"deterministic","source":"FDA Label (no boxed warning)","rawText":"","confidence":1,"sourceType":"fda_label","retrievedAt":"2026-04-19T23:43:07.683799+00:00"},"safety.safetySignals":{"url":"https://api.fda.gov/drug/event.json","method":"api_direct","source":"FDA FAERS","rawText":"","confidence":1,"sourceType":"fda_faers","retrievedAt":"2026-04-19T23:43:19.430680+00:00"},"crossReferences.chemblId":{"url":"https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL1908841/","method":"api_direct","source":"ChEMBL (EMBL-EBI)","rawText":"","confidence":1,"sourceType":"chembl","retrievedAt":"2026-04-19T23:43:18.448562+00:00"},"regulatory.fda_application":{"url":"","method":"deterministic","source":"FDA Label","rawText":"ANDA211002","confidence":1,"sourceType":"fda_label","retrievedAt":"2026-04-19T23:43:07.683811+00:00"}},"allNames":"fusilev","offLabel":[],"synonyms":["levoleucovorin calcium pentahydrate","levoleucovorin","calcium levofolinate","levoleucovorin calcium","levofolene","L-Folinic acid","levofolinic acid","sodium levofolinate","calcium levofolinate hydrate"],"timeline":[{"date":"2008-01-01","type":"neutral","source":"FDA Orange Book","milestone":"Rights transferred from SPECTRUM PHARMS to Acrotech Biopharma"},{"date":"2008-03-07","type":"positive","source":"DrugCentral","milestone":"FDA approval (Spectrum Pharms)"},{"date":"2018-09-21","type":"positive","source":"DrugCentral","milestone":"PMDA approval (Pfizer Japan Inc.)"}],"aiSummary":"Fusilev (levoleucovorin) is a folate analog small molecule developed by Spectrum Pharmaceuticals and currently owned by Acrotech Biopharma. It is FDA-approved since 2008 for various indications, including colorectal cancer, bone marrow suppression, and methotrexate toxicity. Fusilev works by bypassing the enzyme dihydrofolate reductase, which is inhibited by methotrexate, allowing normal cell growth and DNA synthesis. The commercial status of Fusilev is patented, with no generic manufacturers available. Key safety considerations include monitoring for bone marrow suppression and gastrointestinal toxicity.","brandName":"Fusilev","ecosystem":[{"indication":"Adjunct to Fluorouracil Treatment of Colorectal Cancer","otherDrugs":[{"name":"leucovorin","slug":"leucovorin","company":""}],"globalPrevalence":1900000},{"indication":"Bone Marrow Suppression due to Folic Acid Antagonism","otherDrugs":[{"name":"leucovorin","slug":"leucovorin","company":""}],"globalPrevalence":null},{"indication":"Folic acid deficiency","otherDrugs":[{"name":"folic acid","slug":"folic-acid","company":"Lederle"},{"name":"leucovorin","slug":"leucovorin","company":""}],"globalPrevalence":null},{"indication":"Malignant tumor of stomach","otherDrugs":[{"name":"capecitabine","slug":"capecitabine","company":"Hoffmann La Roche"},{"name":"docetaxel","slug":"docetaxel","company":"Sanofi Aventis Us"},{"name":"fluorouracil","slug":"fluorouracil","company":"Spectrum Pharms"},{"name":"nivolumab","slug":"nivolumab","company":"Bristol Myers Squibb"}],"globalPrevalence":null},{"indication":"Megaloblastic anemia","otherDrugs":[{"name":"leucovorin","slug":"leucovorin","company":""}],"globalPrevalence":null},{"indication":"Methotrexate Toxicity","otherDrugs":[{"name":"leucovorin","slug":"leucovorin","company":""}],"globalPrevalence":240000},{"indication":"Pyrimethamine Toxicity","otherDrugs":[{"name":"leucovorin","slug":"leucovorin","company":""}],"globalPrevalence":null},{"indication":"Small intestine cancer","otherDrugs":[{"name":"fluorouracil","slug":"fluorouracil","company":"Spectrum Pharms"},{"name":"oxaliplatin","slug":"oxaliplatin","company":""}],"globalPrevalence":null}],"mechanism":{"novelty":"Follow-on","modality":"Small Molecule","drugClass":"Folate Analog","explanation":"MECHANISM OF ACTION. COBALAMIN [treatment]; FOLATE [prevention]; INTRINSIC FACTOR [facilitator] -Cobalamin is essential for the synthesis of methionine from homocysteine a reaction which also requires folate. In the absence of cobalamin ie, cobalamin deficiency, tetrahydrofolate cannot be regenerated from l-methylfolic acid, and functional folate deficiency occurs ie, methyl trap hypothesis. Gastrointestinal absorption of cobalamin depends on the presence of sufficient intrinsic factor, and lack of intrinisic factor results in cobalamin deficiency.","oneSentence":"Fusilev works by bypassing the enzyme dihydrofolate reductase, allowing normal cell growth and DNA synthesis.","technicalDetail":"Fusilev (levoleucovorin) acts as a rescue agent by bypassing the enzyme dihydrofolate reductase (DHFR), which is inhibited by methotrexate, thereby allowing normal cell growth and DNA synthesis to occur."},"_wikipedia":{"url":"https://en.wikipedia.org/wiki/Folinic_acid","title":"Folinic acid","extract":"Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, and may be used to treat folate deficiency, anemia, and methanol poisoning. It is taken by mouth, injection into a muscle, or injection into a vein.","wiki_history":"== History ==\nFolinic acid was discovered as a needed growth factor for the bacterium Leuconostoc citrovorum in 1948, by Sauberlich and Baumann. This resulted in it being called \"citrovorum factor\", meaning citrovorum growth factor. It had an unknown structure, but was found to be a folate derivative that had to be metabolized in the liver before it could support the growth of L. citrovorum. The synthesis of citrovorum factor by liver cells in culture was eventually accomplished from pteroylglutamic acid in the presence of suitable concentrations of ascorbic acid. The simultaneous addition of sodium formate to such systems increased citrovorum factor activity in the cell-free supernatants (producing, as is now known, the 5-formyl derivative). From this method of preparation of large amounts of the factor, its structure as levo-folinic acid (5-formyl tetrahydrofolic acid) was eventually deduced.\n\nIn September 2025, the US Food and Drug Administration (FDA) initiated the process of approving leucovorin calcium tablets for the treatment of cerebral folate deficiency, a condition associated with developmental delays, autistic features, seizures, and movement issues. \n\nOn 10 March 2026, the FDA approved leucovorin tablets for FOLR1-related cerebral folate transport deficiency in children and adults.","wiki_society_and_culture":"== Society and culture ==\n=== Names ===\n\nFolinic acid should be distinguished from folic acid (vitamin B9). However, folinic acid is a vitamer of folic acid and has the full vitamin activity of this vitamin. Levofolinic acid and its salts are the 2S-form of the molecule. They are the only forms of the molecule that are known to be biologically active.\n\nIt is generally administered as the calcium or sodium salt (calcium folinate [INN], sodium folinate, leucovorin calcium, leucovorin sodium)."},"commercial":{"launchDate":"2008","_launchSource":"DrugCentral (FDA 2008-03-07, SPECTRUM PHARMS)"},"references":[{"id":1,"url":"https://drugcentral.org/drugcard/4384","fields":["approvals","synonyms","ATC","PK","indications","contraindications","DDIs","targets","patents","FAERS"],"source":"DrugCentral"},{"id":2,"url":"https://clinicaltrials.gov/search?intr=levoleucovorin","fields":["trials"],"source":"ClinicalTrials.gov"},{"id":3,"url":"https://pubmed.ncbi.nlm.nih.gov/?term=levoleucovorin","fields":["publications"],"source":"PubMed/NCBI"},{"id":4,"url":"https://en.wikipedia.org/wiki/Folinic_acid","fields":["history","overview"],"source":"Wikipedia"},{"id":5,"url":"https://www.fda.gov/drugs/drug-approvals-and-databases/orange-book-data-files","fields":["patents","exclusivity","genericManufacturers"],"source":"FDA Orange Book"}],"_enrichedAt":"2026-03-30T02:15:48.331245","_validation":{"fieldsValidated":0,"lastValidatedAt":"2026-04-19T23:43:24.755148+00:00","fieldsConflicting":0,"overallConfidence":0.95},"biosimilars":[],"competitors":[{"drugName":"mesna","drugSlug":"mesna","fdaApproval":"1988-12-30","genericCount":9,"patentStatus":"Off-patent — generic available","relationship":"same-class"},{"drugName":"dexrazoxane","drugSlug":"dexrazoxane","fdaApproval":"1995-05-26","genericCount":4,"patentStatus":"Off-patent — generic available","relationship":"same-class"},{"drugName":"leucovorin","drugSlug":"leucovorin","fdaApproval":"1952-06-20","patentExpiry":"Dec 23, 2044","patentStatus":"Patent protected","relationship":"same-class"},{"drugName":"amifostine","drugSlug":"amifostine","fdaApproval":"1995-12-08","genericCount":2,"patentStatus":"Off-patent — generic available","relationship":"same-class"},{"drugName":"rasburicase","drugSlug":"rasburicase","fdaApproval":"2002-07-12","relationship":"same-class"},{"drugName":"palifermin","drugSlug":"palifermin","fdaApproval":"2004-12-15","relationship":"same-class"},{"drugName":"glucarpidase","drugSlug":"glucarpidase","fdaApproval":"2012-01-17","relationship":"same-class"},{"drugName":"arginine","drugSlug":"arginine","fdaApproval":"1973-02-28","patentStatus":"Unknown","relationship":"same-class"},{"drugName":"lysine","drugSlug":"lysine","fdaApproval":"","relationship":"same-class"},{"drugName":"trilaciclib","drugSlug":"trilaciclib","fdaApproval":"2021-02-12","patentExpiry":"Oct 25, 2031","patentStatus":"Patent protected","relationship":"same-class"}],"genericName":"levoleucovorin","indications":{"approved":[{"name":"Adjunct to Fluorouracil Treatment of Colorectal Cancer","source":"DrugCentral","snomedId":"","regulator":"FDA","eligibility":null,"usPrevalence":153000,"globalPrevalence":1900000,"prevalenceMethod":"curated","prevalenceSource":"IARC GLOBOCAN, 2022"},{"name":"Bone Marrow Suppression due to Folic Acid Antagonism","source":"DrugCentral","snomedId":"","regulator":"FDA","eligibility":null},{"name":"Folic acid deficiency","source":"DrugCentral","snomedId":190633005,"regulator":"FDA","eligibility":null},{"name":"Malignant tumor of stomach","source":"DrugCentral","snomedId":363349007,"regulator":"FDA","eligibility":null},{"name":"Megaloblastic anemia","source":"DrugCentral","snomedId":53165003,"regulator":"FDA","eligibility":{"1. Malabsorption of cobalamin":{"due to damage to the ileum":"increased intrinsic factor desired","due to structural or functional damage to the stomach":"increased intrinsic factor desired"},"2. Genetic polymorphisms such as MTHFR":"impede folate metabolism and synthetic folic acid use","3. Inadequate secretion of intrinsic factor":"gastric mucosa lesions, corrosives, extensive neoplasia, endocrine disorders, iron deficiency, subtotal gastrectomy"}},{"name":"Methotrexate Toxicity","source":"DrugCentral","snomedId":"","regulator":"FDA","eligibility":null,"prevalenceClass":"1-9 / 100 000","globalPrevalence":240000,"prevalenceMethod":"orphanet","prevalenceSource":"Orphanet (European Medicines Agency 2015[INST])"},{"name":"Pyrimethamine Toxicity","source":"DrugCentral","snomedId":"","regulator":"FDA","eligibility":null},{"name":"Small intestine cancer","source":"DrugCentral","snomedId":363509000,"regulator":"FDA","eligibility":null},{"name":"Sulfadiazine Toxicity","source":"DrugCentral","snomedId":"","regulator":"FDA","eligibility":null},{"name":"Trimethoprim Toxicity","source":"DrugCentral","snomedId":"","regulator":"FDA","eligibility":null},{"name":"Trimetrexate Toxicity","source":"DrugCentral","snomedId":"","regulator":"FDA"}],"offLabel":[],"pipeline":[]},"currentOwner":"Acrotech Biopharma","drugCategory":"active","labelChanges":[],"relatedDrugs":[{"drugId":"mesna","brandName":"mesna","genericName":"mesna","approvalYear":"1988","relationship":"same-class"},{"drugId":"dexrazoxane","brandName":"dexrazoxane","genericName":"dexrazoxane","approvalYear":"1995","relationship":"same-class"},{"drugId":"leucovorin","brandName":"leucovorin","genericName":"leucovorin","approvalYear":"1952","relationship":"same-class"},{"drugId":"amifostine","brandName":"amifostine","genericName":"amifostine","approvalYear":"1995","relationship":"same-class"},{"drugId":"rasburicase","brandName":"rasburicase","genericName":"rasburicase","approvalYear":"2002","relationship":"same-class"},{"drugId":"palifermin","brandName":"palifermin","genericName":"palifermin","approvalYear":"2004","relationship":"same-class"},{"drugId":"glucarpidase","brandName":"glucarpidase","genericName":"glucarpidase","approvalYear":"2012","relationship":"same-class"},{"drugId":"arginine","brandName":"arginine","genericName":"arginine","approvalYear":"1973","relationship":"same-class"},{"drugId":"lysine","brandName":"lysine","genericName":"lysine","approvalYear":"","relationship":"same-class"},{"drugId":"trilaciclib","brandName":"trilaciclib","genericName":"trilaciclib","approvalYear":"2021","relationship":"same-class"}],"trialDetails":[{"nctId":"NCT06317662","phase":"PHASE2","title":"Testing 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