Folic Acid (Systemic)


VA CLASSIFICATION
Primary: VT120

Commonly used brand name(s): Apo-Folic; Folvite; Novo-Folacid.

Another commonly used name is
Vitamin B 9 .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Nutritional supplement (vitamin)—

diagnostic aid (folate deficiency)—
Note: Folic acid (vitamin B 9) is a water-soluble vitamin.



Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Folic acid deficiency (prophylaxis and treatment)—Folic acid is indicated for prevention and treatment of folic acid deficiency states, including megaloblastic anemia and in anemias of nutritional origin, pregnancy, infancy, or childhood.{01}{40} Folic acid deficiency may occur as a result of inadequate nutrition or intestinal malabsorption but does not occur in healthy individuals receiving an adequate balanced diet. Simple nutritional deficiency of individual B vitamins is rare since dietary inadequacy usually results in multiple deficiencies. For prophylaxis of folic acid deficiency, dietary improvement, rather than supplementation, is advisable. For treatment of folic acid deficiency, supplementation is preferred. {36}
—Folic acid should not be given until the diagnosis of pernicious anemia has been ruled out, since it corrects the hematologic manifestations and masks pernicious anemia while allowing neurologic damage to progress. {04}
—Deficiency of folic acid may lead to megaloblastic {05} and macrocytic anemias {04} and glossitis. {05}
—Recommended intakes may be increased and/or supplementation may be necessary in the following persons or conditions (based on documented folic acid deficiency):

• Alcoholism {20}


• Anemia, hemolytic {05}


• Fever, chronic {03}


• Gastrectomy {03}


• Hemodialysis, chronic {03}


• Infants—low-birthweight, breast-fed, or those receiving unfortified formulas such as evaporated milk or goat"s milk


• Intestinal diseases—celiac disease, tropical sprue, persistent diarrhea {05}


• Malabsorption syndromes associated with hepatic-biliary disease—hepatic function impairment, alcoholism with cirrhosis {05}


• Stress, prolonged {03}

—Some unusual diets (e.g., reducing diets that drastically restrict food selection) may not supply minimum daily requirements of folic acid. Supplementation is necessary in patients receiving total parenteral nutrition (TPN) or undergoing rapid weight loss or in those with malnutrition, because of inadequate dietary intake. {03}
—Recommended intakes for all vitamins and most minerals are increased during pregnancy. Many physicians recommend that pregnant women receive multivitamin and mineral supplements, especially those pregnant women who do not consume an adequate diet and those in high-risk categories (i.e., women carrying more than one fetus, heavy cigarette smokers, and alcohol and drug abusers). {25} Taking excessive amounts of a multivitamin and mineral supplement may be harmful to the mother and/or fetus and should be avoided.
—Some studies have found that folic acid supplementation alone or in combination with other vitamins given before conception and during early pregnancy may reduce the incidence of neural tube defects in infants. {06} {14} {15} {16} {17} {29}
—Recommended intakes for all vitamins and most minerals are increased during breast-feeding. {09}
—Recommended intakes may be increased by the following medications: Analgesics (long-term use) {08}, anticonvulsants, {04} epoetin, {22} {23} estrogens {04}, sulfasalazine. {11}

[Folate deficiency (diagnosis)]1—Folic acid is being used in the diagnosis of folate deficiency. {04}

Unaccepted
Folic acid has not been proven effective for prevention of mental disorders or in the treatment of normocytic, refractory, or aplastic anemias. {04}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    441.41 {37}

Mechanism of action/Effect:

Folic acid, after conversion to tetrahydrofolic acid, is necessary for normal erythropoiesis {05}, synthesis of purine and thymidylates {03}, metabolism of amino acids such as glycine and methionine, {05} and the metabolism of histidine. {05}

Absorption:

Commercially available folic acid is almost completely absorbed from the gastrointestinal tract (mostly in the upper duodenum), even in the presence of malabsorption due to tropical sprue. However, absorption of food folates is impaired in malabsorption syndromes.

Protein binding:

Extensive (to plasma proteins). {05}


Storage

Hepatic (large proportion). {01}

Biotransformation:

Hepatic. Folic acid is converted (in the presence of ascorbic acid) in the liver and plasma to its metabolically active form (tetrahydrofolic acid) by dihydrofolate reductase. {05}

Peak serum concentration:

30 to 60 minutes. {01}

Elimination:
    Renal (almost entirely as metabolites). {01} Excess beyond daily needs is excreted, largely unchanged, in urine. {05}
    In dialysis—Folic acid is removed by hemodialysis {01}; therefore, dialysis patients should receive increased amounts (100 to 300% of USRDA [United States Recommended Daily Allowances]).


Precautions to Consider

Pregnancy/Reproduction

Pregnancy—
Problems in humans have not been documented with intake of normal daily recommended amounts. Folic acid crosses the placenta. However, adequate and well-controlled studies in humans have not shown that folic acid causes adverse effects on the fetus. {01}

Some studies have found that folic acid supplementation alone or in combination with other vitamins given before conception and during early pregnancy may reduce the incidence of neural tube defects in infants. {06} {14} {15} {16} {17} {29}

FDA Pregnancy Category A.{40}

Breast-feeding

Folic acid is distributed into breast milk. {01} However, problems in humans have not been documented with intake of normal daily recommended amounts.

Pediatrics

Problems in pediatrics have not been documented with intake of normal daily recommended amounts.

Folic acid injection that contains benzyl alcohol as a preservative should not be used in newborn and immature infants. The use of benzyl alcohol in neonates has been associated with a fatal toxic syndrome consisting of metabolic acidosis and CNS, respiratory, circulatory, and renal function impairment. {12} {13}


Geriatrics


Problems in geriatrics have not been documented with intake of normal daily recommended amounts.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Analgesics, long-term use or {08}
Anticonvulsants, hydantoin or {01} {20}
Carbamazepine or {01} {18}
Estrogens or {03} {20}
Oral contraceptives or{19} {20}
Phenobarbital or{40}
Primidone{40}    (requirements for folic acid may be increased in patients receiving these medications)

    (concurrent use with folic acid may decrease the effects of hydantoin anticonvulsants by antagonism of their central nervous system [CNS] effects; an increase in hydantoin dosage may be necessary for patients who receive folic acid supplementation {01})


Antacids, aluminum- or magnesium-containing    (prolonged use of aluminum- and/or magnesium-containing antacids may decrease folic acid absorption by lowering the pH of the small intestine; patients should be advised to take antacids at least 2 hours after folic acid {21})


Antibiotics    (may interfere with the microbiologic method of assay for serum and erythrocyte folic acid concentrations and cause falsely low results {01} {04})


Cholestyramine    (concurrent use with folic acid may interfere with absorption of folic acid; folic acid supplementation taken at least 1 hour before or 4 to 6 hours after cholestyramine is recommended in patients receiving cholestyramine for prolonged periods {10})


Methotrexate or {01} {24}
Pyrimethamine or {01} {24}
Triamterene or {24}
Trimethoprim {03} {24}    (act as folate antagonists by inhibiting dihydrofolate reductase; most significant with high doses and/or prolonged use; leucovorin calcium must be used instead of folic acid in patients receiving these medications)


Sulfonamides, including sulfasalazine    (inhibit absorption of folate; folic acid requirements may be increased in patients receiving sulfasalazine {07} {11})


Zinc supplements    (some studies have found that folate may decrease the absorption of zinc, but not in the presence of excessive zinc; other studies have found no inhibition {26} {27} {28})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Vitamin B 12 concentrations in blood     (may be reduced by large and continuous doses of folic acid)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Pernicious anemia    (folic acid will correct hematologic abnormalities but neurologic problems will progress irreversibly; doses of folic acid greater than 0.4 mg per day are not recommended until pernicious anemia has been ruled out, except during pregnancy and lactation {02})


Sensitivity to folic acid {01} {02}


Side/Adverse Effects

Note: No side effects other than an allergic reaction have been reported with folic acid administration, even at doses of up to 10 times the recommended dietary allowances (RDA) for 1 month.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
    
Allergic reaction, specifically {01} {02}
bronchospasm (shortness of breath; troubled breathing; tightness of chest; wheezing), erythema (reddened skin), fever
general malaise {40}( general weakness or discomfort), skin rash or itching


Note: Side effects including abdominal bloating and gas, anorexia, confusion, depression, difficulty in concentrating, excitement, irritability, impaired judgment, nausea, trouble in sleeping, and unpleasant taste were reported in a study of patients taking 15 mg daily.{40}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Folic Acid (Vitamin B 9) (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Description of use
Description should include function in the body, signs of deficiency, and unproven uses


Importance of diet
Importance of proper nutrition; supplement may be needed because of inadequate dietary intake

Food sources of folic acid; effects of processing

Not using vitamins as substitute for balanced diet

Recommended daily intake for folic acid

Before using this dietary supplement
»   Conditions affecting use, especially:
Other medical problems, especially pernicious anemia

Proper use of this dietary supplement

» Proper dosing
Missed dose: No cause for concern because of length of time necessary for depletion; remembering to take as directed

» Proper storage


Side/adverse effects
Signs of potential side effects, especially allergic reaction, specifically bronchospasm, erythema, fever, general malaise, skin rash, or itching


General Dosing Information
Because of the infrequency of single B vitamin deficiencies, combinations are commonly administered. Many commercial combinations of B vitamins are available.

For parenteral dosage forms only
In most cases, parenteral administration is indicated only when oral administration is not acceptable (for example, in nausea, vomiting, preoperative and postoperative conditions) or possible (for example, in malabsorption syndromes or following gastric resection). {01}

Diet/Nutrition
Recommended dietary intakes for folic acid are defined differently worldwide.



For U.S.:
The Recommended Dietary Allowances (RDAs) for vitamins and minerals are determined by the Food and Nutrition Board of the National Research Council and are intended to provide adequate nutrition in most healthy persons under usual environmental stresses. In addition, a different designation may be used by the FDA for food and dietary supplement labeling purposes, as with Daily Value (DV). DVs replace the previous labeling terminology United States Recommended Daily Allowances (USRDAs). {09} {38}



For Canada:
Recommended Nutrient Intakes (RNIs) for vitamins, minerals, and protein are determined by Health and Welfare Canada and provide recommended amounts of a specific nutrient while minimizing the risk of chronic diseases. {39}

Daily recommended intakes for folic acid are generally defined as follows: {09} {39}

Persons
U.S.
(mcg)
Canada
(mcg)
Infants and children
Birth to 3 years of age
25–50
50–80
4 to 6 years of age
75
90
7 to 10 years of age
100
125–180
Adolescent and adult males
150–200
150–220
Adolescent and adult females
150–180
145–190
Pregnant females
400
445–475
Breast-feeding females
260–280
245–275


These are usually provided by adequate diets.

Best dietary sources of folic acid include vegetables, especially green vegetables; potatoes; cereal and cereal products; fruits; and organ meats (liver, kidney). {03} Heat destroys folic acid (50 to 90%) in foods. {05}



Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

FOLIC ACID TABLETS USP

Usual adult and adolescent dose
Deficiency (prophylaxis)
Oral, amount based on normal daily recommended intakes:

Persons
U.S.
(mcg)
Canada
(mcg)
Adolescent and adult males
150–400
150–220
Adolescent and adult females
150–400
145–190
Pregnant females
400 to 800
445–475
Breast-feeding females
260–800
245–275

{40}
Deficiency (treatment)
Treatment dose is individualized by prescriber based on severity of deficiency.

[Diagnostic aid (folate deficiency)]1
Oral, 100 to 200 mcg (0.1 to 0.2 mg) a day for ten days plus low dietary folic acid and vitamin B 12 . {04}


Usual pediatric dose
Deficiency (prophylaxis)
Oral, amount based on normal daily recommended intakes:

Persons
U.S.
(mcg)
Canada
(mcg)
Infants and children
Birth to 3 years of age
25–
50–80
4 to 6 years of age
75–400
90
7 to 10 years of age
100–400
125–180


Deficiency (treatment)
Treatment dose is individualized by prescriber based on severity of deficiency.


Strength(s) usually available
U.S.—


100 mcg (Rx)[Generic]


400 mcg (Rx)[Generic]


800 mcg (Rx)[Generic]


1 mg (Rx) [Folvite][Generic]

Canada—


5 mg (Rx) [Apo-Folic (scored){30}] [Folvite (scored){31}] [Novo-Folacid{32}][Generic]{33}

Note: Some strengths of these folic acid preparations may exceed the dosage range recommended by USP DI Advisory Panels based on the amount necessary to meet normal nutritional needs.


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed container.



Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.


FOLIC ACID INJECTION USP

Usual adult and adolescent dose
Deficiency (prophylaxis)
Intravenous infusion, as part of total parenteral nutrition solutions, the specific amount determined by individual patient need.

Deficiency (treatment)
Intramuscular, intravenous, or deep subcutaneous: 250 mcg (0.25 mg) to 1 mg a day until a hematologic response occurs. {02}

[Diagnostic aid (folate deficiency)]1
Intramuscular, 100 to 200 mcg (0.1 to 0.2 mg) a day for ten days plus low dietary folic acid and vitamin B 1 2. {04}


Usual pediatric dose
See Usual adult and adolescent dose.

Note: Folic acid injection that contains benzyl alcohol as a preservative should not be used in newborn and immature infants. The use of benzyl alcohol in neonates has been associated with a fatal toxic syndrome consisting of metabolic acidosis and CNS, respiratory, circulatory, and renal function impairment.


Strength(s) usually available
U.S.—


5 mg (base) per mL (Rx) [Folvite (benzyl alcohol 1.5%)][Generic]


10 mg per mL (Rx)[Generic]{34}{35}

Canada—


5 mg (base) per mL (Rx) [Folvite]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light. Protect from freezing.



Revised: 12/30/1999



References
  1. Folic acid product information (Lilly—US), Rec 4/90, Rev 1/90.
  1. Folic acid injection product information (LyphoMed—US), Rec 6/86, Rev 7/85.
  1. Elsborg L, Lyngbye J, Ryttig K. Folic acid and folic acid deficiency. A/S Ferrosan Copenhagen, 3/81.
  1. McEvoy GK, editor. AHFS Drug information 90. Bethesda, MD: American Society of Hospital Pharmacists, 1990: 2111–2.
  1. Gilman AG, Goodman LS, Rall TW, Murad F, editors. Goodman and Gilman"s the pharmocological basis of therapeutics. 7th ed. New York: Macmillan, 1985: 1332–6.
  1. Centers for Disease Control: Use of folic acid for prevention of spina bifida and other neural tube defects— 1983-1991. MMWR 1991; 40: 513-16.
  1. Drug Interactions, I. Stockley, 1981, p 102.
  1. Tatro DS, editor. Drug interaction facts. St Louis: Facts and Comparisons, 1990: 162.
  1. National Research Council. Recommended dietary allowances. 10th ed. Washington, DC: National Academy Press, 1989: 150–8.
  1. Questran product information (Mead Johnson–US).
  1. Prouse P, Shawe D, Gumpel J. Macrocytic anemia in patients treated with sulphasalazine for rheumatoid arthritis. Br Med J 1987; 294: 904-5.
  1. FDA Drug Bulletin, 8/82, 12: 10-11.
  1. Hiller J, Brenda G, Rahatzad M, et al. Benzyl alcohol toxicity impact on mortality and intraventricular hemorrhage among very low birth weight infants. Pediatrics 1986; 77(4): 500-6.
  1. Manufacturer comments, 1991.
  1. Bower C, Stanley F. Dietary folate as a risk factor for neural-tube defects: evidence from a case-control study in western Australia. Med J Austral 1989; 150: 613-9.
  1. Milunsky A, Jick H, Jick S, et al. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA 1989; 262(20): 2847-52.
  1. Laurence K, James N, Miller M, et al. Double-blind randomized controlled trial of folate treatment before conception to prevent recurrence of neural-tube defects. Br Med J 1981; 282: 1509-11.
  1. Inoue E. Clinical implications of anticonvulsant-induced folate deficiency. Clin Pharm 1983; 1: 372-3.
  1. D"Arcy P. Drug interactions with oral contraceptives. DICP 1986; 20: 353-62.
  1. Matsui M, Rozovski D. Drug-nutrient interaction. Clin Ther 1982; 4(6): 423-40.
  1. Russell R, Golner B, Krasinski S, et al. Effect of antacid and H 2 receptor antagonists on the intestinal absorption of folic acid. J Lab Clin Med; 112(4): 458-63.
  1. Epogen product information (Amgen—US), Rev 6/89.
  1. Eprex product information (Ortho—Canada), Rec 5/90.
  1. Butterworth C, Tamura T. Folic acid safety and toxicity: a brief review. Am J Clin Nutr 1989; 50: 353-8.
  1. Committee on Nutritional Status during Pregnancy, National Academy of Sciences. Washington, DC: National Academy Press, 1990: 1-23.
  1. Panel consensus, Zinc Supplements monograph 1991.
  1. Milne D, Canfield W, Mahalko J, Sandstead H. Effect of oral folic acid supplements on zinc, copper, and iron absorption and excretion. Am J Clin Nutr 1984; 39: 535-9.
  1. Butterworth C, Hatch K, Cole P, et al. Zinc concentration in plasma and erythrocytes of subjects receiving folic acid supplementation. Am J Clin Nutr 1988; 47: 484-6.
  1. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the medical research council vitamin study. Lancet 1991; 338(8769): 131-7.
  1. Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical Association, 1993: 85.
  1. Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 28th ed. Ottawa: Canadian Pharmaceutical Association, 1993: 473.
  1. Per phone call (Novopharm/Canada), 9/28/93.
  1. Per phone call (Stanley/Canada), 9/28/93.
  1. Olin BR, editor. Drug facts and comparisons. St. Louis: Facts and Comparisons Inc, 1987 Jun: 78a.
  1. Red book 1993. Montvale, NJ: Medical Economics Data, 1993: 256.
  1. Nutrition and Electrolytes Advisory Panel Meeting, 1/95.
  1. Fleeger CA, editor. USP dictionary of USAN and international drug names 1995. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1994: 300.
  1. Food and Drug Administration. Focus on food labeling. FDA Consum. May, 1993.
  1. Health and Welfare Canada. Nutrition recommendations, the report of the scientific committee. Ottawa, Canada: Canadian Government Publishing Centre, 1990: 11-2.
  1. Product Information: Folic acid tablets, Danbury Pharmacal, Danbury, CT, USA, July 1998.
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