Folinic Acid (Leucovorin / Citrovorum Factor)
1. Identity: Chemical Names, Structure, Natural Sources, and Common Forms
1.1 Names and Synonyms
Folinic acid, also known as 5-formyl tetrahydrofolic acid or leucovorin, treats various cancers when employed with 5-fluorouracil (5-FU). Also known as Citrovorum factor or 5-formyl-5,6,7,8-tetrahydrofolic acid, this compound has the chemical designation of Calcium N-[p-[[[(6RS)-2-amino-5-formyl-5,6,7,8-tetrahydro-4-hydroxy-6-pteridinyl]methyl]amino]benzoyl]-L-glutamate (1:1) when formulated as the calcium salt. Trade names include CalciumLeucovorin, Folinic Acid, Citrovorum Factor, Calcium Folinate, NSC-3590, Leucosar, Rescufolin, Rescuvolin, and Wellcovorin.
1.2 Chemical Structure and Stereochemistry
The chemical formula of folinic acid is C₂₀H₂₃N₇O₇. The 5-formyl-THF, which is resistant to oxidation, is used in pharmaceutical preparations; it is called folinic acid. Folinic acid contains two centers of asymmetry. Because folinic acid is synthesized from folic acid, N-(pteroyl)-L-glutamic acid, the optically active carbon atom contained in the glutamic acid residue is in the L form, whereas the optically active carbon atom at position 6, which has been produced by hydrogenation of the double bond in the 5,6-position of the pteroyl radical, is in the racemic (6R,S) form. Synthetic folinic acid (leucovorin) accordingly consists of a 1:1 mixture of two diastereomers. The naturally occurring folinic acid, for example in the liver, is solely in the (6S) form as 5-CHO-(6S)-THF. d,l-leucovorin consists of two diastereomers designated as d-leucovorin and l-leucovorin. l-Leucovorin (5-formyl-(6S)-tetrahydrofolate) is the biologically active isomer.
1.3 Relationship to the Folate Family
Folinic acid is a form of folate, an essential vitamin commonly known as vitamin B9. Folate is a water-soluble B-vitamin, which is also known as vitamin B9 or folacin. Naturally occurring folates exist in many chemical forms; folates are found in food, as well as in metabolically active forms in the human body. Folic acid and folinic acid are both distinct forms of vitamin B9, a crucial nutrient for human health. While often confused, they are not biologically equivalent. The primary difference lies in their chemical structure and their position in the metabolic pathway the body uses to create the active, usable form of folate, L-methylfolate.
Folinic acid, or 5-formyl tetrahydrofolic acid, is a naturally occurring, reduced form of folic acid commonly known in clinical practice as leucovorin. Often, clinicians use the terms folic acid and folinic acid interchangeably, but they are not the same. Folic acid is a synthetic, oxidized, and water-soluble form of folate (vitamin B9) used therapeutically and does not exist in nature, whereas folinic acid exists naturally and is biologically active. Folinic acid represents over 90% of functional folate derivatives in plasma.
1.4 Natural Food Sources
Asparagus, beans, broccoli, strawberries, oranges, mushrooms, peanuts, liver, kidney, and yeast are good sources of folic acid (folate). In fresh uncooked foods, natural folates are mostly present as the tetrahydro forms. Almost all of the known physiological functions of folate are performed by tetrahydrofolic acid, (6S)-FH₄, or by one-carbon derivatives of it including 5-methyl-(6S)-FH₄, 5-formyl-(6S)-FH₄ (folinic acid), 10-formyl-(6R)-FH₄, 5,10-methylene-(6R)-FH₄, 5,10-methenyl-(6R)-FH₄, and 5-formimino-(6S)-FH₄. Naturally occurring folate forms are mainly methyltetrahydrofolates and formyltetrahydrofolates, predominantly existing as polyglutamates. Pentaglutamate is abundant in the liver of most mammals and heptaglutamate is found in plants.
1.5 Common Forms and Preparations
In general, folinic acid is compounded with leucovorin calcium (especially for FDA-approved indications) and can be administered intramuscularly, intravenously, or orally. Leucovorin is supplied in 5, 15, and 25 mg tablets and vials containing 50, 100, or 350 mg of leucovorin as a lyophilized powder. The purified levoleucovorin isomer is commercially available as Fusilev for intravenous administration, dosed at half the equivalent of racemic folinic acid due to its higher potency, facilitating comparable therapeutic effects with reduced volume.
2. Historical Discovery and Development
In 1930–1931, Lucy Wills, while studying pregnant textile workers with macrocytic anemia in Mumbai, India, discovered that a yeast extract provided to these nutritionally deficient individuals cured and prevented their anemia. Mitchell isolated the active ingredient from spinach in 1941 and named it folic acid from the Latin folium, meaning leaf. Subsequently, the synthesis and chemical structure of folate was described in 1945–1946. In 1948, the first reported clinical success in inducing temporary remission of acute leukemia by the antifolate aminopterin was reported, soon followed by success with the less toxic amethopterin (i.e., methotrexate). That same year, in studies exploring links to anemia, a factor in the gram-positive bacteria Leuconostoc citrovorum was identified as required in growth media for deficient species. Two years later in 1950, this "citrovorum factor"—later named leucovorin (folinic acid)—successfully reversed aminopterin and methotrexate toxicity.
Leucovorin (folinic acid) is an active form of folic acid discovered in 1948 from Leuconostoc citrovorum. 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. Folinic acid has been registered since the early 1980s.
Various alkali metal salts of leucovorin were prepared and reported in 1952 by the American Cyanamid Company. The researchers synthesized cyclohexylamine, barium, and calcium salts of leucovorin.
3. Key Constituents, Active Forms, and Mechanisms of Action
3.1 One-Carbon Metabolism and Folate Biochemistry
The only function of folate coenzymes in the body appears to be in mediating the transfer of one-carbon units. Leucovorin is a racemic mixture of tetrahydrofolic acid, which is involved as a cofactor for one-carbon transfer reactions in the synthesis of purines and pyrimidines. Through a vitamin B6-dependent reaction, tetrahydrofolate accepts a one-carbon unit from serine, producing 5,10-methylenetetrahydrofolate and glycine. 5,10-Methylenetetrahydrofolate is required for the synthesis of nucleic acids. The figure shows the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate by a riboflavin (FAD)-dependent enzyme (methylenetetrahydrofolate reductase; MTHFR). 5-Methyltetrahydrofolate is required for the formation of methionine from homocysteine; this reaction also requires the cofactor vitamin B12 and betaine.
3.2 Bypass of Dihydrofolate Reductase
The mechanism of action of leucovorin is based on its ability to restore the tetrahydrofolate pool in cells without requiring reduction by dihydrofolate reductase. Leucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of "one-carbon" moieties. This is in contrast to folic acid, which must be processed by the enzyme dihydrofolate reductase (DHFR) through multiple steps before becoming biologically active. Folinic acid is easily converted directly into active L-5-MTHF and other active folate forms through a simple conversion—it is first converted to 5,10-methylenetetrahydrofolate.
3.3 Metabolic Pathway After Administration
l-Leucovorin (5-formyl-(6S)-tetrahydrofolate) is rapidly metabolized (via 5,10-methenyltetrahydrofolate then 5,10-methylenetetrahydrofolate) to 5-methyl-(6S)-tetrahydrofolate (L-methyl-folate or 5-MTHF), which in turn can be metabolized via other pathways back to tetrahydrofolate and 5,10-methenyltetrahydrofolate. 5,10-methylenetetrahydrofolate is converted to 5-MTHF by an irreversible enzyme-catalyzed reduction using the cofactors FADH₂ and NADPH.
After intravenous administration, serum total reduced folates reach a mean peak of 1,259 ng/mL at approximately 10 minutes. The initial rise in total reduced folates is primarily due to the parent compound 5-formyl-THF. The active metabolite 5-methyl-THF becomes the predominant circulating form with a mean peak of 258 ng/mL occurring at 1.3 hours. Leucovorin is converted in the intestinal mucosa and the liver to 5-methyl-tetrahydrofolate, which is also active as a reduced folate. It is excreted primarily in the urine with minor excretion occurring in the feces.
3.4 Mechanism in Methotrexate Rescue
The rationale for high-dose methotrexate and leucovorin rescue treatment is based on tumor cell uptake of methotrexate via the reduced folate carrier and subsequent intracellular conversion to MTX-polyglutamates (MTX-PGs) by the enzyme folylpolyglutamate synthetase (FPGS). These MTX-PGs are potent inhibitors of key enzymes in folate metabolism, including dihydrofolate reductase (DHFR), thymidylate synthase (TS), 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICARFT) and glycinamide ribonucleotide formyltransferase (GARTF), thereby impairing de novo biosynthesis of purines and thymidylate (for DNA synthesis), amino acids and methylation reactions. Leucovorin is a potent antidote for both the hematopoietic and reticuloendothelial toxic effects of folic acid antagonists by replenishing reduced folate pools. 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 differences in membrane transport and affinity for polyglutamylation.
3.5 Mechanism in 5-FU Potentiation
Reduced folates are cofactors for the 5-fluorodeoxyuridine monophosphate–thymidylate synthetase reaction. When combined with fluorouracil, leucovorin enhances the binding of the fluorouracil metabolite fluorouridine monophosphate to thymidylate synthetase. DNA-directed toxicity is increased, while RNA-directed toxicity is not affected. Specifically, 5-fluorouracil is metabolized to fluorodeoxyuridylic acid, which binds to and inhibits the enzyme thymidylate synthase (an enzyme important in DNA repair and replication). Administration of leucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. In contrast, leucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy, such as 5-fluorouracil.
3.6 Blood–Brain Barrier Transport
In the case of folinic acid/leucovorin, this form can cross from the blood into the brain more easily than other forms. In most humans, the body uses a group of proteins known as the folate receptor alpha (FRα) transport system to carry common food sources of folate from the bloodstream into the brain. Folate is primarily transported across the choroid plexus epithelium attached to the folate receptor α (FRα) using energy-dependent endocytosis. Calcium folinate treatment can bypass the FRα blockade and enter the brain via the reduced folate channel (RFC) and restore folic acid levels and neuronal functioning in the brain.
4. Scientific Evidence by Area of Clinical Use
4.1 Methotrexate Rescue in Oncology
Folinic acid treats various cancers when employed with 5-fluorouracil (5-FU). Additionally, leucovorin serves as an antidote to folic acid antagonists like methotrexate. Folinic acid's properties allow it to function as an antidote, chemotherapy-modulating agent, and rescue agent for the chemotherapy category of medications. 5-CHO-(6R,S)-THF (folinic acid) is used in the form of its calcium salt (leucovorin calcium) as a pharmaceutical for the treatment of megaloblastic folic acid deficiency anemia, as an antidote for enhancing the tolerability of folic acid antagonists specifically of aminopterin, methotrexate and fluorouracil in cancer therapy (leucovorin rescue), and for the treatment of autoimmune diseases such as psoriasis and rheumatoid arthritis, as well as for enhancing the tolerability of certain antiparasitics.
The leucovorin rescue strategy exploits a differential pharmacokinetic advantage: sustained methotrexate inhibition of DHFR (greater than 99% for 24 hours) is considered necessary to initiate antitumor effects. It is assumed that normal cells harbor lower FPGS activities than tumor cells and thus accumulate lower MTX-polyglutamate levels, imposing a less sustained DHFR block. This is among the most well-established applications of folinic acid, with decades of clinical data and regulatory approval underpinning its use.
4.2 Colorectal Cancer: Potentiation of 5-Fluorouracil
The North Central Cancer Treatment Group (NCCTG) and Mayo Clinic collaborated in prospective, randomized clinical trials of new approaches to the chemotherapy of advanced metastatic colorectal cancer. Single agent 5-fluorouracil given by intensive-course rapid intravenous administration served as a control. Included among the experimental treatments were two regimens consisting of 5-FU plus leucovorin (folinic acid). One of these regimens used folinic acid at a dose level of 200 mg/m² daily for 5 days based on earlier studies; the second regimen used folinic acid at 1/10 the dose level (20 mg/m² daily for 5 days).
In one reported study of 5-FU combined with high-dose l-folinic acid (leucovorin) therapy for patients with advanced colorectal carcinoma, patients weekly received both 5-FU (600 mg/m² by intravenous 15-minute infusion) and l-folinic acid (250 mg/m² by intravenous infusion over 2 hours). Forty-eight patients were evaluated for toxicity and 32 for response. The combined complete and partial response rate was 25% in 32 patients. Toxicity was within acceptable limits without grade 4 toxicity. The combination of leucovorin and 5-FU provides a favorable treatment regimen for patients with metastatic colorectal carcinoma. This clinical application has robust support from multiple phase II and phase III randomized trials and represents a standard-of-care use of folinic acid in oncology.
4.3 Megaloblastic Anemia Due to Folate Deficiency
5-Formyl-tetrahydrofolic acid (also known as leucovorin or folinic acid) has long been used in therapeutic doses for several diseases. Examples include rescue from the toxicity of methotrexate chemotherapy, and the synergistic combination with fluorouracil for treatment of various cancers. It is also given to treat acute anemia not due to B12 deficiency. The treatment of megaloblastic anemia attributable to folate deficiency is among the oldest registered clinical uses of the compound. In patients treated for megaloblastic anemia, hematologic monitoring (i.e., complete blood counts) showing improvement generally indicates efficacy.
4.4 Autoimmune and Inflammatory Conditions: Methotrexate Side Effect Mitigation
Methotrexate is a cornerstone therapy for rheumatoid arthritis, but its folate antagonism produces significant toxicity. A 2013 Cochrane systematic review (Shea et al., Cochrane Database of Systematic Reviews, Issue 5) examined this question in depth. Methotrexate is a disease-modifying antirheumatic drug (DMARD) used as a first-line agent for treating rheumatoid arthritis. Pharmacologically, it is classified as an antimetabolite due to its antagonistic effect on folic acid metabolism. Many patients treated with methotrexate experience mucosal, gastrointestinal, hepatic, or hematologic side effects. Supplementation with folic or folinic acid during treatment with methotrexate may ameliorate these side effects.
This Cochrane Review provides conclusive evidence for the efficacy of low-dose folic or folinic acid supplementation in patients taking methotrexate to treat rheumatoid arthritis. The reductions in two major methotrexate side effects (gastrointestinal toxicity and liver enzyme elevations) are impressive. In the review, 16 people out of 100 who took folic acid or folinic acid with their methotrexate developed mouth sores or ulcers. Folinic acid is a derivative of tetrahydrofolic acid that has vitamin activity equivalent to that of folic acid, but its function is unaffected by drugs such as methotrexate. The use of folic or folinic acid has been variable, ranging from regular use in everyone who starts methotrexate to use only in those with side effects. The evidence for this use from the Cochrane review is considered strong (multiple randomized controlled trials, systematic review and meta-analysis level).
4.5 Cerebral Folate Deficiency (CFD)
Cerebral folate deficiency describes an individual with normal serum folate concentrations but low concentrations of folate in the cerebrospinal fluid (CSF) due to impaired ability to transport folate across the blood-brain barrier. Unlike previous studies of folate deficiency associated with CNS abnormalities, this neurometabolic disorder demonstrates below-normal concentration of 5-methyltetrahydrofolate (5-MTHF), one of the active metabolites of folate, in the CSF, but normal systemic folate levels. This condition improved with folinic acid (d,l-leucovorin) treatment.
Cerebral folate deficiency, a disorder in which folate concentrations are below normal in the cerebrospinal fluid (CSF) but not in the blood, was first described in six children with neurodevelopmental regression and neurological abnormalities. Treatment with folinic acid, a reduced form of folate, normalized CSF folate concentrations and significantly improved neurological symptoms. Further case descriptions demonstrated that many of the children with cerebral folate deficiency had ASD and that treatment with folinic acid improved ASD symptoms as well as other neurological symptoms.
In 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.
4.6 Autism Spectrum Disorder (ASD) and Cerebral Folate Deficiency
In an estimated 58–76% of children with ASD, folate receptor alpha autoantibodies (FRAAs) interfere with the normal route of folate transfer to the brain. In these cases, food- or supplement-based sources of folate might be plentiful in the bloodstream but unable to cross into the brain in needed amounts. This can cause a condition called cerebral folate deficiency (CFD). Children with ASD have been found to have impaired transport of folate across the blood-brain barrier due to auto-antibodies that either block or bind to the folate receptor alpha (FR alpha) — the antibodies are known as folate receptor auto-antibodies (FRAA).
A double-blind, placebo-controlled randomized trial published in Molecular Psychiatry (Frye et al., 2016, PMC5794882) evaluated high-dose folinic acid in children with ASD and language impairment. Improvement in verbal communication, as measured by an ability-appropriate standardized instrument, was significantly greater in participants receiving folinic acid as compared with those receiving placebo, resulting in an effect of 5.7 (1.0, 10.4) standardized points with a medium-to-large effect size (Cohen's d = 0.70). FRAA status was predictive of response to treatment.
A subsequent 2021 systematic review and meta-analysis (Rossignol and Frye, Journal of Personalized Medicine) examined the body of evidence more broadly. In a retrospective national survey of 1,286 participants with ASD or their parents/caregivers, a number of nutritional supplements were rated for changes in behaviors. Higher-dose folinic acid (more than 5 mg/day orally) improved cognition in 33%, attention in 29%, and language/communication in 24%. A moderate dose of folinic acid (below 5 mg/day orally) improved language/communication (20%). In some cases, clinical response to d,l-leucovorin is dramatic, especially if this treatment is started early in life, but sometimes improvements can be marked even in adults.
A 12-week randomized clinical trial conducted in China (2021–2023) also evaluated high-dose folinic acid in children with ASD. This randomized clinical trial was conducted from August 2021 to August 2023 at a hospital in Shenzhen, China. Eighty eligible participants were randomly assigned to either the intervention (n = 50) or the control group (n = 30). Research on the safety and efficacy of high-dose folinic acid in Chinese children with autism spectrum disorder (ASD) is limited, and the impact of folate metabolism gene polymorphisms on its efficacy remains unclear. This trial aimed to evaluate the safety and efficacy of high-dose folinic acid intervention (2 mg/kg/day, maximum 50 mg/day) in Chinese children with ASD and explore the association between folate metabolism gene polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G, and MTRR A66G) and efficacy.
One trial (published in the European Journal of Pediatrics) that had reported positive findings was subsequently retracted, which underscores the need for caution in interpreting the totality of ASD evidence. Among the available trials, a wide range of doses were used, with the lowest dose being 5 mg twice daily. All trials were conducted on children ages 2–15 years old. A randomized trial conducted in Iran evaluated calcium folinate as an adjunct to risperidone and found it to be a potentially beneficial complementary therapy for improving speech and behavioral symptoms in children with ASD. Overall, the evidence in ASD remains preliminary and methodologically heterogeneous; the FRAA-positive subgroup appears to show the most consistent benefit, but further large, rigorous trials are needed.
4.7 Prevention of Pemetrexed Toxicity
Pemetrexed, another antifolate used in lung cancer and mesothelioma, also causes folate-pathway toxicity. Folinic acid can be used to reduce pemetrexed-induced toxicity by nullifying the effect of pemetrexed through regeneration of the folate cycle. Folinic acid is shown to selectively rescue host cells after methotrexate treatment, while the anti-tumor effect remains. Pemetrexed toxicity in healthy cells is mainly caused by monoglutamated pemetrexed which inhibits dihydrofolate reductase. Since timely dosing of folinic acid does not affect the efficacy of methotrexate, it can be expected that folinic acid does not influence the efficacy of pemetrexed either. The first dose of folinic acid is administered 24 hours after pemetrexed — the same interval used after high-dose methotrexate. This application is investigational and supported by clinical trial protocols, but broader regulatory approvals remain under evaluation.
4.8 Hereditary Autosomal Recessive Folate Transport Disorders
Several autosomal recessive disorders affecting folate transport and metabolism can be treated with high doses of folinic acid, a folate derivative. These are rare inborn errors of metabolism, and the evidence base is largely limited to case series and individual case reports rather than large clinical trials, given the rarity of these disorders.
5. Body Systems and Health Areas Associated with Folinic Acid
- Hematopoietic system: Treatment of megaloblastic anemia due to folate deficiency; rescue of bone marrow suppression caused by folate antagonists. Leucovorin is a potent antidote for both the hematopoietic and reticuloendothelial toxic effects of folic acid antagonists by replenishing reduced folate pools.
- Central nervous system: Transport of folate across the blood-brain barrier; treatment of cerebral folate deficiency; improving neurological outcomes in related disorders. Folinic acid/leucovorin can cross from the blood into the brain more easily than other forms.
- Gastrointestinal system: Mitigation of chemotherapy-induced mucositis and GI toxicity; direct role in colorectal cancer treatment. Reductions in two major methotrexate side effects — gastrointestinal toxicity and liver enzyme elevations — are impressive.
- Immune/musculoskeletal system: Reduction of methotrexate side effects in inflammatory and autoimmune conditions such as rheumatoid arthritis. Supplementation with folic or folinic acid during treatment with methotrexate may ameliorate mucosal, gastrointestinal, hepatic, and hematologic side effects.
- Oncology: Direct anticancer role through potentiation of 5-FU-based chemotherapy. When combined with fluorouracil, leucovorin enhances the binding of the fluorouracil metabolite fluorouridine monophosphate to thymidylate synthetase. DNA-directed toxicity is increased.
- Developmental and neurodevelopmental: Emerging evidence in ASD, Rett syndrome, and related conditions related to folate transport deficits. Individuals with Rett syndrome, a disorder closely related to ASD, have also been found to have cerebral folate deficiency.
- DNA synthesis and cell proliferation: Underpins all one-carbon transfer biochemistry including purine, pyrimidine, and methionine synthesis. Folate undergoes several transfer/methylation reactions that are important for synthesizing nitrogenous bases in DNA and ribonucleic acid (RNA) and are necessary for the maturation of red blood cells.
6. Dosage Forms and Dosages Reported in Studies
Due to the wide range of folinic acid indications and administration guidelines, specific protocols are available that clinicians should follow; the dosing regimens below are general. Folinic acid is compounded with leucovorin calcium (especially for FDA-approved indications) and can be administered intramuscularly, intravenously, or orally. The timing, dosage, and route of folinic acid administration depend on the desired outcome for the particular indication.
- High-dose methotrexate leucovorin rescue (adults): The dosage is typically 15 mg orally, IM, or IV every 6 hours for 10 doses, starting 24 hours after initiating methotrexate. The maximum oral dose is 25 mg; IM or IV doses may be higher. In patients with delayed methotrexate administration, the dosage is 15 mg orally, IM, or IV every 6 hours.
- Methotrexate rescue (pediatric): 10 mg/m² PO/IM/IV every 6 hours × 10 doses. If serum methotrexate levels are greater than 50 or 5 micromolar at 24 and 48 hours, or if there is a 50% or more increase in serum creatinine within 24 hours after methotrexate initiation, the dosage of leucovorin should be increased 20-fold to 100 mg/m² IV every 3 hours until the methotrexate level is less than 0.05 micromolar.
- Colorectal cancer (5-FU combination): Clinical trials have used folinic acid at a dose level of 200 mg/m² daily for 5 days, and also at 20 mg/m² daily for 5 days. In a separate clinical series, patients weekly received l-folinic acid at 250 mg/m² by intravenous infusion over 2 hours.
- Autism spectrum disorder (investigational oral dosing): A wide range of doses were used in ASD studies, with the lowest dose being 5 mg twice daily. One 12-week randomized trial used 2 mg/kg/day with a maximum of 50 mg/day.
- Available formulations: Leucovorin is supplied in 5 mg, 15 mg, and 25 mg tablets, and vials containing 50, 100, or 350 mg of leucovorin as a lyophilized powder.
7. Safety Considerations, Contraindications, and Interactions
7.1 General Safety Profile
Folinic acid has been registered since the early 1980s. Based on studies and experience, folinic acid has proven to be a safe drug to use. The mechanism of action is already elucidated and the adverse effect profile of folinic acid is well characterized.
7.2 Key Contraindications
- Hypersensitivity to folinic acid or its components are contraindications to its administration.
- Calcium folinate injection is contraindicated in the treatment of pernicious anemia or other megaloblastic anemias where vitamin B12 is deficient. Its use can lead to an apparent response of the hematopoietic system, but neurological damage may occur or progress if already present.
- Intrathecal administration is also contraindicated.
- Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take calcium folinate tablets.
7.3 Cautions in Megaloblastic Anemia
Caution is necessary for patients receiving folinic acid therapy to treat megaloblastic anemia, particularly with concurrent vitamin B12 deficiency or pernicious anemia. It should not be used in patients with pernicious anemia or other anemias resulting from vitamin B12 deficiency. Such use may mask the symptoms of these conditions while allowing the neurological damage to progress.
7.4 Interactions with Fluorouracil (5-FU)
Leucovorin (calcium folinate) potentiates the toxicity of 5-fluorouracil, and fatal adverse reactions have been reported in patients over 65 years of age receiving high-dose treatment with leucovorin simultaneously with fluorouracil. Patients who develop gastrointestinal toxicity with a combination of 5-FU and folinic acid therapy should no longer receive such treatment until symptoms have resolved.
7.5 Interactions with Methotrexate and Antifolates
Administration of leucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. This bidirectional relationship — leucovorin countering methotrexate's therapeutic effects if given too early or at the wrong dose — requires careful timing. Folinic acid is already licensed for use after administration of high-dose methotrexate, which is a more potent inhibitor of cell proliferation than pemetrexed and gets its effectivity by inhibiting dihydrofolate reductase. Since timely dosing of folinic acid does not affect the efficacy of methotrexate, it can be expected that folinic acid does not influence the efficacy of pemetrexed either.
7.6 Clinical Monitoring Requirements
In patients treated with folinic acid for methotrexate toxicity, the recommendation is to monitor serum creatinine and methotrexate levels at 24-hour intervals. A significant decrease in urine output or increased serum creatinine is a sign of a medical emergency in high-dose methotrexate therapy. Aggressive monitoring of methotrexate levels, early recognition of delayed methotrexate excretion, and prompt administration of leucovorin rescue therapy are imperative in reducing morbidity and mortality in such patients. When combined with 5-FU, the recommendation is for providers to monitor complete blood counts (with differential), liver function tests, and electrolytes. Patients who develop diarrhea should be monitored closely until resolution.
7.7 Inactive Diastereomer and Excretion
After administration of 5-CHO-(6R,S)-THF, the (6S) content of this diastereomer mixture is rapidly converted into 5-Me-(6S)-THF, whereas the (6R) content is not metabolized and is slowly excreted with the urine.
References
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