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Folic Acid

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification Numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand Names, Trade Names
   1.6 Manufacturers, Importers
   1.7 Presentation, Formulation
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties of the substance
         3.3.1.1 Colour
         3.3.1.2 State/Form
         3.3.1.3 Description
      3.3.2 Properties of the locally available formulation(s)
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation(s)
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Sample
      8.1.1 Collection
      8.1.2 Storage
      8.1.3 Transport
   8.2 Toxicological analytical methods
      8.2.1 Assay for folic acid may be found in the USP XXII, 1990.
      8.2.2 Test for biological sample
   8.3 Biochemical investigations
      8.3.1 Blood
      8.3.2 Urine
      8.3.3 Others
   8.4 Interpretation
   8.5 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
   9.2 Chronic Poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
   9.3. Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Ear, nose and throat: local effects
      9.4.10 Hematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reaction
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. ADDITIONAL INFORMATION
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    1. NAME

       1.1 Substance

           Folic Acid  (INN)

           (WHO, 1992)

       1.2 Group

           ATC classification index 

           Antianaemic preparations (B03)/Vitamin B12 and folic acid
           (B03B)/Folic acid and derivatives (B03BB).

           (WHO, 1992)

       1.3 Synonyms

           Acidum Folicum; Folacin; PGA; Pteroylglutamic Acid;
           Pteroylmonoglutamic Acid; Wills' factor; Vitamin M;
           liver Lactobacillus casei factor; Folsaure. 

           (Reynolds, 1993; Budavari, 1989)

           (To be completed by each Centre using local data) 

       1.4 Identification Numbers

           1.4.1 CAS number

                 Folic acid 59-30-3

                 Sodium folate 6484-89-5

           1.4.2 Other numbers

                 RTECS

                 LP5425000

       1.5 Brand Names, Trade Names

           Acfol (Torlan, Spain), Folacid (Netherlands), Folaemin 
           (Netherlands), Folasic (Nelson, Australia), Foldine (France), 
           Folettes (Australia), Folicid (USV, Australia), Folico 
           (Ecobi, Italy), Folina (Tosi, Italy), Folsan (Kali-Chemie, 
           Germany), Folvite (Lederle, Canada)(Lederle, 
           Switzerland)(Lederle, USA), Lexpec (R.P. Drugs, United 
           Kingdom), Nifolin (Denmark), Nivofolacid (Novopharm, Canada), 
           Speciafoldine (Specia, France) 

           Combination Preparations; Fefol-Ferrous sulfate USP and folic 
           acid (SKF, Philippines), Ferro-Folsan-Ferrous sulfate, 
           succinic acid, folic acid (Phil.), Iberet-Folic-500-Iron, 

           Vitamin C, Vitamin B Complex, Folic Acid (Philippines). 

           (To be completed by each Centre using local data)

       1.6 Manufacturers, Importers

           To be completed by each Centre using local data.

       1.7 Presentation, Formulation

           Oral 

           Folic acid tablets (monocomponent) or in combination with 
           other vitamins and minerals. Strengths usually available are 
           100 mcg, 250 mcg, 400 mcg, 800 mcg, 1 mg and 5 mg. 

           Syrup 2.5 mg/5 mL

           Parenteral 

           Folate sodium injection; strength usually available is 
           equivalent of folic acid 5 mg/mL 

           (To be completed by each Centre using local data)

    2. SUMMARY

       2.1 Main risks and target organs

           Folic acid is relatively non-toxic. However, there have been 
           reports of reactions to parenteral injections. Allergic 
           reactions to folic acid have been rarely reported. 

       2.2 Summary of clinical effects

           Severe allergic reactions are characterized by hypotension, 
           shock, bronchospasm, nausea, vomiting, rash, erythema. 
           Itching may also occur. 

           Adverse gastrointestinal and central nervous system effects 
           have been reported. 

           Treatment with folic acid is usually well tolerated except 
           for rare reports of allergic reactions. 

       2.3 Diagnosis 

           Clinical, haematological and analytical aspects to be 
           addressed. No clinical signs and symptoms are typical for 
           folic acid overdose. Diagnosis should be based on listing and 
           circumstantial evidence. 

       2.4 First aid and management principles

           In case of massive overdose, gastric lavage or induced 
           vomiting could be considered, if seen within 1 to 2 hours 
           after ingestion. Repeat dose activated charcoal to be given, 
           followed by supportive treatment. In case of anaphylaxis, 
           treatment with epinephrine (adrenaline) and support of vital 
           functions should be provided. 

           For adverse reactions not related to overdose, withdraw drug 
           and provide symptomatic and supportive therapy. 

    3. PHYSICO-CHEMICAL PROPERTIES

       3.1 Origin of the substance

           Folic acid was isolated in 1941 by Mitchell and co-workers 
           from green leafy vegetables, liver, yeast and fruits. 
           Synthetic folic acid is commercially available. 

       3.2 Chemical structure

           Structural formula

             


           Molecular formula

           C19H19O6 

           Molecular weight 

           441.4

           Chemical names

           N-[4(2-Amino-4-hydroxypteridin-6-ylmethylamino)benzoyl]-L(+)-
           glutamic acid. 

           N-{4-[[(2-Amino-1,4-dihihydro-4-oxo-6-
           pteridinyl)methyl]amino]benzoyl}-L-glutamic acid. 

           N-{p-[[2-amino-4-hydroxy-6-pteridinyl)methyl]amino]benzoyl}-
           glutamic acid. 

           (Reynolds, 1993; Budavari, 1989)

       3.3 Physical properties

           3.3.1 Properties of the substance

                 3.3.1.1 Colour

                         Yellow to orange brown

                 3.3.1.2 State/Form

                         Crystalline powder

                 3.3.1.3 Description

                         Odourless 

                         Readily soluble in alkali, hydroxides and 
                         carbonates. Insoluble in alcohol, acetone, 
                         chloroform and ether. Solutions are inactivated 
                         by ultraviolet light. Alkaline solutions are 
                         sensitive to oxidation and acid solutions are 
                         sensitive to heat. Dissociation constant - pKa 
                         4.7, 6.8, 9.0 (30) (Moffat, 1986). 

           3.3.2 Properties of the locally available formulation(s) 

                 To be completed by each Centre using local data

       3.4 Other characteristics

           3.4.1 Shelf-life of the substance

                 No data available.

           3.4.2 Shelf-life of the locally available formulation(s) 

                 To be completed by each Centre using local data.

           3.4.3 Storage conditions

                 Preserve in well closed, light resistant containers. 
                 For injection-preserve in single dose or in multiple 
                 dose containers, preferably of type 1 glass (USP, 
                 1990). 
                  
                 Store between 15 to 30 C
                 
                 Protect from freezing

                 (To be completed by each Centre using local data)

           3.4.4 Bioavailability

                 Folic acid is rapidly absorbed from gastrointestinal 
                 tract following oral administration. Peak folate 
                 activity in blood is 30 to 60 minutes after oral 
                 administration. 

                 (To be completed by each Centre using local data)

           3.4.5 Specific properties and composition

                 Commercially available folic acid is prepared 

                 synthetically as yellowish orange crystalline powder. 

                 Folic acid injection is a sterile solution of folic 
                 acid in water, prepared with the aid of sodium 
                 hydroxide or sodium carbonate which results in 
                 formation of sodium folate which is the soluble sodium 
                 salt of folic acid. Commercially available folic acid 
                 injection has a pH of 8 to 11 and the aqueous solutions 
                 are heat sensitive and decompose rapidly in the 
                 presence of light and/or riboflavin, so solutions 
                 should be protected from light. 

                 Folic acid is incompatible with oxidizing and reducing 
                 agents and with heavy metal ions (McEvoy, 1990). 

                 (To be completed by each Centre using local data)

    4. USES

       4.1 Indications

           4.1.1 Indications

                 For the prevention and treatment of vitamin B 
                 deficiency, 

                 For the treatment of megaloblastic anaemia and 
                 macrocytic anaemia due to folic acid deficiency. 

                 Folic acid supplements may be required in low birth 
                 weight infants, infants breastfed by folic acid 
                 deficient mothers, or those with prolonged diarrhoea 
                 and infection. 

                 Other conditions which may increase folic acid 
                 requirements include alcoholism, hepatic disease, 
                 haemolytic anaemia, lactation, oral contraceptive use 
                 and pregnancy. 

                 It has been given to pregnant mothers to reduce the 
                 risk of birth defects (Klaassen et al., 1986). 

                 Folic acid has been suggested in the management of 
                 methanol poisoning, but its efficacy has not been 
                 proven (Ellenhorn & Barceloux, 1988). 

           4.1.2 Description

                 Not applicable.

       4.2 Therapeutic dosage

           4.2.1 Adults
                         
                 Folate deficient megoblastic anaemia 

                  Therapeutic dose

                 5 mg daily orally for 4 months; up to 15 mg daily may 
                 be required in malabsorption states.(UK) 

                 250 mcg to 1.0 mg orally daily (USA)
                         
                  Prophylactic dose

                 200 to 500 mcg orally daily (UK)
                 400 mcg orally daily (USA)
                         
                 Other indications

                  Prophylactic dose

                 5 mg daily or weekly by mouth in thalassaemia or 
                 sickle-cell anaemia (and sometimes in patients 
                 receiving renal dialysis)  
                         
                 Note: Folic acid may also be administered by 
                 intramuscular, intravenous or subcutaneous injection as 
                 the sodium salt. 

                 (Reynolds, 1993)

           4.2.2 Children

                  Dietary supplements

                 100 mcg/day may be increased to 500 mcg to 1 mg/day 
                 when conditions causing increased requirements are 
                 present. 

                  Deficiency states

                 250 mcg to 1 mg/day until haematological response 
                 occurs. 

                  Maintenance

                 Infants                  100 mcg/day.
                 Children up to 4 years   up to 300 mcg/day. 
                 Children above 4 years   400 mcg/day.

                 (Reynolds, 1993)

       4.3 Contraindications

           It should be given with caution to patients with abnormal 
           renal function. 

           It is also contra-indicated in patients who show 
           hypersensitivity reactions to folic acid. 

           Caution is advised in patients who may have folate dependent 
           tumours (Reynolds, 1989). 

           Folic acid should never be given alone or in conjunction with 
           inadequate amounts of Vitamin B12 for the treatment of 
           undiagnosed megaloblastic anaemia. Although folic acid may 
           produce a haematopoietic response in patients with 
           megaloblastic anaemia due to Vitamin B12, it fails to prevent 
           the onset of subacute combined degeneration of the cord 
           (Reynolds, 1989). 

    5. ROUTES OF ENTRY

       5.1 Oral

           Tablets

       5.2 Inhalation

           Not applicable.

       5.3 Dermal

           Not applicable.

       5.4 Eye

           Not applicable.

       5.5 Parenteral

           Aqueous solution.

       5.6 Other

           Not relevant.

    6. KINETICS

       6.1 Absorption by route of exposure

           Oral

           Folic acid is rapidly absorbed from the proximal part of the 
           gastrointestinal tract following oral administration. It is 
           mainly absorbed in the proximal portion of the small 
           intestine. The naturally occurring folate polyglutamate is 
           enzymatically hydrolyzed to monoglutamate forms in the 
           gastrointestinal tract prior to absorption. The peak folate 
           activity in blood after oral administration is within 30 to 
           60 minutes (McEvoy, 1990). Enterohepatic circulation of 
           folate has been demonstrated. 

       6.2 Distribution by route of exposure

           Tetrahydrofolic acid and its derivatives are distributed in 
           all body tissues. Folate is actively concentrated in the CSF 
           at about 0.016 to 0.021 mg/ml while the normal erythrocyte 
           level is about 0.175 to 0.316 mg/ml. The liver contains half 
           of the total body stores of folate and is the principal 
           storage site (McEvoy, 1990). 

       6.3 Biological half-life by route of exposure

           No data available.

       6.4 Metabolism

           Folic acid once absorbed is acted upon by hepatic 
           dihydrofolate reductase to convert to its metabolically 
           active form which is tetrahydrofolic acid. 

           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 transporting 
           and storage form of folate in the body. Larger doses may 
           escape metabolism by the liver and appear in the blood mainly 
           as folic acid. 

       6.5 Elimination by route of exposure

           Oral
           
           Following oral administration of single 0.1 to 0.2 mg doses 
           of folic acid in health 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. Small amounts 
           of orally administered folic acid have been recovered from 
           faeces. About 0.05 mg/day of normal body folate stores is 
           lost by a combination of urinary and faecal excretion and 
           oxidative cleavage of the molecule. 

           Folic acid is also excreted in the breastmilk.

    7. PHARMACOLOGY AND TOXICOLOGY

       7.1 Mode of action

           7.1.1 Toxicodynamics

                 Folic acid is relatively non-toxic. Toxicity studies in 
                 mice showed that folic acid could cause convulsions, 
                 ataxia and weakness. Histopathological studies in some 
                 strains of mice showed that toxic doses may also cause 
                 acute renal tubular necrosis. A possible relationship 
                 between folic acid neurotoxicity and cholinergic 
                 receptors in the pyriform cortex and amygdala has been 

                 shown (McGeer et al, 1983). 

           7.1.2 Pharmacodynamics

                 Folic acid is transformed into different coenzymes that 
                 are responsible for various reactions of intracellular 
                 metabolism mainly conversion of homocysteine to 
                 methionine, conversion of serine to glycine, synthesis 
                 of thymidylate, histidine metabolism, synthesis of 
                 purines and utilization or generation of formate. 

                 In man, nucleoprotein synthesis and the maintenance of 
                 normal erythropoiesis requires exogenous folate. Folic 
                 acid is the precursor of tetrahydrofolic acid which is 
                 active and acts as a co-factor for 1-carbon transfer 
                 reactions in the biosynthesis of purines and 
                 thymidylates of nucleic acids. 

       7.2 Toxicity

           7.2.1 Human data

                 7.2.1.1 Adults

                         There is little data available on folic acid 
                         toxicity in humans. A case of 2 patients who 
                         showed exacerbation of psychotic behaviour 
                         during treatment with folic acid has been 
                         reported (Prakash et al., 1982). The 
                         significance of this finding is uncertain since 
                         other authors have suggested that folic acid 
                         has antipsychotic properties. 

                         Adverse gastrointestinal and central nervous 
                         system effects have been reported rarely in 
                         patients receiving 15 mg of folic acid daily 
                         for one month. However, other studies have 
                         failed to confirm these findings (McEvoy, 
                         1990). 

                 7.2.1.2 Children

                         No data available.

           7.2.2 Relevant animal data

                 Toxicity in different strains of mice showed that toxic 
                 doses of folic acid may lead to convulsions, ataxia and 
                 weakness (Parchure et al., 1985). Histopathological 
                 studies in some strains of mice showed acute renal 
                 tubular necrosis. 

           7.2.3 Relevant in vitro data

                 Cytomorphological effects of folic acid were studied 

                 using in-vitro establishment human oral epithelium. A 
                 concentration twice that used clinically (200 mcg/ml of 
                 folic acid) did not induce marked cytotoxic reaction in 
                 cultured cells. The most pronounced changes were 
                 cultures which showed degenerating cells showing 
                 oedema, increased translucency of the cytoplasm, 
                 flattened cells and atypical filaments (Jainkittivong  
                 et al., 1989). 

       7.3 Carcinogenicity

           No data available.

       7.4 Teratogenicity

           No data available.

       7.5 Mutagenicity

           No data available.

       7.6 Interactions

           Folic acid therapy may increase phenytoin metabolism in 
           folate deficient patients resulting in decreased phenytoin 
           serum concentration. It has also been reported that 
           concurrent administration of folic acid and chloramphenicol 
           in folate deficient patients may result in antagonism of the 
           haematopoietic response to folic acid. 

           The use of ethotoin or mephenytoin concurrently with folic 
           acid may decrease the effects of hydantoins by increasing 
           hydantoin metabolism. 

           Trimethoprim acts as a folate antagonist by inhibiting 
           dihydrofolate reductase, so in patients receiving this drug 
           leucovorin calcium must be given instead of folic acid. Folic 
           acid may also interfere with the effects of pyrimethamine. 

           Aminopterin (4 aminofolic acid) and methotrexate (4 amino- 10 
           methylfolic acid) antagonizes reduction of folic acid to 
           tetrahydrofolic acid. Methotrexate continues to be used as an 
           antineoplastic drug whose activity may be dependent on 
           blocking certain syntheses, e.g., of purines, in which folic 
           acid is required, thereby depriving neoplastic cells of 
           compounds essential for their proliferation. Calcium 
           leucovorin is used therapeutically as a potent antidote for 
           the toxic effects of folic acid antagonists used as 
           antineoplastic agents. Methotrexate or pyrimethamine or 
           triamterene also acts as folate antagonist by inhibiting 
           dihydrofolic reductase (USP DI, 1983). 

           Analgesics, anticonvulsants, antimalarials and 
           corticosteroids may cause folic acid deficiency (USP DI, 
           1983). 

           Folic acid precipitates in some proprietary amino acid 
           solutions and in the presence of high concentration of 
           calcium ions, but it appears to be stable and remains in 
           solution provided the pH remains above 5. There have also 
           been reports of folic acid being absorbed by the polyvinyl 
           chloride containers and administration set, however, other 
           studies have not substantiated such observations. 

           Regarding intravenous incompatibilities, calcium gluconate 
           and folic acid injections have been shown to interact even 
           though a precipitate is not present. The recoverable amount 
           of folic acid from a 10 mg/ml solution declined with 
           increasing concentrations (0.5 to 10 mg/ml) of calcium 
           gluconate. This interaction was reversed by the addition of 
           edetic acid (Trissel, 1986). 

       7.7 Main adverse effects

           Allergic reactions to folic acid have been rarely reported 
           including erythema, rash, itching, general malaise and 
           bronchospasm. Adverse gastrointestinal and central nervous 
           system effects have been reported in patients receiving 15 mg 
           of folic acid daily for one month. 

    8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

       8.1 Sample

           8.1.1 Collection

           8.1.2 Storage

                 Pharmaceutical product, should be preserved in well 
                 closed, light resistant containers, preferably type 1 
                 glass. 

           8.1.3 Transport

       8.2 Toxicological analytical methods

           8.2.1 Assay for folic acid may be found in the USP XXII, 
                 1990. 

                 Identification: 
                 Folic acid injection: to a volume of the injection 
                 equivalent to about 100 mg of folic acid add water to 
                 make about 25 mL. Adjust with hydrochloric acid to a pH 
                 of 3.0 cool to 5, then filter, and wash the precipitate 
                 of folic acid with cold water until the last washing 
                 shows an absence of chloride. Then wash with acetone, 
                 and dry at 80 for 1 hour: the ultraviolet absorption 
                 spectrum of a 1 in 100,000 solution of the folic acid 
                 so obtained in sodium hydroxide solution (1 in 250) 
                 exhibits maxima and minima at the same wavelengths as 
                 that of a similar solution of USP Folic Acid RS, 

                 concomitantly measured. The ratio A256/A365 is between 
                 2.80 and 3.00. 

                 Folic acid tablet-digest a quantity of powdered 
                 tablets, equivalent to about 100 mg of folic acid, with 
                 100 mL of sodium hydroxide solution (1 in 250), and 
                 filter. Proceed as directed in the identification test 
                 under Folic Acid Injection (USP, 1985). 

           8.2.2 Test for biological sample

                 Blood may be used for microbiological assay or 
                 competitive binding technique to determine the plasma 
                 and red cell folate levels (USP XX11, 1990). 

       8.3 Biochemical investigations

           8.3.1 Blood

                 BUN, Creatinine-to test for renal function AST, ALT, 
                 Alkaline Phosphatase-to test for liver status 

           8.3.2 Urine

                 No data available.

           8.3.3 Others

                 No data available.

       8.4 Interpretation

           Normal serum total folate concentration have been reported to 
           range from 0.005 to 0.015 mg/mL (AHFS Drug Information, 
           1990). Use of antibiotics may interfere with microbiological 
           assay for serum and erythrocyte folic acid concentration and 
           cause falsely low levels (US XX11, 1990). 

       8.5 References
       
    Position   Radical   Congener

       N       -CH       CH H PteGlu        Methyltetrahydrofolate 
       N       -CHO      5-CHOH PteGlu      Folinic acid (Citrovorum 
                                              factor) 
       N       -CHO      10-CHOH PteGlu     10 Formyltetrahydrofolate 
       N       -CH-      5, 10-CHH PteGlu   5, 10-Methenyltetrahydro-
                                              folate
       N       -CH-      5, 10-CH H PteGlu  5, 10 Methylenetetrahydro-
                                              folate
       N       -CHNH     CH OHH PteGlu      Forminiotetrahydrofolate
       N       -CH OH    CH OHH PteGlu      Hydroxymethyltetrahydro-
                                              folate

    Structures and Nomenclature of Folic Acid and Congeners (Goodman & 
    Gillman, 1990). 
       
    9. CLINICAL EFFECTS

       9.1 Acute poisoning 

           9.1.1 Ingestion

                 No data available.

           9.1.2 Inhalation

                 Not known.

           9.1.3 Skin exposure

                 No data available.

           9.1.4 Eye contact

                 No data available.

           9.1.5 Parenteral exposure

                 Therapeutic doses may cause anaphylaxis.

       9.2 Chronic Poisoning

           9.2.1 Ingestion

                 Unconfirmed reports of gastrointestinal and central 
                 nervous system effects have been reported rarely in 
                 patients receiving 15 mg of folic acid daily for one 
                 month (McEvoy, 1990). 
                 
           9.2.2 Inhalation

                 Not known.

           9.2.3 Skin exposure

                 No data available.

           9.2.4 Eye contact

                 No data available.

           9.2.5 Parenteral exposure
                         
                 No data available.

       9.3. Course, prognosis, cause of death

           No data available.

       9.4 Systematic description of clinical effects

           9.4.1 Cardiovascular

                 Hypertension and shock may be seen as a manifestation 
                 of allergic reaction. 

           9.4.2 Respiratory

                 Bronchospasm may be seen as a manifestation of allergic 
                 reaction. 

           9.4.3 Neurological
                                   
                 9.4.3.1 Central nervous system (CNS)

                         No data available.
                                   
                 9.4.3.2 Peripheral nervous system

                         No data available.

                 9.4.3.3 Autonomic nervous system 

                         No data available.
                         
                 9.4.3.4 Skeletal and smooth muscle

                         Unconfirmed reports of general malaise and 
                         ataxia have been received following therapeutic 
                         doses. 

           9.4.4 Gastrointestinal

                 Nausea and vomiting as an adverse reaction has been 
                 reported. 

           9.4.5 Hepatic

                 No data available.

           9.4.6 Urinary

                 9.4.6.1 Renal

                         No data available.

                 9.4.6.2 Other

                         No data available.

           9.4.7 Endocrine and reproductive systems

                 No data available.

           9.4.8 Dermatological

                 No data available.

           9.4.9 Ear, nose and throat: local effects

                 No data available.

           9.4.10 Hematological

                  No data available.

           9.4.11 Immunological

                  No data available.

           9.4.12 Metabolic

                  9.4.12.1 Acid-base disturbances

                           No data available.

                  9.4.12.2 Fluid and electrolyte disturbances

                           No data available.

                  9.4.12.3 Others
                                   
                           No data available.

           9.4.13 Allergic reaction

                  Rash, erythema and itching.

           9.4.14 Other clinical effects

                  No data available.

           9.4.15 Special risks

                  No data available.

       9.5 Other

           Unknown

       9.6 Summary

           Not relevant

    10. MANAGEMENT

        10.1 General principles

             In cases of overdose, treatment is symptomatic and 

             supportive and is guided by the clinical features. 

             In case of anaphylactic reaction standard treatment should 
             be given. (See Treatment Guide on Anaphylaxis). 

             In case of massive ingestion gastric lavage or induced 
             vomiting could be considered if seen within 1 to 2 hours 
             after ingestion. Activated charcoal should be given 
             repeatedly in view of the enterohepatic circulation of 
             folic acid. 

        10.2 Relevant laboratory analyses

             10.2.1 Sample collection

                    Collect blood for plasma and red cell folate levels. 

             10.2.2 Biomedical  analysis

                    Request for other test would depend on patient 
                    presentation. 

                    There are no confirmed reports of folic acid 
                    overdose in humans. In case of an overdose, 
                    determination of blood urea nitrogen and creatinine 
                    level would be appropriate because of the 
                    possibility of renal toxicity which has been 
                    reported in experimental mice. Determination of 
                    liver function (AST, ALT, Alkaline phosphatase) 
                    should also be done due to the possibility of 
                    hepatotoxicity, (the liver being the primary storage 
                    site of folic acid). 

             10.2.3 Toxicological analysis

                    Not relevant

             10.2.4 Other investigations

                    Not relevant

        10.3 Life supportive procedures and symptomatic/specific treatment

             Treatment is largely supportive. In case of anaphylactic 
             reaction, epinephrine (adrenaline) should be given. 
             Maintain a clear airway and aspirate secretions from 
             airway. Administer oxygen and perform endotracheal 
             intubation when necessary. Support ventilation using 
             appropriate mechanical device. Control convulsions with 
             appropriate drug regimen. Perform cardio-respiratory 
             resuscitation when necessary. Correct hypotension with 
             isotonic fluids and  inotropic agents. 

        10.4 Decontamination

             In case of massive ingestion induce vomiting or gastric 
             lavage,  if seen within 1 to 2 hours after ingestion. 
             Repeat dose activated charcoal. 

        10.5 Elimination
             
             Adequate hydration would be sufficient to eliminate the 
             drug through the kidneys. 

        10.6 Antidote treatment

             10.6.1 Adults

                    No antidote.

             10.6.2 Children

                    No antidote.

        10.7 Management discussion

             Folic acid is relatively non-toxic and management is 
             directed toward symptomatic and supportive therapy. 

             The only allergic reaction to folic acid, which is life 
             threatening, is anaphylaxis. For anaphylaxis one should 
             give epinephrine (adrenaline) and (if considered necessary) 
             corticosteroids and fluids. 

             For hypotension unresponsive to volume expansion, one may 
             give dopamine. 

             Repeated doses of activated charcoal are necessary to 
             remove excess folic acid from the enterohepatic 
             recirculation. 

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             There is little data available on folic acid toxicity in 
             humans. A case of 2 patients who showed exacerbation of 
             psychotic behaviour during treatment with folic acid has 
             been reported (Prakash et al., 1982). The significance of 
             this finding is uncertain since other authors have 
             suggested that folic acid has antipsychotic properties. 

        11.2 Internally extracted data on cases
                         
             Unknown

        11.3 Internal cases

             To be completed by each Centre using local data
             
    12. ADDITIONAL INFORMATION

        12.1 Availability of antidotes

             Not relevant

        12.2 Specific preventive measures

             Not relevant

        12.3 Other

             Not relevant

    13. REFERENCES

        Braunwald E, Isselbacher K,  Petersdorf R, Wilson J,  & Martin J 
        eds. (1987) Harrison's principles of internal medicine, 11 th 
        ed., New York, McGraw-Hill Book Company. 

        Budavari S ed. (1989) The Merck Index: an encyclopedia of 
        chemicals, drugs, and biologicals, 11th ed. Rahway, New Jersey, 
        Merck and Co., Inc.  p 660 
             
        Ellenhorn MJ & Barceloux DG (1988) Medical toxicology, diagnosis 
        and treatment of human poisoning, New York, Elsevier, pp 30, 79. 

        Gilman AG, Rall TW, Nies AS & Taylor P eds.(1990) Goodman and  
        Gilman's the pharmacological basis of therapeutics, 8th ed. New 
        York, Pergamon Press, pp 1294-1296, 1302-1306. 

        Goldfrank LR, Flomenbaum NE, Lewin NA, Weisman RS, Howland MA, & 
        Kulberg AG  eds. (1990) Goldfrank's toxicologic emergencies, 
        Norwalk, Appleton-Century- Crofts. 

        Goth, A Medical Pharmacology: Principles and Concepts, 5th 
        Edition, C.V. Mosby Company, Maruzen Company Limited 1980. 

        Haddad LM & Winchester JF eds. (1983) Clinical management of 
        poisoning and drug overdose. Philadelphia, Saunders. 

        Jainkittivong A, Arenholt-Bindsler D, Jepsen A, & Philipsen HP 
        (1989) Effect of folic acid on human oral epithileum in-vitro. J 
        Dent Assoc Thai, 39: 121-127. 

        Klaassen CD, Amdur MO, & Doull J (1986) Casarett & Doull's 
        toxicology: the basic science of poisons. New York, Macmillan 
        Publishing Company, p 211. 

        Krupp M, Chatton M & Tierney L (1986) Current medical diagnosis 
        and treatment. Lange Medical Company. 

        McEvoy GK ed. (1990) American hospital formulary service, drug 
        information. Bethesda, American Society of Hospital Pharmacists. 
        
        McGeer PL, McGeer EG, Nagai T, & Wong PT, A possible 
        relationship between folic acid neurotoxicity and cholinergic 
        receptors in the pyriform cortex and amygdala, J. Neural Transm 
        Suppl, 1983, 18: 327-344. 

        Moffat AC ed.  (1986) Clarke's isolation and identification of 
        drugs in pharmaceuticals, body fluids, and post-mortem material. 
        2nd ed. London, The Pharmaceutical Press. 

        Osola, Pratt R (1973) The US Dispensary, 27th ed. J.B. 
        Lippincott Company, 
        
        Parchure M, Ambaye RV, Lalitha VS, & Gokhale SV( 1985) Acute 
        toxicity of folic acid in mice. Experientia, 41(1): 72-73. 

        Prakash R & Petrie WM (1982) Psychiatric changes associated with 
        an excess of folic acid. Am  J Psychiatry, 139(9):1192-1193 

        Reynolds JEF ed. (1989) Martindale: the extra pharmacopoeia, 
        29th ed. London, The Pharmaceutical Press. pp 1262-1263 

        Reynolds JEF ed. (1993) Martindale: the extra pharmacopoeia, 
        30th ed. London, The Pharmaceutical Press. pp 1039-1040 

        Trissel LA (1986)  Handbook on injectable drugs. Bethesda, 
        American Society of Hospital Pharmacists. 

        USP DI Drug Information for the Health Care Provider, Vol. 1, 
        1983. 

        United States Pharmacopeia, 21st rev. The National formulary 
        16th ed. (1985)  Rockville MD, United States Pharmacopeial 
        Convention. 

        United States Pharmacopeia, 22nd rev. The National formulary 
        17th ed. (1990)  Rockville MD, United States Pharmacopeial 
        Convention. 

        US Pharmacopeia, National Formulary, 22nd ed., 1990. 

        White, Handler and Smith Principles of Biochemistry, 4th ed., 
        McGraw-Hill Book Company, 1970. 

        WHO (1992) Anatomical Therapeutic Chemical (ATC) classification 
        index. Oslo, WHO Collaborating Centre for Drug Statistics 
        Methodology, p19. 

        WHO (1992) International nonproprietary names (INN) for 
        pharmaceutical substances. Geneva, World Health Organisation, 
        p 13. 

    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 
        ADDRESS(ES) 

        Author         Dr E.S. Castillo
                       National Poison Control & Information Service 
                       Department of Pharmacology
                 UP College of Medicine
                 Manila
                       Philippines

        Date           August 1991.

        Reviewer       -

        Peer Review    Drs Pronczuk, Tempowski, Hartigan-Go, Ten-Ham. 
                       Newcastle-upon-Tyne, United Kingdom, February 
                       1992Newcastle-upon-Tyne, United Kingdom, February 
                       1992          
       
    


    See Also:
       Toxicological Abbreviations