Overview
Folinic Acid (also known as 5-formyl tetrahydrofolic acid or leucovorin) is the 5-formyl derivative of tetrahydrofolic acid, a necessary co-factor in the body. Commercially available leucovorin is composed of a 1:1 racemic mixture of the dextrorotary and levorotary isomers, while levoleucovorin contains only the pharmacologically active levo-isomer. In vitro, the levo-isomer has been shown to be rapidly converted to the biologically available methyl-tetrahydrofolate form while the dextro form is slowly excreted by the kidneys. Despite this difference in activity, the two commercially available forms have been shown to be pharmacokinetically identical and may be used interchangeably with limited differences in efficacy or side effects (Kovoor et al, 2009). As folate analogs, leucovorin and levoleucovorin are both used to counteract the toxic effects of folic acid antagonists, such as methotrexate, which act by inhibiting the enzyme dihydrofolate reductase (DHFR). They are indicated for use as rescue therapy following use of high-dose methotrexate in the treatment of osteosarcoma or for diminishing the toxicity associated with inadvertent overdosage of folic acid antagonists. Injectable forms are also indicated for use in the treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible and for use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer. Folic acid is an essential B vitamin required by the body for the synthesis of purines, pyrimidines, and methionine before incorporation into DNA or protein. However, in order to function in this role, it must first be reduced by the enzyme dihydrofolate reductase (DHFR) into the cofactors dihydrofolate (DHF) and tetrahydrofolate (THF). This important pathway, which is required for de novo synthesis of nucleic acids and amino acids, is disrupted when high-dose methotrexate is used for cancer therapy. As methotrexate functions as a DHFR inhibitor to prevent DNA synthesis in rapidly dividing cells, it also prevents the formation of DHF and THF. This results in a deficiency of coenzymes and a resultant buildup of toxic substances that are responsible for numerous adverse side effects associated with methotrexate therapy. As levoleucovorin and leucovorin are analogs of tetrahydrofolate (THF), they are able to bypass DHFR reduction and act as a cellular replacement for the co-factor THF, thereby preventing these toxic side effects.
Indication
For the treatment of osteosarcoma (after high dose methotrexate therapy). Used to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists, and to treat megaloblastic anemias due to folic acid deficiency. Also used in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer.
Associated Conditions
- Advanced Colorectal Cancer
- Advanced Esophageal Cancers
- Anemia of Pregnancy
- Bladder Cancer
- Folate and iron deficiency
- Folate deficiency
- Folic acid antagonist overdose
- Iron Deficiency (ID)
- Macrocytic anemia
- Megaloblastic anemia
- Pancreatic Metastatic Cancer
- Postpartum Anemia
- Stage IV Gastric Cancer
- Hypochromic anemia
- Methotrexate toxicity
- Normochromic anemia
- Pyrimethamine hematologic toxicity
Research Report
A Comprehensive Monograph on Leucovorin (Folinic Acid): From Molecular Mechanisms to Clinical Practice
1.0 Drug Identification and Chemical Profile
1.1 Overview: A Dual-Role Folate Analog in Therapeutics
Leucovorin, known interchangeably as folinic acid, is a chemically reduced derivative of folic acid that occupies a unique and critical position in modern pharmacotherapy.[1] Its clinical utility is defined by two distinct and seemingly contradictory pharmacological roles. Primarily, it functions as a "rescue" agent, or antidote, administered to mitigate the severe, dose-limiting toxicities of folic acid antagonists, most notably the chemotherapeutic agent methotrexate.[1] In this capacity, it selectively protects healthy host cells from cytotoxic damage. Conversely, Leucovorin also serves as a chemopotentiator, purposefully administered to enhance the cytotoxic efficacy of fluoropyrimidine-based chemotherapy, such as 5-fluorouracil (5-FU), particularly in the treatment of colorectal cancer.[1] This monograph is structured around this central duality, exploring the molecular basis and clinical implications of these opposing functions.
The drug's history dates back to its 1948 discovery as an essential growth cofactor for the bacterium Leuconostoc citrovorum, leading to its original name, "citrovorum factor".[1] With a long history of clinical use, it received its initial approval from the U.S. Food and Drug Administration (FDA) in 1952, underscoring its enduring importance in medicine.[6]
1.2 Chemical Identity and Physicochemical Properties
Leucovorin is classified as a small molecule folate analog.[2] Its precise chemical identity and properties are fundamental to its biological activity.
Clinical Trials
Title | Posted | Study ID | Phase | Status | Sponsor |
---|---|---|---|---|---|
2025/07/31 | Not Applicable | Not yet recruiting | |||
2025/07/31 | Not Applicable | Not yet recruiting | |||
2025/07/22 | Not Applicable | Not yet recruiting | |||
2025/07/17 | Not Applicable | Not yet recruiting | |||
2025/06/29 | Not Applicable | Not yet recruiting | |||
2025/06/19 | Phase 2 | Not yet recruiting | GERCOR - Multidisciplinary Oncology Cooperative Group | ||
2025/06/17 | Phase 1 | Recruiting | |||
2025/05/31 | Phase 3 | Not yet recruiting | |||
2025/05/06 | Phase 3 | Not yet recruiting | |||
2025/04/30 | Phase 3 | Not yet recruiting |
FDA Drug Approvals
Approved Product | Manufacturer | NDC Code | Route | Strength | Effective Date |
---|---|---|---|---|---|
Slate Run Pharmaceuticals, LLC | 70436-120 | INTRAVENOUS, INTRAMUSCULAR | 500 mg in 1 1 | 7/18/2023 | |
Sagent Pharmaceuticals | 25021-813 | INTRAVENOUS, INTRAMUSCULAR | 50 mg in 5 mL | 11/9/2022 | |
Sagent Pharmaceuticals | 25021-815 | INTRAVENOUS, INTRAMUSCULAR | 200 mg in 20 mL | 11/9/2022 | |
South Coast Specialty Compounding, Inc. d/b/a Park Compounding | 70260-430 | ORAL | 2.5 mg in 1 1 | 11/25/2015 | |
Leading Pharma, LLC | 69315-186 | ORAL | 15 mg in 1 1 | 9/11/2023 | |
Jaymac Pharma | 64661-650 | ORAL | 2.5 mg in 1 1 | 6/9/2019 | |
Sagent Pharmaceuticals | 25021-816 | INTRAVENOUS, INTRAMUSCULAR | 350 mg in 17.5 mL | 11/9/2022 | |
Ingenus Pharmaceuticals, LLC | 50742-181 | ORAL | 5 mg in 1 1 | 8/7/2020 | |
Slate Run Pharmaceuticals, LLC | 70436-116 | INTRAVENOUS, INTRAMUSCULAR | 50 mg in 1 1 | 7/18/2023 | |
Hikma Pharmaceuticals USA Inc. | 0054-4499 | ORAL | 25 mg in 1 1 | 12/14/2023 |
EMA Drug Approvals
Approved Product | Authorization Holder | Status | Issued Date |
---|---|---|---|
No EMA approvals found for this drug. |
HSA Drug Approvals
Approved Product | Manufacturer | Approval Number | Dosage Form | Strength | Approval Date |
---|---|---|---|---|---|
NYRIN INJECTION 50 mg/5 ml | SIN11058P | INJECTION | 50 mg/5 ml | 8/3/1999 | |
NYRIN INJ. 15 mg/ml | SIN10318P | INJECTION | 15 mg/ml | 10/29/1998 | |
NYRIN INJECTION 3 mg/ml | SIN11059P | INJECTION | 3 mg/ml | 8/3/1999 | |
CALCIUM FOLINATE INJECTION 10 mg/ml | SIN07916P | INJECTION | 10 mg/ml | 11/15/1994 | |
NYRIN TABLET 15 mg | SIN10357P | TABLET | 15 mg | 11/3/1998 |
NMPA Drug Approvals
Approved Product | Company | Approval Number | Drug Type | Dosage Form | Approval Date |
---|---|---|---|---|---|
No NMPA approvals found for this drug. |
PPB Drug Approvals
Approved Product | Registration No. | Company | Licence No. | Strength | Registration Date |
---|---|---|---|---|---|
No PPB approvals found for this drug. |
TGA Drug Approvals
Approved Product | ARTG ID | Sponsor | Registration Type | Status | Registration Date |
---|---|---|---|---|---|
No TGA approvals found for this drug. |
Health Canada Drug Approvals
Approved Product | Company | DIN | Dosage Form | Strength | Market Date |
---|---|---|---|---|---|
No Health Canada approvals found for this drug. |
CIMA AEMPS Drug Approvals
Approved Product | Company | Registration Number | Pharmaceutical Form | Prescription Type | Status |
---|---|---|---|---|---|
No CIMA AEMPS (Spain) approvals found for this drug. |
Philippines FDA Drug Approvals
Approved Product | Company | License Number | Dosage Form | Strength | Approval Date |
---|---|---|---|---|---|
No Philippines FDA approvals found for this drug. |
Saudi SFDA Drug Approvals
Approved Product | Company | License Number | Dosage Form | Strength | Approval Date |
---|---|---|---|---|---|
No Saudi SFDA approvals found for this drug. |
Malaysia NPRA Drug Approvals
Approved Product | Company | Registration Number | Dosage Form | Strength | Approval Date |
---|---|---|---|---|---|
No Malaysia NPRA approvals found for this drug. |
UK EMC Drug Information
Medicine Name | MA Holder | MA Number | Pharmaceutical Form | Active Ingredient | Authorization Date |
---|---|---|---|---|---|
No UK EMC drug information found for this drug. |
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