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
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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