ATC Class:B03BB01

VA Class:VT102

AHFS Class:

• Vitamin B Complex 88:08

Generic Name(s):

• Folic Acid

Folic acid is a water-soluble, B complex vitamin.

Folic acid is used for the treatment of megaloblastic and macrocytic anemias resulting from folate deficiency. The drug is usually indicated in the treatment of nutritional macrocytic anemia; megaloblastic anemias of pregnancy, infancy, and childhood; and megaloblastic anemia associated with primary liver disease, alcoholism and alcoholic cirrhosis, intestinal strictures, anastomoses, or sprue. Folate deficiency may also result from increased loss of folate secondary to renal dialysis or the administration of some drugs such as phenytoin, primidone, barbiturates, methotrexate, nitrofurantoin, or sulfasalazine.

Folic acid is not effective in the treatment of normocytic, refractory, or aplastic anemias or, when used alone, in the treatment of pernicious anemia. Folic acid antagonists (e.g., methotrexate, pyrimethamine, trimethoprim) inhibit folic acid reductases and prevent the formation of tetrahydrofolic acid. Therefore, folic acid is not effective as an antidote following overdosage of these drugs, and leucovorin calcium must be used.

In large doses, folic acid is used in the treatment of tropical sprue. In patients with this disease, the drug appears to exert a beneficial effect on the underlying mucosal abnormality as well as to correct folate deficiency.

Although prophylactic administration of folic acid is not required in most individuals, supplemental folic acid may be required to prevent deficiency of the vitamin in patients with conditions that increase folic acid requirements such as pregnancy, nursing, or chronic hemolytic anemia.

In some patients, such as those with nutritional megaloblastic anemia associated with vitamin B₁₂ deficiency or tropical or nontropical sprue, a simultaneous deficiency of folic acid and cyanocobalamin may exist, and combined therapy may be warranted. Likewise, combined folic acid and iron therapy may be indicated for prevention or treatment of megaloblastic anemia associated with iron deficiency as may occur in conditions such as sprue, megaloblastic anemia of pregnancy, and megaloblastic anemia of infants.

Dietary Requirements

The National Academy of Sciences (NAS) has issued a comprehensive set of Recommended Dietary Allowances (RDAs) as reference values for dietary nutrient intakes since 1941.140 In 1997, the NAS Food and Nutrition Board (part of the Institute of Medicine [IOM]) announced that they would begin issuing revised nutrient recommendations that would replace RDAs with Dietary Reference Intakes (DRIs).140 DRIs are reference values that can be used for planning and assessing diets for healthy populations and for many other purposes and that encompass the Estimated Average Requirement (EAR), the Recommended Dietary Allowance (RDA), the Adequate Intake (AI), and the Tolerable Upper Intake Level (UL).140 DRIs apply to the healthy general population, with RDAs and AIs defining the nutrient levels necessary for healthy individuals.140 Intake at the level of the RDA or AI would not necessarily replete the nutrient in undernourished individuals nor would it be adequate for disease states marked by increased requirements of the nutrient.140

The EAR is the nutrient intake value that is estimated to meet the requirement defined by a specific indicator of adequacy in 50% of individuals in a life-stage and gender group.140 In the past, recommended nutrient intake values (e.g., RDAs) often were based principally on levels needed to prevent deficiency, whereas EARs consider these levels as well as levels associated with disease risk reduction (e.g., osteoporosis).140 The RDA currently is defined as the daily dietary intake level that is sufficient to meet the nutrient requirements of nearly all (97-98%) healthy individuals in a given life-stage and gender group; RDAs apply to individuals not to groups, and the EAR serves as the basis for establishing the RDA.140 Although RDAs also previously were defined as the level of intake of essential nutrients that, on the basis of scientific knowledge, were judged to be adequate to meet the known nutrient needs of practically all healthy individuals, the current methods for establishing RDAs differ from those used in the past and, together with EARs and other reference values, address increased understanding of both population and individual nutrient needs.140

The RDA for a given nutrient, in a prescriptive sense, is the goal for dietary intake in individuals.140 If data are insufficient or too controversial to establish an RDA for a given life-stage group, an AI will be used instead.140 AIs are used when scientific evidence is insufficient to calculate a given EAR, which is needed for establishing the RDA.140 AIs are based on observed or experimentally determined approximations of the average nutrient intake, by a defined population or subgroup, that appears to sustain a defined nutritional state (e.g., usual circulating nutrient levels, nutrient levels for normal growth).140 In the absence of definitive data needed to establish the EAR and RDA, the AI may be used as the goal for nutrient intake in healthy individuals; however, the AI should not be considered equivalent to the RDA, and in some cases it actually may exceed the RDA that eventually gets established.140

The NAS has established an EAR and RDA for folate for adults based principally on red cell folate, which reflects tissue folate stores.140 For some life-stage groups, plasma homocysteine and plasma or serum folate concentrations also were considered.140 Because evidence currently available on the role of folate in reducing the risk of vascular disease (by reducing plasma homocysteine concentrations), cancer, and psychiatric and mental disorders is limited,141,142,143 the NAS did not use risk reduction as a basis for setting the EAR and RDA.140 While NAS has issued recommendations on folate intake for women capable of becoming pregnant, NAS considered prevention of neural tube defects inappropriate for use as an indicator for setting the EAR for women of childbearing age.140 (See Uses: Prevention of Neural Tube Defects.) The EAR and RDA for children and adolescents 1-18 years of age were established based on data in adults, since specific data in children and adolescents currently are unavailable.140 An AI has been set for infants up to 6 months of age based on the observed mean folate intake of infants fed principally human milk.140 An AI for infants 6-12 months of age has been set based on the AI for younger infants and data from adults.140 Data from research studies that measured folate intake and assessed infant status are compatible with the established AI.140

The principal goal of maintaining an adequate intake of folate in the US and Canada is to prevent megaloblastic changes in the bone marrow and other rapidly dividing cells.140 The role of folate in reducing the risk of vascular disease and other chronic disorders remains to be determined.140,141,142,143,144,145 Adequate intake of folate can be accomplished through consumption of foodstuffs, including folate-fortified foodstuffs, use of dietary supplements, or both.140 In the US, folate principally is obtained from fortified ready-to-eat cereals and vegetables (e.g., green beans, vegetable soup).140 As of January 1998, all enriched grains (e.g., enriched bread, pasta, flour, breakfast cereal, rice) are required to be fortified with 1.4 mg of folic acid/kg.140 Since enriched cereal grains are widely consumed in the US, these foodstuffs are expected to become an important contributor of folate and to increase folate intake.140 The NAS cautions that most currently available information on food folate composition underestimates folate concentration because of limitations in the analytical methods used and recent changes in folate fortification, and conclusions regarding the EAR for folate intake should not be based on these data.140

For specific information on currently recommended AIs and RDAs of folate for various life-stage and gender groups, see Dosage: Dietary and Replacement Requirements, under Dosage and Administration.

Prevention of Neural Tube Defects

Because available evidence indicates that prophylactic therapy with folic acid initiated before pregnancy can reduce the risk of fetal neural tube defects, including spina bifida, anencephaly, and encephalocele, during gestation, the US Public Health Service, the US Preventive Services Task Force, the American Academy of Pediatrics (AAP), the NAS, and others currently recommend that adequate folic acid intake be ensured in all women of childbearing potential.101,103,104,105,106,109,111,116,118,119,120,121,123,130,132,134,140,148 At a minimum, current evidence indicates that adequate intake of folic acid for at least 1 month before conception and through early pregnancy is needed to reduce the risk of fetal neural tube defects.101,103,104,119,121,126,127,128,129,130,131,133,148 However, because most pregnancies in the US are unplanned, the US Public Health Service, the US Preventive Services Task Force, and the NAS currently state that it would be prudent for all such women to consume folic acid through fortified foods and/or supplements (in addition to consuming food folate from a varied diet) on a regular, continuous basis as long as they are capable of conception.101,140,148 A higher dose of folic acid has been recommended prior to and during the first 3 months after conception for women with a history of prior neural tube defect pregnancy who are again planning pregnancy.101,102,103,104,118,140

While a level of 0.4 mg of folate daily generally can be obtained through careful selection of foods,101,107,112,113,133,135 evidence for the protective effect from folic acid is much stronger than that from food folate.140 As of January 1998, all enriched grains (e.g., enriched bread, pasta, flour, breakfast cereal, rice) are required to be fortified with 1.4 mg of folic acid/kg of grain.140 In contrast to previous recommendations that relied principally on food folate, NAS currently recommends that women capable of becoming pregnant consume 0.4 mg of folic acid daily from fortified food and/or supplements.140 The US Preventive Services Task Force recommends that women planning a pregnancy and women capable of becoming pregnant consume 0.4-0.8 mg of folic acid daily from supplements.148

Women of childbearing potential should be advised of the various alternatives (i.e., fortified food, supplements) for ensuring adequate daily intake of folic acid and encouraged to meet a goal of 0.4 mg daily.101 Women with a history of prior pregnancy complicated by fetal development of a neural tube defect and women receiving certain anticonvulsants are at high risk of a pregnancy with neural tube defects; such women should consult a clinician for advice if pregnancy is contemplated.101,102,148 While the possibility exists that lower dosages may be comparably effective, the US Public Health Service recommends that an increase in folic acid intake to 4 mg daily during the period of greatest risk (1 month before and 3 months after conception) be considered for women with a history of prior pregnancy complicated by fetal development of a neural tube defect.101,102,103,110,114,125 This dosage currently is recommended because the most rigorous study to date demonstrating benefit in reducing the risk of neural tube defects in such women employed it rather than because of superiority to alternative dosages.101,102,104,105 Because this dosage is high and may be associated with some risk, such women should consult their clinician in weighing the benefits versus risks of such high-dose supplementation.101

It should be recognized that the underlying cause(s) of neural tube defects remains to be elucidated more fully and that adequate intake of folic acid is expected only to avert some but not all cases of such defects.101,120,124

Cardiovascular Disease

There is substantial evidence linking homocysteine concentrations to risk of ischemic heart disease and stroke.145,146,147 Folate is an important regulator of the metabolism of homocysteine; blood concentrations of homocysteine are inversely related to blood concentrations of folate.145,147 Data from randomized studies indicate that dietary supplementation with folic acid reduces blood homocysteine concentrations.145 Whether supplemental folic acid alters the risk of cardiovascular disease in patients with preexisting vascular disease has been investigated in several small randomized studies.147 However, the studies have yielded inconsistent results, and interpretation is limited by statistical limitations (i.e., inadequate power).147 A meta-analysis of 12 studies published before July 2006 was undertaken to qualify the relationship between supplemental folic acid and the risk of cardiovascular disease and all-cause mortality in patients with vascular disease.147 This meta-analysis found no important benefit or harm of folic acid supplementation on the risk of cardiovascular disease, coronary heart disease, stroke, or all-cause mortality in this patient population.147

Administration

Folic acid is usually administered orally. When oral administration is not feasible or when malabsorption is suspected, the drug may be administered by deep IM, subcutaneous, or IV injection. However, most patients with malabsorption are able to absorb oral folic acid.

Dosage

Dosage of folic acid injection (sodium folate) is expressed in terms of folic acid. In general, although patient response to folic acid therapy depends on the degree and nature of the deficiency, once proper corrective measures are undertaken, folate-deficient patients generally respond rapidly. During the first 24 hours of treatment, the patient experiences an improved sense of well-being, and within 48 hours, the bone marrow begins to become normoblastic. Reticulocytosis generally begins within 2-5 days following initiation of folic acid therapy.

Dietary and Replacement Requirements

The Adequate Intake (AI) (see Uses: Dietary Requirements) of folate currently recommended by the National Academy of Sciences (NAS) for healthy infants up to 6 months of age is 65 mcg daily and for those 6-12 months of age is 80 mcg daily.140 This AI is based on the observed mean folate intake of infants fed principally human milk; data currently are unavailable to support the thesis that intake of folate from infant formula needs to be different than that from human milk to achieve the same folate status.140

Because bioavailability of folic acid differs from that of food folates, the recommended dietary allowance (RDA) is expressed in terms of dietary folate equivalents/day.140 Dietary food folate equivalents (DFE) are calculated as follows: 1 mcg of dietary folate equivalent = 1 mcg of food folate = 0.5 mcg of folic acid taken in the fasting state = 0.6 mcg of folic acid taken with food.140 The RDA of folate currently recommended by the NAS for healthy children 1-3, 4-8, 9-13, or 14-18 years of age is 0.15, 0.2, 0.3, or 0.4 mg of DFE daily, respectively.140 The RDA of folate for healthy adults 19-50 years of age and 51 years of age and older is 0.4 mg of DFE daily.140

Folate requirements increase substantially during pregnancy because of the acceleration in single-carbon transfer reactions.140 The RDA of folate recommended by NAS for pregnant women is 0.6 mg DFE daily.140 Folate requirements in lactating women include the amount required to maintain folate status and the amount required to replace the folate secreted daily in human milk.140 The RDA of folate recommended by NAS for lactating women is 0.5 mg DFE daily.140 Folate intake exceeding these RDAs may be needed by women who are pregnant with more than one fetus and mothers nursing more than one infant.140

The usual therapeutic dosage of folic acid for adults and children is 0.25-1 mg daily; however, some patients may require larger doses. Daily maintenance doses of 0.1 mg for infants, up to 0.3 mg for children younger than 4 years of age, 0.4 mg for adults and children 4 years of age and older, and 0.8 mg for pregnant and lactating women appear sufficient to maintain a normoblastic bone marrow after clinical symptoms have subsided and the blood components have returned to normal. In alcoholics, patients with hemolytic anemia or chronic infections, and patients receiving anticonvulsants or methotrexate, higher maintenance dosages may be required. Oral dosages of 3-15 mg daily have been recommended for patients with tropical sprue.

Prevention of Neural Tube Defects

To reduce the risk of fetal development of neural tube defects, the NAS currently recommends that women of childbearing potential receive 0.4 mg of folic acid daily through fortified foods and/or supplements in addition to food folate consumed from a varied diet.140 The US Preventive Services Task Force recommends that women planning a pregnancy and women capable of becoming pregnant consume 0.4-0.8 mg of folic acid daily from supplements; folic acid should be initiated 1 month before conception and continued during the first 2-3 months of pregnancy.148 While optimum dosage remains to be established, a dosage of 4 mg daily initiated 1 month before and continued for 3 months after conception has been shown to be beneficial in reducing the risk of neural tube defects in women with a history of prior pregnancy complicated by such defects.148 (See Uses: Prevention of Neural Tube Defects.) Such women should maintain the lower level of folic acid intake (i.e., 0.4 mg daily) during other periods of continued childbearing potential.

Adverse Effects

Folic acid is relatively nontoxic. Allergic reactions to folic acid preparations have been reported rarely and have included erythema, rash, itching, general malaise, and bronchospastic respiratory difficulty. One patient experienced symptoms suggesting anaphylaxis following injection of the drug. Adverse GI effects such as anorexia, nausea, abdominal distention, flatulence, and a bitter/bad taste and adverse CNS effects such as altered sleep patterns, difficulty in concentrating, irritability, overactivity, excitement, mental depression, confusion, and impaired judgment have been reported rarely in patients receiving 15 mg of folic acid daily for one month. Decreased serum vitamin B₁₂ concentrations may occur in patients receiving prolonged folic acid therapy.

Precautions and Contraindications

Folic acid should be administered with extreme caution to patients with undiagnosed anemia, since folic acid may obscure the diagnosis of pernicious anemia by alleviating hematologic manifestations of the disease while allowing neurologic complications to progress. This may result in severe nervous system damage before the correct diagnosis is made. Adequate doses of vitamin B₁₂ may prevent, halt, or improve neurologic changes caused by pernicious anemia. (See Vitamin B₁₂ 88:08.)

In folate-deficient patients, folic acid therapy may increase phenytoin metabolism, resulting in decreased phenytoin serum concentrations. Although this interaction is not usually clinically important, an increase in seizure frequency may occur in some patients.

It has been reported that concurrent administration of chloramphenicol and folic acid in folate-deficient patients may result in antagonism of the hematopoietic response to folic acid. Although the importance and mechanism of the interaction is unclear, the hematologic response to folic acid in patients receiving both drugs should be carefully monitored.

Laboratory Test Interferences

Falsely low serum and erythrocyte folate concentrations may occur with the L. casei assay method in patients who have received anti-infectives, such as tetracycline, which suppress the growth of the organism.

Pharmacology

In man, an exogenous source of folate is required for nucleoprotein synthesis and the maintenance of normal erythropoiesis. Folic acid is not metabolically active as such, but is the precursor of tetrahydrofolic acid which is involved as a cofactor for 1-carbon transfer reactions in the biosynthesis of purines and thymidylates of nucleic acids. Impairment of thymidylate synthesis in patients with folic acid deficiency is thought to account for the defective DNA synthesis that leads to megaloblast formation and megaloblastic and macrocytic anemias. Folate is involved in amino acid interconversions (e.g., catabolism of histidine to glutamic acid, interconversion of serine and glycine, conversion of homocysteine to methionine), and generation of formate.140

Pharmacokinetics

Absorption

Folic acid is absorbed rapidly from the GI tract following oral administration; the vitamin is absorbed mainly from the proximal portion of the small intestine. Naturally occurring folate polyglutamates are enzymatically hydrolyzed in the GI tract to monoglutamate forms of folic acid prior to absorption. Following oral administration, peak folate activity in blood occurs within 30-60 minutes. Synthetic folic acid is almost 100% bioavailable when administered in fasting individuals.140 While the bioavailability of naturally occurring folate in food is about 50%, bioavailability of synthetic folic acid consumed with a meal ranges from 85-100%.140

Normal serum total folate concentrations have been reported to range from 0.005-0.015 mcg/mL. In general, serum folate concentrations below 0.005 mcg/mL indicate folate deficiency and concentrations below 0.002 mcg/mL usually result in megaloblastic anemia.

Distribution

Tetrahydrofolic acid and its derivatives are distributed into all body tissues; the liver contains about one-half of total body folate stores. Folate is actively concentrated in CSF, and normal CSF concentrations are reported to be about 0.016-0.021 mcg/mL. Normal red cell folate concentrations range from 0.175-0.316 mcg/mL. Folic acid is distributed into milk.

Elimination

Following absorption of 1 mg or less, folic acid is largely reduced and methylated in the liver to N ⁵-methyltetrahydrofolic acid, which is the main transport form of folate in the body. Larger doses of folic acid may escape metabolism by the liver and appear in the blood mainly as folic acid.

Following oral administration of single 0.1- to 0.2-mg doses of folic acid in healthy adults, only a trace amount of the drug appears in urine. Following administration of large doses, the renal tubular reabsorption maximum is exceeded, and excess folate is excreted unchanged in urine. After doses of about 2.5-5 mg, about 50% of a dose is excreted in urine and after a 15-mg dose, up to 90% may be recovered in urine. Small amounts of orally administered folic acid have been recovered from feces. About 0.05 mg per day of normal body folate stores is lost by a combination of urinary and fecal excretion and oxidative cleavage of the molecule.

Chemistry and Stability

Chemistry

Folic acid is a water-soluble, B complex vitamin. Folic acid (pteroylmonoglutamic acid) is prepared synthetically and consists of a p -aminobenzoic acid molecule linked at one end to a pteridine ring and at the other end to one glutamic acid molecule.140 Folic acid rarely occurs naturally in food; folic acid is used in vitamin supplements and to fortify food products.140 Naturally occurring conjugates of folic acid (food folate; pteroylpolyglutamates) are present in a wide variety of foods, particularly liver, kidneys, yeast, leafy green vegetables, other vegetables, citrus fruits and juice, and legumes; food folates consist of 1-6 additional glutamate molecules joined in a peptide linkage to the γ-carboxyl of glutamate.140

Folic acid occurs as a yellow or yellowish-orange, crystalline powder. Folic acid is very slightly soluble in water, insoluble in alcohol, and readily soluble in dilute solutions of alkali hydroxides and carbonates. Folic acid injection is a sterile solution of folic acid in water for injection prepared with the aid of sodium hydroxide or sodium carbonate; the addition of sodium hydroxide or sodium carbonate to the injection results in formation of sodium folate, which is the soluble sodium salt of folic acid. Commercially available folic acid injection is clear, yellow to orange-yellow in color and has a pH of 8-11.

Stability

Aqueous solutions of folic acid are heat-sensitive and decompose rapidly in the presence of light and/or riboflavin; solutions should be protected from light. Folic acid is incompatible with oxidizing and reducing agents and with heavy metal ions. Specialized references should be consulted for specific compatibility information.

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