Folic acid is a water-soluble, B-complex vitamin that is available orally and parenterally. This vitamin is found in a variety of foods including liver, kidneys, yeast, and leafy, green vegetables. One of the most beneficial roles of folate appears to be its ability to reduce homocysteine concentrations in neural tube defects. A deficiency in folic acid can cause a variety of hematologic complications including megaloblastic and macrocytic anemias; however, folate supplementation can mask the early symptoms of vitamin B12 deficiency. In addition to treating megaloblastic and macrocytic anemias as well as tropical sprue, folic acid is used for the treatment of primary homocystinuria and Wernicke/Korsakoff syndrome, and for methotrexate toxicity prophylaxis in persons receiving low-dose methotrexate. Unlike the folic acid derivative leucovorin, folic acid is not clinically useful in offsetting the action of folate reductase inhibitors because it requires the enzyme dihydrofolate reductase for activation. Folic acid is also ineffective in the treatment of aplastic and normocytic anemias. Folic acid can substantially decrease the risk of congenital neural tube defects and daily folic acid supplementation is recommended in all persons planning to or who could become pregnant.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Liquid Formulations
-Extemporaneous oral suspension: Shake well before administering. Measure dosage with calibrated measuring device.
Extemporaneous Compounding-Oral
NOTE: Extemporaneously compounded folic acid oral suspension is not FDA-approved.
Extemporaneous preparation of 1 mg/mL folic acid oral suspension
-Using a mortar and pestle, grind ten 1-mg folic acid tablets to a fine powder.
-Add a small amount of vehicle (simple syrup or 1:1 mixture of Ora-Plus and Ora-Sweet) and mix to a uniform paste.
-Transfer to amber plastic bottle.
-Rinse mortar and pestle with vehicle and transfer to bottle.
-Add enough vehicle to bring the final volume to 10 mL.
-Label bottle with 'Shake well before use'.
-Storage: The oral suspension is stable for 60 days at room temperature or refrigerated.
Injectable Administration
-The parenteral route is only indicated when oral therapy is not feasible.
-Folic acid is administered subcutaneously, intravenously, or by deep intramuscular injection.
-Do not use preparations containing benzyl alcohol in neonates.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The color of the solution may range from yellow to orange-yellow.
-Storage: Discard unused portion of punctured vial within 28 days after initial use.
Intravenous Administration
IV Push
-Doses of 5 mg or less may be administered undiluted as slow IV push over at least 1 minute.
Intermittent IV Infusion
Dilution
-Dilute in 50 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection.
-Storage: The diluted solution of folic acid (up to 0.1 mg/mL) is stable for 30 hours protected from light.
Intermittent IV Infusion Administration
-Administer over 30 minutes.
Continuous IV Infusion
-Folic acid injection may be added to parenteral nutrition solution.
Intramuscular Administration
-Inject deeply into a large muscle mass.
Subcutaneous Administration
-Inject subcutaneously taking care not to inject intradermally.
Folic acid is relatively nontoxic in humans. In rare instances, allergic or anaphylactoid reactions, including erythema, skin rash, pruritus, general malaise, and respiratory difficulty due to bronchospasm, have been reported.
Anorexia, nausea, abdominal distention, flatulence, and bitter or bad taste/dysgeusia have been reported in patients receiving high-dose folic acid (15 mg/day for 1 month).
Altered sleep patterns, difficulty concentrating, irritability, overactivity, excitability, mental depression, confusion, and impaired judgement have been reported in patients receiving high-dose folic acid (15 mg/day for 1 month). Prolonged folic acid therapy may result in decreased vitamin B12 serum concentrations.
Folic acid is contraindicated for use in patients with folic acid hypersensitivity.
Use folic acid with caution in patients with undiagnosed anemia. Folic acid may obscure pernicious anemia, as hematologic remission can occur while neurological manifestations remain progressive, potentially causing irreversible central nervous system effects. Avoid doses greater than 0.4 mg/day until the diagnosis of pernicious anemia is ruled out. Folic acid alone is improper therapy in the treatment of pernicious anemia, other megaloblastic anemias where vitamin B12 is deficient, and conditions that manifest with cobalamin deficiency.
Folic acid injection contains aluminum. Thus, aluminum toxicity may occur with prolonged administration in high-risk patients, including those with renal impairment or renal failure. Patients with renal impairment, who receive parenteral aluminum at rates more than 4 to 5 mcg/kg/day, may develop aluminum toxicity (central nervous system and bone toxicity). Tissue loading may occur at lower administration rates.
Many formulations of folic acid injection contain benzyl alcohol as a preservative, which may cause allergic reactions. Use folic acid injection cautiously in those patients with benzyl alcohol hypersensitivity. Avoid injectable folic acid preparations containing benzyl alcohol in neonates because benzyl alcohol has been associated with 'gasping syndrome,' a potentially fatal condition characterized by metabolic acidosis and CNS, respiratory, circulatory, and renal dysfunction. Additionally, the injection products contain aluminum which may reach toxic concentrations with prolonged administration in premature neonates with immature kidneys. Premature neonates may also be at particular risk because they may require large amounts of calcium and phosphate solutions, which also contain aluminum.
Appropriate maternal folic acid intake is essential to the fetus and no harms are associated with appropriate folic acid supplementation during pregnancy as recommended in expert guidelines. There is significant evidence that most fetal neural tube defects (NTDs) can be prevented if folic acid therapy is initiated before conception and continued during early pregnancy (the first 12 weeks of conception) in both persons with increased risk and those with no known increased risk for having an NTD-affected pregnancy. While not all NTDs are preventable with folic acid supplementation, a large percentage are.
Appropriate maternal folic acid intake is important during lactation, and no problems have been identified with supplementation to achieve adequate intake goals during breast-feeding. Previous American Academy of Pediatrics (AAP) recommendations considered folic acid supplementation compatible with breast-feeding.
For the treatment of folate deficiency megaloblastic anemia, including persons with tropical sprue:
-for the treatment of folate deficiency megaloblastic anemia due to malnutrition or dietary deficiency (i.e., alcohol use disorders) or conditions associated with increased demands (i.e., pregnancy/lactation):
Oral dosage:
Adults: 1 to 5 mg PO once daily, initially; resistant cases may require higher doses. Reduce dose to 0.4 mg PO once daily when clinical symptoms have subsided and laboratory parameters have normalized.
Pregnant or Lactating Persons: 1 to 5 mg PO once daily, initially; resistant cases may require higher doses. Reduce dose to 0.8 mg PO once daily when clinical symptoms have subsided and laboratory parameters have normalized.
Children and Adolescents 4 to 17 years: 1 to 5 mg PO once daily, initially; resistant cases may require higher doses. Reduce dose to 0.4 mg PO once daily when clinical symptoms have subsided and laboratory parameters have normalized.
Children 1 to 3 years: 1 to 5 mg PO once daily, initially; resistant cases may require higher doses. Reduce dose to 0.1 to 0.3 mg PO once daily when clinical symptoms have subsided and laboratory parameters have normalized.
Infants: 1 to 5 mg PO once daily, initially; resistant cases may require higher doses. Reduce dose to 0.1 mg PO once daily when clinical symptoms have subsided and laboratory parameters have normalized.
Intravenous, Intramuscular, or Subcutaneous dosage:
Adults: 1 to 5 mg IV, IM, or subcutaneously once daily, initially; resistant cases may require higher doses. Reduce dose to 0.4 mg IV, IM, or subcutaneously once daily when clinical symptoms have subsided and laboratory parameters have normalized.
Pregnant or Lactating Persons: 1 to 5 mg IV, IM, or subcutaneously once daily, initially; resistant cases may require higher doses. Reduce dose to 0.8 mg IV, IM, or subcutaneously once daily when clinical symptoms have subsided and laboratory parameters have normalized.
Children and Adolescents 4 to 17 years: 1 to 5 mg IV, IM, or subcutaneously once daily, initially; resistant cases may require higher doses. Reduce dose to 0.4 mg IV, IM, or subcutaneously once daily when clinical symptoms have subsided and laboratory parameters have normalized.
Children 1 to 3 years: 1 to 5 mg IV, IM, or subcutaneously once daily, initially; resistant cases may require higher doses. Reduce dose to 0.1 to 0.3 mg IV, IM, or subcutaneously once daily when clinical symptoms have subsided and laboratory parameters have normalized.
Infants: 1 to 5 mg IV, IM, or subcutaneously once daily, initially; resistant cases may require higher doses. Reduce dose to 0.1 mg IV, IM, or subcutaneously once daily when clinical symptoms have subsided and laboratory parameters have normalized.
-for the treatment of folate deficiency megaloblastic anemia in malabsorptive states (i.e., nontropical sprue and other gastrointestinal disorders):
Oral dosage:
Adults: 5 mg PO once daily. May increase the dose up to 15 mg PO once daily for 4 months.
Infants, Children, and Adolescents: 5 mg PO once daily. May increase the dose up to 15 mg PO once daily for 4 months.
Intravenous, Intramuscular, or Subcutaneous dosage:
Adults: 5 mg IV, IM, or subcutaneously once daily. May increase the dose up to 15 mg IV, IM, or subcutaneously once daily for 4 months.
Infants, Children, and Adolescents: 5 mg IV, IM, or subcutaneously once daily. May increase the dose up to 15 mg IV, IM, or subcutaneously once daily for 4 months.
-for the treatment of folate deficiency megaloblastic anemia in persons with tropical sprue:
Oral dosage:
Adults: 5 mg PO once daily for 6 months.
Infants, Children, and Adolescents: 5 mg PO once daily for 6 months.
Intravenous, Intramuscular, or Subcutaneous dosage:
Adults: 5 mg IV, IM, or subcutaneously once daily for 6 months.
Infants, Children, and Adolescents: 5 mg IV, IM, or subcutaneously once daily for 6 months.
-for the treatment of folate deficiency megaloblastic anemia in chronic hemolytic states or dialysis:
Oral dosage:
Adults: 5 mg PO once daily, initially. May increase the dose by 5 mg/day based on plasma homocysteine concentrations. Dose range: 5 mg PO once weekly to 15 mg PO once daily based on diet, plasma homocysteine concentrations, and/or rate of hemolysis. Max: 15 mg/day.
Infants, Children, and Adolescents: 5 mg PO once daily, initially. May increase the dose by 5 mg/day based on plasma homocysteine concentrations. Dose range: 5 mg PO once weekly to 15 mg PO once daily based on diet, plasma homocysteine concentrations, and/or rate of hemolysis. Max: 15 mg/day.
Intravenous, Intramuscular, or Subcutaneous dosage:
Adults: 5 mg IV, IM, or subcutaneously once daily, initially. May increase the dose by 5 mg/day based on plasma homocysteine concentrations. Dose range: 5 mg IV, IM, or subcutaneously once weekly to 15 mg IV, IM, or subcutaneously once daily based on diet, plasma homocysteine concentrations, and/or rate of hemolysis. Max: 15 mg/day.
Infants, Children, and Adolescents: 5 mg IV, IM, or subcutaneously once daily, initially. May increase the dose by 5 mg/day based on plasma homocysteine concentrations. Dose range: 5 mg IV, IM, or subcutaneously once weekly to 15 mg IV, IM, or subcutaneously once daily based on diet, plasma homocysteine concentrations, and/or rate of hemolysis. Max: 15 mg/day.
For nutritional supplementation:
-for nutritional supplementation in healthy persons based on recommended dietary allowances (RDA):
Oral dosage:
Adults: 0.4 mg/day PO.
Pregnant Persons: 0.6 mg/day PO.
Lactating Persons: 0.5 mg/day PO.
Adolescents 14 to 17 years: 0.4 mg/day PO.
Children 9 to 13 years: 0.3 mg/day PO.
Children 4 to 8 years: 0.2 mg/day PO.
Children 1 to 3 years: 0.15 mg/day PO.
Infants 7 to 11 months: 80 mcg/day PO is the recommended Adequate Intake. No RDA has been established.
Infants 1 to 6 months: 65 mcg/day PO is the recommended Adequate Intake. No RDA has been established.
Neonates: 65 mcg/day PO is the recommended Adequate Intake. No RDA has been established.
-for nutritional supplementation in persons with sickle cell disease:
Oral dosage:
Adults: 1 mg PO once daily. In the acute crisis, a dose of 5 mg/day has been used; however, 1 mg/day is stated to be more than adequate.
Children and Adolescents: 1 mg PO once daily. In the acute crisis, a dose of 5 mg/day has been used; however, 1 mg/day is stated to be more than adequate.
-for nutritional supplementation in persons with thalassemia:
Oral dosage:
Adults: 1 mg PO once daily.
Children and Adolescents: 1 mg PO once daily.
For methotrexate toxicity prophylaxis* in patients receiving low-dose (e.g., once weekly) methotrexate:
Oral dosage:
Adults: 1 mg PO once daily or 6 days per week, skipping the day methotrexate is administered, is most commonly reported regimen and recommended by most guidelines. However, optimal dosage is not well established and variable dosage regimens are used including 5 mg PO once daily, 5 mg PO once or twice weekly, and 10 mg once weekly.
Children and Adolescents: 1 mg PO once daily or 6 days per week, skipping the day methotrexate is administered, is most commonly reported regimen and recommended by most guidelines. However, optimal dosage is not well established and variable dosage regimens are used including 400 mcg PO once daily, 800 mcg PO once weekly, 5 mg PO once or twice weekly, and 10 mg once weekly.
For neural tube defect prophylaxis* in persons of reproductive age who may become pregnant:
NOTE: Daily folic acid supplementation to prevent neural tube defects (NTDs) is recommended in all persons planning to or who could become pregnant.
-for neural tube defect prophylaxis in those at average risk of neural tube defects:
NOTE: Average risk persons include those without a prior pregnancy with NTDs or who do not have an underlying condition that may increase risk for NTDs (e.g., taking anticonvulsant medications).
Oral dosage:
Adults: 0.4 to 0.8 mg PO once daily starting at least 1 month prior to anticipated conception and continuing through the first 2 to 3 months of pregnancy.
Adolescents: 0.4 to 0.8 mg PO once daily starting at least 1 month prior to anticipated conception and continuing through the first 2 to 3 months of pregnancy.
-for neural tube defect prophylaxis in those at high-risk for an NTD-affected pregnancy:
NOTE: Persons at increased risk of NTDs include those with a history of pregnancy complicated by fetal NTDs or those with seizure disorders.
Oral dosage:
Adults: 4 mg PO once daily starting 3 months prior to conception and continuing until 12 weeks of gestational age.
Adolescents: 4 mg PO once daily starting 3 months prior to conception and continuing until 12 weeks of gestational age.
For the adjunct treatment of primary homocystinuria:
Oral dosage:
Adults: 0.8 to 5 mg/day PO, initially; adjust to clinical response to a usual dose range of 5 to 15 mg/day PO in 2 to 3 divided doses. Doses as high as 40 to 100 mg/day PO have been reported.
Infants, Children, and Adolescents: 0.8 to 5 mg/day PO, initially; adjust to clinical response to a usual dose range of 5 to 15 mg/day PO in 2 to 3 divided doses. Doses as high as 40 to 100 mg/day PO have been reported.
Neonates: Very limited data; 5 mg PO every 2 days was reported in a case series in 4 neonates.
For the treatment of Wernicke/Korsakoff syndrome*:
Oral dosage:
Adults: 0.4 to 1 mg PO once daily for several days.
Intravenous dosage:
Adults: 0.4 to 1 mg IV once daily for several days.
Therapeutic Drug Monitoring:
Typical serum concentrations of folic acid are 5-15 ng/ml. In general, serum folate concentrations < 5 ng/ml are considered indicative of folate deficiency. Serum folate concentrations < 2 ng/ml can result in megaloblast formation.
Maximum Dosage Limits:
-Adults
1 mg/day PO/IV is FDA-approved maximum; however, doses as high as 5 mg/day PO/IV have been used off-label.
-Geriatric
1 mg/day PO/IV is FDA-approved maximum; however, doses as high as 5 mg/day PO/IV have been used off-label.
-Adolescents
1 mg/day PO/IV is FDA-approved maximum; however, doses as high as 5 mg/day PO/IV have been used off-label.
-Children
1 mg/day PO/IV is FDA-approved maximum; however, doses as high as 5 mg/day PO/IV have been used off-label.
-Infants
1 mg/day PO/IV.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Capecitabine: (Moderate) Monitor for an increase in capecitabine-related adverse reactions if coadministration with folic acid is necessary. Capecitabine is an orally administered prodrug of fluorouracil; leucovorin enhances the binding of fluorouracil to thymidylate synthase, increasing exposure to fluorouracil. Folic acid (vitamin B9) is converted to folinic acid in vivo; leucovorin is the calcium salt of folinic acid. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.
Chloramphenicol: (Minor) Concurrent use of chloramphenicol with folic acid can antagonize the hematopoietic response to folic acid. Hematologic response should be monitored in patients requiring folic acid if chloramphenicol is administered concomitantly.
Cholestyramine: (Moderate) Chronic administration of cholestyramine may interfere with folic acid, vitamin B9 oral absorption. Patients receiving both drugs should take folic acid 1 hour before or 4 to 6 hours after a dose of cholestyramine.
Colesevelam: (Moderate) It is not known if colesevelam can reduce the absorption of oral vitamin supplements including fat soluble vitamins A, D, E, and K. To minimize potential interactions, administer vitamins at least 4 hours before colesevelam.
Fosphenytoin: (Minor) Concurrent use of folic acid, vitamin B9 and phenytoin (and fosphenytoin) may result in decreased folic acid serum concentrations and decreased anticonvulsant effect. It is important to maintain adequate folic acid concentrations in epileptic patients taking enzyme-inducing anticonvulsants, and maintenance doses may require upward adjustment. However, in large amounts, folic acid may counteract the anticonvulsant effect of some agents, including phenytoin. Therefore, it has been recommended that oral folic acid supplementation not exceed 1 mg/day in epileptic patients taking anticonvulsants. If large doses are used, monitor phenytoin concentrations upon folic acid initiation, dose titration, and discontinuation and adjust the anticonvulsant dosage as appropriate. Prolonged administration of phenytoin reportedly has resulted in a folate deficiency in 27% to 91% of patients. Megaloblastic anemia occurs in fewer than 1% of patients receiving phenytoin. The proposed mechanisms of this phenomenon include an increase in folate catabolism, folate malabsorption, or use of folic acid secondary to enzyme induction by phenytoin. Some evidence suggests that the anticonvulsant effect of phenytoin is partially the result of a reduction in folic acid concentrations. Folic acid replacement has resulted in an increase in metabolism of phenytoin and a decrease in phenytoin concentration in some patients, apparently through increased metabolism and/or redistribution of phenytoin in the brain and CSF. A clinically significant increase in seizure activity has occurred with this drug combination in rare instances, especially when doses of 4 mg/day or more were utilized.
Methotrexate: (Moderate) Folic acid may compete with methotrexate for entry into cells. However, in some situations, folic acid supplementation may be used to decrease adverse reactions such as mouth sores in patients receiving methotrexate for arthritis and other non-malignant diseases. Folic acid, vitamin B9, is NOT effective for methotrexate rescue therapy since folic acid requires dihydrofolate reductase for bioactivation and methotrexate inhibits this enzyme. Therefore folic acid should not be used to prevent toxicity of moderate- to high-dose methotrexate therapy.
Pafolacianine: (Major) Discontinue use of folic acid or folic acid-containing supplements 48 hours before administration of pafolacianine. Folic acid may reduce binding of pafolacianine to folate receptors overexpressed on ovarian cancer cells and could reduce the detection of malignant lesions.
Phenobarbital: (Minor) Concurrent use of folic acid, vitamin B9 and phenobarbital may result in decreased folic acid serum concentrations and decreased anticonvulsant effect. It is important to maintain adequate folic acid concentrations in epileptic patients taking enzyme-inducing anticonvulsants, and maintenance doses may require upward adjustment. However, in large amounts, folic acid may counteract the anticonvulsant effect of some agents, including phenobarbital. Therefore, it has been recommended that oral folic acid supplementation not exceed 1 mg/day in epileptic patients taking anticonvulsants. If large doses are used, monitor phenobarbital concentrations upon folic acid initiation, dose titration, and discontinuation. Adjust the anticonvulsant dosage as appropriate.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Minor) Concurrent use of folic acid, vitamin B9 and phenobarbital may result in decreased folic acid serum concentrations and decreased anticonvulsant effect. It is important to maintain adequate folic acid concentrations in epileptic patients taking enzyme-inducing anticonvulsants, and maintenance doses may require upward adjustment. However, in large amounts, folic acid may counteract the anticonvulsant effect of some agents, including phenobarbital. Therefore, it has been recommended that oral folic acid supplementation not exceed 1 mg/day in epileptic patients taking anticonvulsants. If large doses are used, monitor phenobarbital concentrations upon folic acid initiation, dose titration, and discontinuation. Adjust the anticonvulsant dosage as appropriate.
Phenytoin: (Minor) Concurrent use of folic acid, vitamin B9 and phenytoin may result in decreased folic acid serum concentrations and decreased anticonvulsant effect. It is important to maintain adequate folic acid concentrations in epileptic patients taking enzyme-inducing anticonvulsants, and maintenance doses may require upward adjustment. However, in large amounts, folic acid may counteract the anticonvulsant effect of some agents, including phenytoin. Therefore, it has been recommended that oral folic acid supplementation not exceed 1 mg/day in epileptic patients taking anticonvulsants. If large doses are used, monitor phenytoin concentrations upon folic acid initiation, dose titration, and discontinuation and adjust the anticonvulsant dosage as appropriate. Prolonged administration of phenytoin reportedly has resulted in a folate deficiency in 27% to 91% of patients. Megaloblastic anemia occurs in fewer than 1% of patients receiving phenytoin. The proposed mechanisms of this phenomenon include an increase in folate catabolism, folate malabsorption, or use of folic acid secondary to enzyme induction by phenytoin. Some evidence suggests that the anticonvulsant effect of phenytoin is partially the result of a reduction in folic acid concentrations. Folic acid replacement has resulted in an increase in metabolism of phenytoin and a decrease in phenytoin concentration in some patients, apparently through increased metabolism and/or redistribution of phenytoin in the brain and CSF. A clinically significant increase in seizure activity has occurred with this drug combination in rare instances, especially when doses of 4 mg/day or more were utilized.
Primidone: (Minor) Concurrent use of folic acid, vitamin B9 and phenobarbital and primidone may result in decreased folic acid serum concentrations and decreased anticonvulsant effect. It is important to maintain adequate folic acid concentrations in epileptic patients taking enzyme-inducing anticonvulsants, and maintenance doses may require upward adjustment. However, in large amounts, folic acid may counteract the anticonvulsant effect of some agents, including phenobarbital and primidone. Therefore, it has been recommended that oral folic acid supplementation not exceed 1 mg/day in epileptic patients taking anticonvulsants. If large doses are used, monitor phenobarbital concentrations upon folic acid initiation, dose titration, and discontinuation. Adjust the anticonvulsant dosage as appropriate.
Pyrimethamine: (Moderate) Pyrimethamine is a folate antagonist. Some evidence suggests that administration of folic acid to leukemia patients receiving pyrimethamine for Pneumocystis carinii resulted in exacerbation of leukemia symptoms. Folic acid, vitamin B9 reportedly interferes with the action of pyrimethamine in treating toxoplasmosis. Further study is needed to confirm these interactions.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Minor) Folate antagonists, such as trimethoprim, especially when used in high doses or over a prolonged period, inhibit dihydrofolate reductase and thus may inhibit the action of folic acid, vitamin B9.
Sulfasalazine: (Minor) Sulfasalazine exhibits antifolate activity, and can inhibit the absorption and lower the plasma concentrations of folic acid, vitamin B9. Patients receiving sulfasalazine treatment may require folic acid supplementation.
Trimethoprim: (Minor) Folate antagonists, such as trimethoprim, especially when used in high doses or over a prolonged period, inhibit dihydrofolate reductase and thus may inhibit the action of folic acid, vitamin B9.
Folic acid, a biochemically inactive compound, is the precursor for tetrahydrofolic acid and methyltetrahydrofolate. Tetrahydrofolic acid, methyltetrahydrofolate, and other folic acid congeners are essential for the maintenance of normal erythropoiesis and are also required cofactors for the synthesis of purine and thymidylate nucleic acids. They are also necessary for the interconversion of amino acids such as the metabolism of histidine to glutamic acid and the interconversion of serine and glycine. Folic acid congeners are transported across cells by receptor-mediated endocytosis where they function and are stored. Other processes involving folate coenzymes include generation and use of formate and methylation of transfer RNA. Impaired thymidylate synthesis, which leads to faulty DNA synthesis, is responsible for megaloblastic and macrocytic anemias.
An important role of folic acid is the formation of methionine from homocysteine using vitamin B12 as a cofactor. Adequate folic acid intakes can normalize high homocysteine levels via increased remethylation of homocysteine to methionine via 5-methyltetrahydrofolate-homocysteine methyltransferase (a.k.a.; methionine synthetase). Reduced folic acid intake is associated with hyperhomocysteinemia. Hyperhomocysteinemia is recognized as an independent risk factor for atherosclerosis of the coronary, cerebral, and peripheral vasculature. There is mounting evidence that elevated plasma homocysteine (and therefore decreased serum methionine) contributes to congenital neural tube defects. High serum homocysteine levels may also be important in the pathogenesis of colon cancer, diabetic retinopathy, and other diseases.
Folic acid is administered orally and parenterally. Folic acid congeners are extensively bound to plasma proteins and are distributed throughout the body including the CSF. They also appear in breast milk. After administration of small doses, reduction and methylation of folic acid to methyltetrahydrofolate occurs in the liver. Following large doses, folic acid may appear unchanged in the plasma. Active forms of folic acid are reabsorbed through enterohepatic recirculation. Folic acid is eliminated primarily renally as metabolites. When body stores become saturated, excess folic acid is excreted unchanged in the urine.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Oral Route
Following oral administration, folic acid is rapidly absorbed from the small intestine. It appears in the plasma approximately 15 to 30 minutes after an oral dose and peak concentrations are attained within 1 hour. Because dietary folate is primarily in the polyglutamyl form, it must be converted to the monoglutamate form by intestinal conjugase enzymes prior to absorption. The monoglutamate form is then reduced and methylated to methyltetrahydrofolate by dihydrofolate reductase during transport across the intestinal mucosa. Absorption of dietary folic acid is impaired in the presence of malabsorption syndromes; however, the absorption of synthetic, commercially available folic acid is unaffected.
Intravenous Route
After intravenous administration, the Tmax occurs within 30 minutes and the drug is rapidly cleared from the plasma.
-Special Populations
Renal Impairment
Folic acid is removed by hemodialysis.