Note: Doses are expressed as folic acid. For oral dosing, folic acid 1 mg = dietary folate equivalent (DFE) 1.67 mg (if administered with food) or DFE 2 mg (if taken on an empty stomach).
Alcohol withdrawal syndrome (adjunctive agent) (off-label use): Oral, IV: 400 mcg to 1 mg daily until no longer at risk (ASAM 2020; Flannery 2016). Note: IV route is preferred for patients with suspected or confirmed Wernicke encephalopathy who are critically ill (ASAM 2020; Flannery 2016).
Megaloblastic and macrocytic anemias due to folate deficiency:
Oral: 1 to 5 mg once daily (Cook 2014); doses up to 15 mg once daily have also been recommended (Hoffbrand 2015).
Manufacturer's labeling: Dosing in the prescribing information may not reflect current clinical practice. Oral, IM, IV, SUBQ: Initial: 0.4 to 1 mg/day.
Maintenance dose: 0.4 mg/day.
Pregnant and lactating women: Maintenance dose: 0.8 mg/day.
Methanol toxicity (adjunctive cofactor therapy) (off-label use): Therapy should continue until methanol and formic acid have been completely eliminated (Zakharov 2015). Cofactors are adjunctive to antidotal therapy and should never be used alone.
IV: 50 to 70 mg every 4 hours (Osterloh 1986).
Oral: 50 mg every 3 to 4 hours (Zakharov 2015).
Prevention of neural tube defects (off-label use): Oral:
Females of childbearing potential: 0.4 mg/day (ACOG 187 2017) or 0.4 to 0.8 mg/day (USPSTF [Bibbins-Domingo 2017]). Supplementation should start ≥1 month prior to pregnancy and continue through 12 weeks gestation (ACOG 187 2017).
Females at high risk, who have had a previous pregnancy with a neural tube defect, or with family history of neural tube defects: 4 mg/day. Supplementation should start ≥3 months prior to pregnancy and continue through 12 weeks gestation (ACOG 187 2017).
Supplementation to reduce toxicity associated with antifolate chemotherapy (off-label use): Oral:
To reduce toxicity associated with pemetrexed: Administer folic acid 0.35 to 1 mg once daily, beginning 1 to 3 weeks prior to pemetrexed treatment initiation; continue for 3 weeks after the last pemetrexed dose; administer with intramuscular cyanocobalamin supplementation (Scagliotti 2008, Vogelzang 2003).
To reduce toxicity associated with pralatrexate: Administer folic acid 1 to 1.25 mg once daily (O’Connor 2011), beginning 10 days prior to pralatrexate treatment initiation; continue for 30 days after the last pralatrexate dose; administer with intramuscular cyanocobalamin supplementation.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
(For additional information see "Folic acid: Pediatric drug information")
Note: Doses are expressed as folic acid. For oral dosing, folic acid 1 mg = dietary folate equivalent (DFE) 1.67 mg (when taken with food) or DFE 2 mg (if taken on an empty stomach). Compounded oral suspensions may be available in multiple concentrations; precautions should be taken to verify and avoid confusion between the different concentrations; dose should be clearly presented as mg amount.
Anemia (folic acid deficiency); treatment:
Note: Parenteral route may be necessary for severe disease or if gastrointestinal absorption is impaired.
Initial: Infants, Children, and Adolescents: Oral, IM, IV, SUBQ: 0.5 to 1 mg daily for 3 to 4 weeks until definite hematologic response (Kliegman 2020).
Maintenance: Note: A multivitamin containing 0.2 mg folic acid may be adequate for maintenance (Kliegman 2020).
Infants: Oral, IM, IV, SUBQ: 0.1 mg/day.
Children <4 years: Oral, IM, IV, SUBQ: 0.1 to 0.3 mg/day.
Children ≥4 years and Adolescents: Oral, IM, IV, SUBQ: 0.1 to 0.4 mg/day.
Parenteral nutrition, maintenance requirement of folic acid (ASPEN [Vanek 2012]; ESPGHAN/ESPEN/ESPR/CSPEN [Bronsky 2018]):
Infants: IV: 56 mcg/kg/day.
Children and Adolescents: IV: 140 mcg/day.
Gingival hyperplasia due to phenytoin, prevention: Limited data available: Children ≥6 years and Adolescents: Oral: 0.5 mg/day; dosing based on results from a double-blind, randomized, placebo-controlled trial of 120 pediatric patients (treatment arm, n=62; age range: 6 to 15 years) who were started on phenytoin therapy; folate treatment resulted in lower rate of hyperplasia (treatment arm: 21% vs placebo: 88%); severity was also lower in treated patients compared to placebo (Arya 2011).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Refer to adult dosing. Vitamin B12 deficiency must be ruled out before initiating folate therapy due to frequency of combined nutritional deficiencies.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, Oral [preservative free]:
FA-8: 0.8 mg [dye free, sugar free, yeast free]
Generic: 5 mg, 20 mg
Solution, Injection, as sodium folate:
Generic: 5 mg/mL (10 mL)
Tablet, Oral:
Generic: 400 mcg, 800 mcg, 1 mg
Tablet, Oral [preservative free]:
FA-8: 800 mcg [DSC] [dye free]
Generic: 400 mcg [DSC], 800 mcg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Injection, as sodium folate:
Generic: 5 mg/mL (10 mL)
Tablet, Oral:
Generic: 5 mg, 25 mg
Oral preferred, but may also be administered by deep IM, SubQ, or IV injection.
IV administration: May administer ≤5 mg dose undiluted over ≥1 minute or may dilute ≤5 mg in 50 mL of NS or D5W and infuse over 30 minutes. May also be added to IV maintenance solutions and given as an infusion.
Oral (preferred): May be administered without regard to meals
Parenteral:
IM, SubQ: May administer undiluted deep IM or SubQ
IV: May administer doses ≤5 mg undiluted over ≥1 minute or may further dilute and infuse over 30 minutes. May also be given as an infusion when added to IV maintenance solutions.
Megaloblastic and macrocytic anemias due to folate deficiency: Treatment of megaloblastic and macrocytic anemias due to folate deficiency
Alcohol withdrawal syndrome (adjunctive agent); Methanol toxicity (adjunctive cofactor therapy) (alternative to leucovorin calcium); Neural tube defects; Supplementation to reduce toxicity associated with antifolate chemotherapy
Folic acid may be confused with folinic acid (leucovorin calcium)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency not defined.
Cardiovascular: Flushing (slight)
Central nervous system: Malaise (general)
Dermatologic: Erythema, pruritus, skin rash
Hypersensitivity: Hypersensitivity reaction
Respiratory: Bronchospasm
Hypersensitivity to folic acid or any component of the formulation
Disease-related concerns:
• Anemia: Monotherapy: Not appropriate for monotherapy with pernicious, aplastic, or normocytic anemias when anemia is present with vitamin B12 deficiency.
• Pernicious anemia: Doses >0.1 mg/day may obscure pernicious anemia with continuing irreversible nerve damage progression.
Dosage form specific issues:
• Aluminum: The parenteral product may contain aluminum; toxic aluminum concentrations may be seen with high doses, prolonged use, or renal dysfunction. Premature neonates are at higher risk due to immature renal function and aluminum intake from other parenteral sources. Parenteral aluminum exposure of >4 to 5 mcg/kg/day is associated with CNS and bone toxicity; tissue loading may occur at lower doses (Federal Register 2002). See manufacturer’s labeling.
• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997], CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.
Other warnings/precautions:
• Methanol toxicity: Folic acid should be used only if leucovorin is unavailable. Leucovorin is the reduced form of folic acid; leucovorin is rapidly converted to tetrahydrofolic acid derivatives which are the storage forms of folate in the body. Because leucovorin does not require metabolic reduction, it is the preferred form of folate in the treatment of methanol toxicity (Barceloux 2002).
• Resistance to treatment: May occur with depressed hematopoiesis, alcoholism, and deficiencies of other vitamins.
None known.
Fluorouracil Products: Folic Acid may enhance the adverse/toxic effect of Fluorouracil Products. Risk C: Monitor therapy
Fosphenytoin: Folic Acid may decrease the serum concentration of Fosphenytoin. Risk C: Monitor therapy
Green Tea: May decrease the serum concentration of Folic Acid. Risk C: Monitor therapy
Pafolacianine: Folic Acid may diminish the diagnostic effect of Pafolacianine. Risk X: Avoid combination
PHENobarbital: Folic Acid may decrease the serum concentration of PHENobarbital. Risk C: Monitor therapy
Phenytoin: Folic Acid may decrease the serum concentration of Phenytoin. Risk C: Monitor therapy
Primidone: Folic Acid may decrease the serum concentration of Primidone. Additionally, folic acid may decrease concentrations of active metabolites of primidone (e.g., phenobarbital). Risk C: Monitor therapy
Pyrimethamine: Folic Acid may diminish the therapeutic effect of Pyrimethamine. Management: Folic acid doses greater than 2.5 mg per day should be avoided due to the potential for sulfadoxine/pyrimethamine treatment failure. Consider limiting folic acid use to no more than 0.4 mg per day for women of child-bearing age. Risk D: Consider therapy modification
Raltitrexed: Folic Acid may diminish the therapeutic effect of Raltitrexed. Risk X: Avoid combination
Sulfadoxine: Folic Acid may diminish the therapeutic effect of Sulfadoxine. Management: Folic acid doses greater than 2.5 mg per day should be avoided due to the potential for sulfadoxine/pyrimethamine treatment failure. Consider limiting folic acid use to no more than 0.4 mg per day for women of child-bearing age. Risk D: Consider therapy modification
SulfaSALAzine: May decrease the serum concentration of Folic Acid. Risk C: Monitor therapy
Folate supplementation during the periconceptual period decreases the risk of neural tube defects. All females planning a pregnancy or who may potentially become pregnant should begin folic acid supplementation prior to conception. Higher doses are required in females at high risk of neural tube defects (ACOG 187 2017; USPSTF [Bibbins-Domingo 2017]).
Water soluble vitamins cross the placenta (IOM 1998).
Folate requirements increase during pregnancy (IOM 1998). Folate supplementation during the periconceptual period decreases the risk of neural tube defects. Higher doses are required in females at high risk of neural tube defects (ACOG 187 2017; USPSTF [Bibbins-Domingo 2017]). Folic acid is also indicated for the treatment of anemias due to folate deficiency in pregnant women.
Folate is present in breast milk; concentrations are not affected by dietary intake unless the mother has a severe deficiency. Folate requirements increase in breastfeeding women (IOM 1998).
As of January 1998, the FDA has required manufacturers of enriched flour, bread, corn meal, pasta, rice, and other grain products to add folic acid to their products. The intent is to help decrease the risk of neural tube defects by increasing folic acid intake. Other foods which contain folic acid include dark green leafy vegetables, citrus fruits and juices, and lentils.
Dietary adequate intake (AI) (IOM 1998): Expressed as dietary folate equivalents:
1 to 6 months: 65 mcg/day
7 to 12 months: 80 mcg/day
Dietary recommended daily allowance (RDA) (IOM 1998): Expressed as dietary folate equivalents:
1 to 3 years: 150 mcg/day
4 to 8 years: 200 mcg/day
9 to 13 years: 300 mcg/day
>13 years: 400 mcg/day
Pregnancy: 600 mcg/day
Lactation: 500 mcg/day
Therapeutic: 0.005 to 0.015 mcg/mL
Folic acid is necessary for formation of a number of coenzymes in many metabolic systems, particularly for purine and pyrimidine synthesis; required for nucleoprotein synthesis and maintenance in erythropoiesis; stimulates WBC and platelet production in folate deficiency anemia.
In patients exposed to methanol, the toxic metabolite formic acid is bound to tetrahydrofolate and metabolized to carbon dioxide and water by 10-formyltetrahydrofolate dehydrogenase. Hypothetically, administration of folic acid enhances the metabolism of formic acid to nontoxic metabolites (Barceloux 2002).
Absorption: Proximal part of small intestine
Metabolism: Hepatic
Bioavailability: Oral: Folic acid supplement: ~100%; In presence of food: 85%; Dietary folate: 50% (IOM 1998)
Time to peak: Oral: 1 hour
Excretion: Urine
Capsules (FA-8 Oral)
0.8 mg (per each): $0.04
Capsules (Folic Acid Oral)
5 mg (per each): $0.07
20 mg (per each): $0.08
Solution (Folic Acid Injection)
5 mg/mL (per mL): $4.38 - $5.90
Tablets (Folic Acid Oral)
1 mg (per each): $0.04 - $0.36
400 mcg (per each): $0.02
800 mcg (per each): $0.03
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