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folic acid; folate; vitamin B9

Body stores: generally 5-10 mg. Pharmacology: Indications: - prevention & treatment of folate deficiency [15] - treatment of megaloblastic anemia - treatment of hyperhomocysteinemia (see Folgard Rx) - homocystinuria - pregnancy* - prevention of neural tube defects in fetus [11,21] - periconceptional folic acid reduces risk for autism in offspring (women) [14] - prevention of congenital heart disease [7] - lactating mother [15] - prevention of hypertension (women) - prevention of stroke in patients with hypertension [18,20] (2.7% vs. 3.4%) especially among those with low serum folate - adjunct for treatment of depression [12] - all persons planning to or who could become pregnant* [22] * folic acid fortification of cereal grains prevents > 1300 neural tube defects annually [16] * folic acid supplementation in high-risk pregnancy is only 37% [17] * daily supplement containing 0.4 to 0.8 mg [22] Contraindications: - NOT useful for secondary prevention of: [3] a) myocardial infarction b) stroke - NOT useful for prevention of Alzheimer's disease or vascular demenia [23] Dosage: 1) RDA (male) 0.15-0.2 mg/day, female 0.15-0.18 mg/day or 400 ug/day 2) pregnancy: 0.4-1 mg PO QD (begin 1 month before conception, continue for 2-3 months after delivery) [4,11] 3) alcoholics 1 mg PO QD Tablets: 400 ug, 800 ug, 1 mg. Injection: 5 mg/mL (10 mL) Adverse effects: - doses > 1 mg/day may obscure hematologic manifestations of pernicious anemia (vit B12 deficiency) - supplementation may increase risk of prostate cancer (RR=1.24) [6] - supplementation may increase risk of colorectal cancer (RR=1.28) [19] - supplementation of folic acid 0.8 mg, vit B12 0.4 mg & vit B6 40 mg QD increases a) risk of cancer overall (RR=1.07) b) risk of dying of cancer c) all cause mortality - hazzard ratio 1.2-1.4, number needed to harm 40-90 [8] - folic acid impairs immune surveillance of cancer cells & might stimulate the growth of established cancers - supplementation of up to 2.0 mg/day for 5 years not associated with increased risk of cancer of any type [13] - folic acid supplementation alone was associated with an increased risk of Alzheimer's disease (RR=1.34) & vascular dementia (RR=1.61) [23] - corresponding reductions in volumes of hippocampus & amygdala noted [23] - these adverse effects not observed when folic acid was combined with with other B vitamins [23] Drug interactions: - 5-aminosalicylic acid, oral contraceptives, phenytoin, & sulfasalazine may decrease folate levels Mechanism of action: -> 0.5 mg folate QD decreases serum homocysteine 18%

Interactions

molecular events

Related

folate antagonist; folic acid analog; folic acid antagonist folate deficiency folate in serum/plasma folate metabolism folate receptor or folate-binding protein N5-formyltetrahydrofolate (folinic acid, citrovorum factor, Fusilev)

Specific

dihydrofolate tetrahydrofolate (THF)

General

biopterin B vitamin

Properties

MISC-INFO: elimination route KIDNEY pregnancy-category A safety in lactation +

Database Correlations

PUBCHEM correlations KEGG correlations

References

  1. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  2. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  3. Journal Watch 23(17):134, 2003 Liem A et al Secondary prevention with folic acid: effects on clinical outcomes. Coll Cardiol 41:2105, 2003 PMID: 12821232
  4. Journal Watch 24(10):82, 2004 Cleves MA, Hobbs CA, Collins HB, Andrews N, Smith LN, Robbins JM. Folic acid use by women receiving routine gynecologic care. Obstet Gynecol. 2004 Apr;103(4):746-53. PMID: 15051568
  5. Journal Watch 25(11):87-88, 2005 Botto LD, Lisi A, Robert-Gnansia E, Erickson JD, Vollset SE, Mastroiacovo P, Botting B, Cocchi G, de Vigan C, de Walle H, Feijoo M, Irgens LM, McDonnell B, Merlob P, Ritvanen A, Scarano G, Siffel C, Metneki J, Stoll C, Smithells R, Goujard J. International retrospective cohort study of neural tube defects in relation to folic acid recommendations: are the recommendations working? BMJ. 2005 Mar 12;330(7491):571. Epub 2005 Feb 18. PMID: 15722368 http://bmj.bmjjournals.com/cgi/content/full/330/7491/571
  6. Figueiredo JC et al Folic acid and risk of prostate cancer: Results from a randomized clinical trial. J Natl Cancer Inst 2009 Mar 18; 101:432. PMID: 19276452
  7. Ionescu-Ittu R et al, Prevalence of severe congenital heart disease after folic acid fortification of grain products: time trend analysis in Quebec, Canada BMJ 2009;338:b1673 PMID: 19436079 http://www.bmj.com/cgi/content/full/338/may12_2/b1673
  8. Ebbing M et al Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA 2009 Nov 18; 302:2119. PMID: 19920236 - Drake BF and Colditz GA Assessing cancer prevention studies - A matter of time. JAMA 2009 Nov 18; 302:2152 PMID: 19920243
  9. Department of Veterans Affairs, VA National Formulary
  10. Prescriber's Letter 17(1): 2010 Folic Acid and Cancer Risk Detail-Document#: 260109 (subscription needed) http://www.prescribersletter.com
  11. Wolff T et al Folic acid supplementation for the prevention of neural tube defects: an update of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2009 May 5;150(9):632-9. PMID: 19414843 U.S. Preventive Services Task Force. Folic acid for the prevention of neural tube defects: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009 May 5;150(9):626-31. PMID: 19414842 - corresponding NGC guideline withdrawn Dec 2014
  12. Prescriber's Letter 18(10): 2011 Folate for Depression Detail-Document#: 271003 (subscription needed) http://www.prescribersletter.com
  13. Vollset SE et al Effects of folic acid supplementation on overall and site- specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals. The Lancet, Early Online Publication, 25 January 2013 PMID: 23352552 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)62001-7/abstract - Miller JW and Ulrich CM. Folic acid and cancer - Where are we today? Lancet 2013 Jan 25 PMID: 23352551
  14. Suren P et al Association Between Maternal Use of Folic Acid Supplements and Risk of Autism Spectrum Disorders in Children JAMA. 2013;309(6):570-577. PMID: 23403681 http://jama.jamanetwork.com/article.aspx?articleid=1570279 - Berry RJ et al Periconceptional Folic Acid and Risk of Autism Spectrum Disorders. JAMA. 2013;309(6):611-613 PMID: 23403688 http://jama.jamanetwork.com/article.aspx?articleid=1570262
  15. Deprecated Reference
  16. Williams J et al Updated Estimates of Neural Tube Defects Prevented by Mandatory Folic Acid Fortification - United States, 1995-2011. MMWR Weekly. January 16, 2015 / 64(01);1-5 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6401a2.htm
  17. Arth A et al Supplement Use and Other Characteristics Among Pregnant Women with a Previous Pregnancy Affected by a Neural Tube Defect - United States, 1997-2009 MMWR Weekly. January 16, 2015 / 64(01);6-9 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6401a3.htm
  18. Huo Y et al Efficacy of Folic Acid Therapy in Primary Prevention of Stroke Among Adults With Hypertension in ChinaThe CSPPT Randomized Clinical Trial. JAMA. Published online March 15, 2015 PMID: 25771069 http://jama.jamanetwork.com/article.aspx?articleid=2205876 - Stampfer M, Willett W Folate Supplements for Stroke Prevention. Targeted Trial Trumps the Rest. JAMA. Published online March 15, 2015 PMID: 25770867 http://jama.jamanetwork.com/article.aspx?articleid=2205875
  19. Wien TN, Pike E, Wisloff T, Staff A, Smeland S, Klemp M. Cancer risk with folic acid supplements: a systematic review and meta-analysis. BMJ Open. 2012;2:e000653. PMID: 22240654
  20. Reuters Staff Folic Acid Cuts Stroke Risk in Hypertensive Patients With High Total Cholesterol. Medscape. Nov 02, 2016. http://www.medscape.com/viewarticle/871281 - Qin X, Li J, Spence JD, Zhang Y et al Folic Acid Therapy Reduces the First Stroke Risk Associated With Hypercholesterolemia Among Hypertensive Patients. Stroke. 2016 Nov;47(11):2805-2812. PMID: 27729579
  21. US Preventive Services Task Force Folic Acid Supplementation for the Prevention of Neural Tube Defects. US Preventive Services Task Force Recommendation Statement. JAMA. 2017;317(2):183-189. PMID: 28097362 http://jamanetwork.com/journals/jama/fullarticle/2596300 - Mills JL Strategies for Preventing Folate-Related Neural Tube Defects. Supplements, Fortified Foods, or Both? JAMA. 2017;317(2):144-145 PMID: 28097344 http://jamanetwork.com/journals/jama/fullarticle/2596
  22. US Preventive Services Task Force Folic Acid Supplementation to Prevent Neural Tube Defects. US Preventive Services Task Force Reaffirmation Recommendation Statement. JAMA. 2023;330(5):454-459 PMID: 37526713 https://jamanetwork.com/journals/jama/fullarticle/2807739 - Viswanathan M, Urrutia RP, Hudson KN et al Folic Acid Supplementation to Prevent Neural Tube Defects. Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2023;330(5):460-466 PMID: 37526714 https://jamanetwork.com/journals/jama/fullarticle/2807740
  23. Ling Y, Yan S, Huang X et al Associations of folate/folic acid supplementation alone and in combination with other B vitamins on dementia risk and brain structure: evidence from 466,224 UK Biobank participants. J Gerontol A Biol Sci Med Sci. 2023 Nov 29:glad266. PMID: 38029284 https://academic.oup.com/biomedgerontology/advance-article/doi/10.1093/gerona/glad266/7455295

Component-of

acetylcysteine/folic acid/methylcobalamin alpha tocopherol/ascorbate/beta carotene/calcium carbonate/cholecalciferol/cobalamin/docosahexaenoate/folic acid/magnesium oxide/nicotinamide/pyridoxine/riboflavin/thiamine/zinc oxide alpha tocopherol/ascorbate/beta carotene/calcium carbonate/cholecalciferol/cobalamin/ferrous fumarate/folic acid/nicotinamide/pantothenate/pyridoxine/riboflavin/sodium docusate/thiamine/zinc oxide alpha tocopherol/ascorbate/beta carotene/calcium carbonate/cholecalciferol/cobalamin/folic acid/magnesium oxide/nicotinamide/pyridoxine/riboflavin/thiamine/zinc oxide alpha tocopherol/ascorbate/biotin/biotin/cobalamin/ergocalciferol/folic acid/multivitamin/nicotinamide/panthenol/pyridoxine/riboflavin/thiamine/vitamin a/vitamin k alpha tocopherol/ascorbate/biotin/cholecalciferol/cobalamin/folic acid/nicotinamide/panthenol/pyridoxine/riboflavin/thiamine/vitamin a/vitamin k alpha tocopherol/ascorbate/calcium carbonate/carbonyl iron/cholecalciferol/cobalamin/cupric 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acid/succinate calcium carbonate/cholecalciferol/cyanokit/folic acid calcium carbonate/cobalamin/folic acid/pyridoxine calcium carbonate/folic acid/magnesium carbonate cholecalciferol/cobalamin/fatty acid omega 3/folic acid/phytosterol/pyridoxine cholecalciferol/cobalamin/folic acid/pyridoxine/riboflavin cholecalciferol/folic acid cobalamin/docosahexaenoate/eicosapentaenoate/folic acid/phytosterol/policosanol/pyridoxine cobalamin/docosahexaenoate/eicosapentaenoate/folic acid/phytosterol/pyridoxine cobalamin/fatty acid omega 3/folic acid/phytosterol/pyridoxine cobalamin/folic acid cobalamin/folic acid/heme/heme iron polypeptide/polypeptide/polysaccharide iron complex cobalamin/folic acid/heme/heme iron polypeptide/polysaccharide/polysaccharide iron complex cobalamin/folic acid/iron/polysaccharide iron complex cobalamin/folic acid/polysaccharide iron complex cobalamin/folic acid/pyridoxine docosahexaenoate/eicosapentaenoate/folic acid/hypericum perforatum ferrous fumarate/folic acid ferrous fumarate/folic acid/polysaccharide/polysaccharide iron complex ferrous sulfate/folic acid Folgard Rx 2.2 (folate, B12, B6) folic acid/heme folic acid/inositol folic acid/lactobacillus casei folic acid/methylcobalamin/pyridoxine folic acid/nicotinamide/zinc oxide folic acid/nicotinamide/zinc/zinc oxide folic acid/polysaccharide/polysaccharide iron complex folic acid/proto oncogene tyrosine kinase fer polypill (Polycap) Souvenaid; Fortasyn Connect