Ácido Folico - Acesso 03.05.17 Micromedex

201753 Drug details MICROMEDEX®
FOLIC ACID
Avaliações do DRUGDEX®
DOSING/ADMINISTRATION
Adult Dosing
Normal Dosage
Intramuscular route
Folic acid deficiency
a) The usual intramuscular dose for folic acid deficiency is up to 1 milligram (mg)
per day (mg/d) for adults until resolution of clinical symptoms of deficiency. Once
the blood indices return to normal, the recommended daily maintenance dose is 0.4
mg/d for adults and 0.8 mg/d for pregnant and lactating women, but never less
than 0.1 mg/d. Higher doses may be required in the presence of resistant cases,
alcoholism, hemolytic anemia, anticonvulsant therapy, chronic infection [5],
smoking, pregnant adolescents, or socioeconomic conditions [6].
Megaloblastic anemia

Intravenous route
a) The usual intravenous dose for folic acid deficiency is up to 1 milligram (mg) per
day (mg/d) for adults until resolution of clinical symptoms of deficiency. Once the
blood indices return to normal, the recommended daily maintenance dose is 0.4

Oral route
a) The usual oral dose for folic acid deficiency is up to 1 milligram (mg) per day
(mg/d) for adults until resolution of clinical symptoms of deficiency. Once the blood
indices return to normal, the recommended daily maintenance dose is 0.4 mg/d for
adults and 0.8 mg/d for pregnant and lactating women, but never less than 0.1
mg/d. Higher doses may be required in the presence of resistant cases, alcoholism,
hemolytic anemia, anticonvulsant therapy, chronic infection [7], smoking, pregnant
adolescents, or socioeconomic conditions [6].
Homocystinemia
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a) Folic acid alone at a dose of 0.5 milligrams (mg) per day was effective in
reducing both fasting homocysteine concentrations and the increase in
homocysteine caused by a methionine load. Folic acid 5 mg was no more effective
than 0.5 mg [22].

b) In patients with documented coronary artery disease and elevated plasma
homocysteine, folic acid 400 micrograms (mcg) daily for 90 days lowered plasma
homocysteine as effectively (by 30%) as did 1 milligram (mg) per day or 5mg/day.
All treatments provided vitamin B6 12.5 mg and vitamin B12 500 mcg daily [23].
Pregnancy vitamin/iron prophylaxis
a) Neural Tube Defect, prophylaxis (against first occurrence)
1) Daily dosing of folic acid 400 micrograms was more effective than folic acid
2800 micrograms/week for achieving red blood cell folate levels considered to be
protective against neural tube defects (905 nanomoles/liter). Fifty percent of 37
women receiving the weekly dose and 75% of 35 women receiving the daily dose
had red blood cell folate levels above 905 nanomoles/liter by 12 weeks. At 6
weeks, only 23% of the daily folic acid group had red blood cell folate levels above
905 nanomoles/liter, possibly suggesting that women desiring to become pregnant
should begin taking folic acid earlier than the currently recommended 4 weeks
[49].

2) For the prevention of neural tube defects, all women of childbearing age who
are capable of becoming pregnant should take 0.4 milligrams of folic acid daily.
This dose is usually found in any multivitamin [38][39][40]. Folic acid should be
administered at least 1 month before pregnancy and for the first 3 months of
pregnancy [40]; (Mulinare, 1993). Doses from 0.5 milligrams to 1 milligram/day
are often administered during pregnancy. Prenatal vitamins contain 0.8 milligrams
to 1 milligram of folic acid [39].

3) An analysis of published data showed that, for every increase of 0.1 milligram
(mg) folic acid intake per day, serum folate increases approximately 1
nanogram/milliliter (ng/mL) in women of childbearing age and approximately 2.5
ng/mL in older people. Furthermore, a doubling of serum folate roughly halves the
risk of bearing a child with a neural tube defect (NTD). For women with the
average serum folate of women of childbearing age in the United Kingdom (5
ng/mL), increasing folic acid intake by 0.4 mg/day (the level recommended during
the periconceptional period in the United States) reduces risk of an NTD birth by
36%. An increased folic acid intake of 5 mg/day reduces risk by 85%. On this
basis, the authors recommend that women intending to become pregnant take
supplemental folic acid 5 mg/day [41].

4) Folic acid supplements, folic acid intake from fortified cereals, and vitamin C
supplements were found to predict red cell folate levels in women (n=189)
intending to become pregnant. Only women taking folic acid supplements
(typically 400 micrograms/day) had red cell folate levels of 906 nmol/L (400
ng/mL) that is considered by some to be optimal for prevention of neural tube
defects. In nonusers of supplements, 500 micrograms of folate per day from
foods and fortified cereals may be necessary to achieve equivalent red cell folate
levels. One woman in 8 had a red cell folate level below 200 nanograms/milliliter,
indicative of negative folate balance. Supplemental iron was negatively related to
red cell folate level. With folic acid supplement users, zinc was also inversely
related to red cell folate level [50].

5) Supplemental intake of folate (400 mcg/day) as folic acid (ie, synthetic form) or
in folic acidfortified foods raised red blood cell folate to levels thought to be
protective against neural tube defects, whereas eating 400 mcg folate per day
from foods naturally rich in folate did not. It is presumed that the explanation lies2/30
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from foods naturally rich in folate did not. It is presumed that the explanation lies
in the greater bioavailability of folic acid, as compared to the polyglutamate form
of folate that occurs naturally in foods [51].

b) Neural Tube Defect, prophylaxis (against recurrence)
1) Women with history of a pregnancy resulting in a neural tube defect should
receive 4 milligrams/day starting 1 month before pregnancy and throughout the
first 3 months of pregnancy [38][39][40]; (Mulinare, 1993). However, the
Canadian College of Medical Geneticists recommends a range of 0.8 milligrams to
5 milligrams/day [52]. Doses as high as 10 milligrams/day have not shown any
acute or chronic toxicity [42].

Recommended dietary allowance
a) The recommended daily allowance of folate is 400 micrograms (mcg) for men,
400 mcg for women, 600 mcg for pregnant women, and 500 mcg for lactation
women [24].

Toxicity of drug, Methotrexate
a) Offlabel dosage: 1 mg/day orally OR 5 mg/week orally [63]

Subcutaneous route
a) The usual subcutaneous dose for folic acid deficiency is up to 1 milligram (mg)

Dosage in Geriatric Patients
A) HYPERHOMOCYSTEINEMIA
1) Supplements of folic acid 600 micrograms per day (with dietary intake, providing
approximately 900 micrograms total folic acid intake per day) were estimated to be sufficient
to ensure that 95% of the elderly population would be without cardiovascular risk (ie, plasma
homocysteine lower than 10 micromoles/liter) from folate deficiency. This conclusion was
based on a randomized, placebocontrolled, doserange study with 368 adults, aged 6575
years. The recommendation is based on an assumption of adequate vitamin B12 intake [69].

Dosage Adjustment During Dialysis
A) In patients with a satisfactory level of nutrition, supplemental folate is not necessary to
ensure adequate erythropoiesis [70][71][72]. However, homocysteine, a risk factor for
atherosclerosis, accumulates in the blood of dialysis patients and is inversely related to folate
status. If plasma homocysteine is above the normal range (5 to 15 micromoles/liter), one
recommendation is to supplement folate at a level of 5 mg/day. Reductions in homocysteine of
25% to 30% can be expected within 4 to 6 weeks. If after 8 weeks homocysteine is still
elevated, the dose can be increased stepwise by 5 mg/day to a maximum of 15 mg/day [73].
Pediatric Dosing
Normal Dosage
Intramuscular route
per day (mg/d) for children (regardless of age) until resolution of clinical symptoms
of deficiency. Once the blood indices return to normal, the recommended daily
maintenance dose is 0.1 mg/d for infants, up to 0.3 mg/d for children under 4
years of age, and 0.4 mg/d for children aged 4 years or older, but never less than
0.1 mg/d [5].

b) The recommended intramuscular dose for preterm infants is 100 micrograms
daily from day 7 to discharge from hospital [8].
0.1 mg/d [5].

Intravenous route
day (mg/d) for children (regardless of age) until resolution of clinical symptoms of
deficiency. Once the blood indices return to normal, the recommended daily
0.1 mg/d [5].
0.1 mg/d [5].

Oral route
(mg/d) for children (regardless of age) until resolution of clinical symptoms of
0.1 mg/d [7].
0.1 mg/d [7].

a) The recommended daily allowance of folate is 65 to 80 micrograms (mcg) for
children 1 year of age and younger, 150 mcg for children aged 1 to 3 years, 200
mcg for children aged 4 to 8 years, 300 mcg for children aged 9 to 13 years, and
400 mcg for children aged 14 to 18 years [24].

Subcutaneous route
0.1 mg/d [5].
0.1 mg/d [5].

FDA Uses
FDA Labeled Indication
1) Overview
FDA Approval: Adult, yes; Pediatric, yes

Efficacy: Adult, Effective; Pediatric, Effective

Recommendation: Adult, Class IIa; Pediatric, Class IIa

Strength of Evidence: Adult, Category A; Pediatric, Category B

See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS

2) Summary:
Effective in treating megaloblastic anemias that are caused by folic acid deficiency [7][5]

3) Adult:
a) Folic acid is effective in treating megaloblastic anemias that are caused by folic acid
deficiency. Folic acid doses above 0.1 mg per day may mask vitamin B12 deficiency, which can
also cause megaloblastic anemia. It is important to verify the adequacy of vitamin B12 status
when treating megaloblastic anemia [7][5].

NonFDA Uses
Acute lymphoid leukemia; Prophylaxis
1) Overview
FDA Approval: Adult, no; Pediatric, no

Efficacy: Adult, Evidence is inconclusive

Recommendation: Adult, Class IIb

Strength of Evidence: Adult, Category B


2) Summary:
Maternal folate supplementation was associated with reduced incidence of childhood acute
lymphoblastic leukemia (ALL) in a casecontrol study [25]

3) Adult:
a) Maternal supplementation with iron and folate during pregnancy was associated with
protection against common childhood acute lymphoblastic leukemia (ALL). In an study
conducted in Australia, 83 children, aged 0 to 14 years and treated for ALL between 1984 and
1992, were each matched to 2 controls by sex, date of birth (within 6 months), and broad
region of residence. Information, including use of dietary supplements during pregnancy,
elicited from parents, resulted in examination of 67 independent variables in an attempt to
determine causes of ALL. Of those variables, 69% had previously been associated with ALL,
12% were known to be hematotoxic or carcinogenic in humans, and, for 19%, there was no
strong basis for an a priori hypothesis. Among those variables for which there was no previous
association, supplementation during pregnancy with iron and folate showed a highly significant
(p=0.001) inverse association with ALL. Nearly all women who took folate supplements also
took iron supplements. Hence, it was not possible to separate the effects of folate from those
of iron. However, the effect of iron alone was not significant. The protective effect of folate
(with iron) was not altered by the time at which folate was first taken or by the duration of
use. The crude odds ratio for folate use in pregnancy and common ALL was 0.37. No other
known causes of ALL explained the inverse association between folate and ALL [25].

Agerelated cognitive decline; Prophylaxis
1) Overview

Efficacy: Adult, Evidence favors efficacy




2) Summary:
Daily folic acid supplementation for 3 years significantly improved global cognitive
performance, particularly memory and information processing speed, among older adults in a
Dutch, doubleblind, randomized, placebocontrolled FACIT (Folic Acid and Carotid Intima
media Thickness) trial (n=818) [4]

3) Adult:
a) In a 3year, Dutch, doubleblind, randomized, placebocontrolled FACIT (Folic Acid and
Carotid Intimamedia Thickness) trial (n=818), daily folic acid supplementation for 3 years was
more effective than placebo in improving global cognitive performance, particularly memory
and information processing speed, among older adults. The vast majority (72%) of the
patients were male (mean age 60 years), had at least middle to high educational background,
and none had early signs of dementia. They were randomized to receive either placebo
(n=413) or oral folic acid supplementation 800 micrograms (mcg) (n=405) once daily for 3
years. The compliance rate was 99% in both groups. Serum folate concentrations at 3 years
significantly increased from baseline for the folic acid group compared with the placebo group
(+64 nanomoles/liter (nmol/L) vs +1 nmol/L; p less than 0.001). In contrast to the folic acid
group, subjects in the placebo group experienced a rise in plasma total homocysteine levels at
3 years from baseline (2.9 micromoles/L vs +0.5 micromoles/L; p less than 0.001), which has
been associated with poor cognitive performance. Based on the intenttotreat analysis, folic
acid improved the global cognitive function with a 3year mean Zscore improvement of 0.067
versus 0.017 with placebo (mean difference 0.05; 95% confidence interval (CI), 0.004 to
0.096; p=0.033). While both treatments led to significant improvement in memory and
information processing speed, the 3year change was significantly better in the folic acid group
than the placebo group with respect to memory (mean Zscore change, 0.48 vs 0.348; mean
difference 0.132; 95% CI, 0.032 to 0.233; p=0.01) and information processing speed (0.072
vs 0.159; mean difference, 0.087; 95% CI, 0.016 to 0.158; p=0.016). However, folic acid did
not significantly affect sensorimotor speed, complex speed, word fluency, or performance on6/30
not significantly affect sensorimotor speed, complex speed, word fluency, or performance on
the MiniMental State Examination from baseline or relative to placebo [4].

Anemia Tribavirin adverse reaction
1) Overview


Recommendation: Adult, Class III



2) Summary:
Folic acid was of no benefit in treating ribavirininduced anemia [26]

3) Adult:
a) Folic acid was of no benefit in ameliorating the hemolytic anemia caused by ribavirin.
Eighty patients receiving interferon alfa2b induction therapy and ribavirin (1000 milligrams if
weighing less than 70 kilograms (kg) and 1200 if weighing 70 kg or more) for treatment of
hepatitis C were randomized to receive folic acid 1 milligram (mg) daily or no supplementation.
Fortythree patients completed 24 weeks of treatment. Changes in hemoglobin and in
hemolysis parameters did not differ significantly between the groups [26].

Antiepileptic adverse reaction Folic acid deficiency
1) Overview


Recommendation: Adult, Class I; Pediatric, Class I

Strength of Evidence: Adult, Category B; Pediatric, Category B


2) Summary:
Administration of folic acid can correct many of the anticonvulsantinduced abnormalities
caused by the inhibitory effects of phenytoin on folate absorption

3) Adult:
a) Anticonvulsants such as phenytoin are known to cause folate deficiency which can be
manifested by a number of disorders including depressed serum folate level, CNS alterations
(mental changes), megaloblastic anemia, neuropathy, and motor disorders (areflexia, ataxia).
Some data suggest that this is due to the inhibitory effects of phenytoin on folate absorption
and that administration of folic acid can correct many of the anticonvulsantinduced
abnormalities. However, it should be noted that folic acid has also been reported to antagonize
phenytoin therapeutic effects by lowering serum phenytoin levels and, in some cases, resulting
in loss of epileptic seizure control.

b) Doses of 5 milligrams three times daily have been used with improvement noted within 1 to
2 weeks [27][28][29][30][31][32][33].

Cancer; Prophylaxis
1) Overview





2) Summary:
Observational studies strongly suggest a protective effect of folate against colon cancer [34]

Increased folate intake reduces breast cancer risk among women who consume more than 15
grams of alcohol per day [35][36]

3) Adult:
a) Daily use of a multivitamin potentially containing folic acid for 15 years was associated with
reduced risk of death from colon cancer in moderate to heavy alcohol users but not in those
who drank less than 2 alcoholic drinks per day. Although the original report of the Cancer
Prevention Study II (at 7 years of followup) showed no association between multivitamin use
and death from colon cancer, this reanalysis of data from over 800,000 participants after 16
years of followup showed an overall relative risk of 0.89 (95% confidence interval 0.8 to 0.99)
for death from colon cancer for individuals taking multivitamins daily for 15 years or more.
Among subjects who consumed 2 or more alcoholic drinks per day, relative risk for 15year
multivitamin users was 0.71 (95% confidence interval 0.56 to 0.91), whereas for subjects who
consumed lower levels of alcohol, the relative risk was 0.94 (95% confidence interval 0.72
1.2). There was no decrease in risk of death from rectal cancer associated with multivitamin
use. Because of the known effects of alcohol on folic acid status, it is presumed that folic acid
is the component of the multivitamin that is primarily responsible for the protective effect
against death from colon cancer [35].

b) There was no association between folate intake and risk of breast cancer in a large
population; however, among those women of the cohort with higher levels of alcohol
consumption (more than 15 grams alcohol per day), the risk of breast cancer was higher when
folate intake was low. Alcohol is known to cause a modest increase in breast cancer risk. Data
from the Nurses' Health Study (over 88000 participants for this analysis) were stratified
according to alcohol intake. In the group of women who consumed more than 15 grams of
alcohol per day, consumption of 600 micrograms or more of folic acid per day reduced the
relative risk (RR) of breast cancer to 0.55, compared to those consuming 150 to 300
micrograms per day (reference group). The RR for those consuming folate 300 to 599
micrograms per day or less than 150 micrograms per day did not differ from that of the
reference group. In the group of women consuming less than 15 grams of alcohol per day,
folate intake did not affect rates of breast cancer occurrence [36].

c) Longterm multivitamin supplementation reduces the risk of colon cancer in women; data is
consistent with the hypothesis that folic acid within the multivitamin preparations is the
protective agent. Nearly 89,000 women who were free of cancer in 1980 were followed to
1994, with assessment of cancer status every 2 years and repeated updating of dietary and
supplemental vitamin intake. During the test period, there were 442 new cases of colon
cancer. After controlling for age, family history, and behavioral factors known to influence
cancer risk (smoking, aspirin use, intake of red meat, intake of alcohol, etc), the relative risk
factor for women consuming more than 400 micrograms (mcg) folic acid per day (versus those
consuming less than 200 mcg/day) was 0.69 (95% confidence interval, 0.520.93). With
respect to length of use, the reduced risk was significant for women who had taken
supplements for 15 years or more, but not for women who had taken them for shorter times.
Among constituents of multivitamin preparations, only folic acid showed a consistently
negative association with colon cancer occurrence (Giovanucci et al, 1998). Further analysis of
this data set showed a marked reduction in the effect of family history of colon cancer when
folate was consumed at 400 or more micrograms (mcg) per day. In comparison to women
without a family history who consumed 200 mcg or less of folate per day, women without a
family history who consumed more than 400 mcg /day had a relative risk (RR ) of 0.81,
women with a family history who consumed 200 mcg or less of folate had a RR of 2.49, and
women with a family history who consumed more than 400 mcg/day had a RR of 1.3. The
reduction in risk with higher folate intake was greater among patients with a family history of8/30
reduction in risk with higher folate intake was greater among patients with a family history of
colon cancer: among women with a family history, those consuming 400 mcg or more of folate
per day had a RR of 0.48 compared to those consuming 200 mcg or less. Intake of methionine
(which is also involved in methyl transfer) was also inversely correlated with colon cancer risk
among subjects with a family history but not in those without family history. High levels of
ethanol intake (more than 30 grams/day) were positively correlated with colon cancer risk
(RR=3.79) in those with positive family history [34].

Cerebrovascular accident; Prophylaxis
1) Overview





2) Summary:
Folic acid supplementation with or without other B vitamins did not definitively show a reduced
risk of stroke in a metaanalysis of 8 randomized trials (n=16,841); however, a significant risk
reduction was demonstrated with folic acid supplementation in a stratified analysis in patients
with no history of stroke, with more than 20% reduction in homocysteine levels, treated for
more than 36 months, and who lived in regions without folic acid fortification or partially
fortified grain [67].

In the Heart Outcomes Prevention Evaluation (HOPE) study, lowering of homocysteine levels
with a daily combination supplement of folic acid, vitamin B12, and vitamin B6 did not reduce
the risk of the composite endpoint of death from cardiovascular causes, myocardial infarction,
and stroke compared with placebo in highrisk patients; however, there were significant fewer
strokes in the active treatment group [54].

In the Norwegian Vitamin (NORVIT) trial, lowering homocysteine levels with folic acid and
vitamin B12, with or without vitamin B6, did not lower the risk of myocardial infarction (MI)
and stoke compared with placebo in patients with history of an acute MI [55].

High doses of folic acid, vitamin B12, and vitamin B6 did not reduce the risk of stroke or
coronary heart disease events compared with low doses of folic acid, vitamin B12, and vitamin
B6 in patients with hyperhomocysteinemia and a history of stroke in the Vitamin Intervention
for Stroke Prevention (VISP) trial [56].

3) Adult:
a) Metaanalysis
1) According to a metaanalysis consisting of 16,841 subjects, folic acid supplementation in
combination with or without other B vitamins, slightly reduced the overall risk of stroke. Eight
randomized clinical trials comparing folic acid (with or without other B vitamins)
supplementation with either placebo, a lower dose of folic acid, or usual care for at least 6
months and included stroke as a clinical endpoint were included in this metaanalysis. Patients
were men and women receiving folic acid ranging from 0.5 milligrams (mg)/day to 15 mg/day
with the average duration of 24 to 72 months. Patients also had preexisting conditions,
including history of stroke, coronary heart disease (CHD), endstage renal disease (ESRD), or
esophageal dysplasia. Homocysteine levels varied and ranged from 12.1 to 35
micromoles/liter (L). Four studies were done in regions without grain fortification with folic
acid, three studies were conducted in regions with folic acid fortification, and one study was
done in regions with and without fortified grain. In the pooled analysis, folic acid
supplementation reduced the risk of stroke by 18% (95% confidence interval (CI), 0.68 to
1.00; p=0.045). In the stratified analysis, there was a greater benefit of folic acid
supplementation in patients with no history of stroke (relative risk (RR), 0.75; 95% CI, 0.62
to 0.90; p=0.002) when compared to patients who had a history of stroke (RR, 1.04; 95% CI,
0.84 to 1.29; p=0.71), or in patients whose homocysteine level was lowered by more than 9/30
0.84 to 1.29; p=0.71), or in patients whose homocysteine level was lowered by more than
20% (RR, 0.77; 95% CI, 0.63 to 0.94; p=0.012) when compared to patients whose
homocysteine lowering was less than 20% (RR, 0.89; 95% CI, 0.55 to 1.42; p=0.62).
Patients treated for more than 36 months had a greater risk reduction (RR, 0.71; 95% CI,
0.57 to 0.87; p=0.001) than patients who were treated for 36 months or less (RR, 1.00; 95%
CI, 0.83 to 1.21; p=0.95). In addition, patients had a greater benefit from folic acid
supplementation in regions without folic acid fortification or partially fortified grain (RR, 0.75;
95% CI, 0.62 to 0.91; p=0.003) than patients who lived in regions of fortified grain (RR,
0.89; 95% CI, 0.55 to 1.42; p=0.62) [67]. The authors suggest that hypertensive populations
without preexisting ESRD or CHD, but with low folic acid levels and hyperhomocysteinemia
could benefit most from folic acid supplementation for the primary prevention of stroke [68].

b) Clinical Trials
1) In the Heart Outcomes Prevention Evaluation (HOPE) study, lowering of homocysteine
levels with a daily combination supplement of folic acid, cyanocobalamin (vitamin B12), and
pyridoxine (vitamin B6) supplement did not reduce the risk of the composite endpoint of
death from cardiovascular causes, myocardial infarction, and stroke compared with placebo in
highrisk patients; however, there were significant fewer strokes in the active treatment
group. Patients studied were men and women 55 years of age or older with a history of
vascular disease (coronary, cerebrovascular, peripheral vascular) or diabetes and additional
risk factors for atherosclerosis. Patients taking more than 0.2 mg of folic acid per day in a
vitamin supplement were excluded from the study. The HOPE trial was a 5year, multicenter,
doubleblind clinical trial (n=5522). Patients were randomized to receive a combination tablet
including: folic acid 2.5 mg, pyridoxine 50 mg, and cyanocobalamin 1 mg or matching placebo
once daily. The mean homocysteine levels in the active treatment group decreased to 0.3
milligrams per liter (mg/L) from baseline and the placebo group increased to 0.1 mg/L from
baseline. The composite primary endpoint of death from cardiovascular causes, myocardial
infarction, and stroke was not significantly different between treatment groups. In this study,
519 (18.8%) primary outcome events occurred in the active treatment group compared to
547 (19.8%) occurrences in the placebo group (relative risk (RR), 0.95; 95% confidence
interval (CI), 0.84 to 1.07; p=0.41). There were no significant differences between the two
study groups in rates of cardiovascular related deaths or myocardial infarctions when the
individual components of the composite endpoint were analyzed separately. There were
statistically significant fewer strokes in the active treatment group (n=111; 4%) compared to
placebo (n=147; 5.3%) (RR, 0.75; 95% CI, 0.59 to 0.97; p=0.03); however, the number of
strokes was much less than the number of cardiovascular events. Also, the confidence
intervals around the estimated risk reduction for strokes were wide and were not adjusted for
the multiplicity of outcomes compared. In addition, there was no difference between study
groups on the number of total ischemic events (RR, 1.03; 95% CI, 0.94 to 1.13; p=0.57).
However, there was a significant difference in the number of patients hospitalized for
unstable angina in the active treatment group compared to the placebo group (RR, 1.24; 95%
CI, 1.04 to 1.49; p=0.02) [54].

2) In the Norwegian Vitamin (NORVIT) trial, lowering homocysteine levels with folic acid and
cyanocobalamin (vitamin B12), with or without pyridoxine (vitamin B6) did not lower the risk
of myocardial infarction (MI) and stoke compared with placebo in patients with history of an
acute MI. In addition, there was a trend toward a harmful effect from this combination
supplement. The study included men and women who were between 30 to 85 years of age
who had a previous acute MI 7 days before randomization. Patients with comorbid diseases
associated with a life expectancy of less than four years, prescribed treatment with Bvitamins
or untreated vitamin B deficiency were not allowed to participate in the study. In this
multicenter, 3year, randomized, doubleblind study (n=3500), patients were randomized in a
twobytwo factorial design to receive one of four treatments including: folic acid 0.8 mg,
cyanocobalamin 0.4 mg, and pyridoxine 40 mg (referred to as the combination therapy), or
folic acid 0.8 mg and cyanocobalamin 0.4 mg, or pyridoxine 40 mg, or placebo. The mean
homocysteine levels decreased by 27% in the two groups of patients who received folic acid
and cyanocobalamin. In patients who received pyridoxine only, the mean homocysteine level
did not change significantly from baseline. Treatment with folic acid and cyanocobalamin,
with or without pyridoxine, was not associated with a reduced risk of nonfatal and fatal MI
and nonfatal or fatal stoke (primary endpoint). The rate ratio for the combination therapy
versus placebo was 1.22 (95% CI, 1 to 1.5; p=0.05), a trend toward an increased events
rate. Pyridoxine supplementation 40 mg per day was associated with a 17% increase in the
risk of MI (p=0.05), and the combination therapy was associated with a 30% increase risk of
MI (p=0.05); however, these analyses were not adjusted for multiple comparisons and could
MI (p=0.05); however, these analyses were not adjusted for multiple comparisons and could
have been explained by chance [55].

3) High doses of folic acid, cobalamin (vitamin B12), and pyridoxine (vitamin B6), did not
reduce the risk of stroke or coronary heart disease (CHD) events compared with low doses of
folic acid, vitamin B12, and vitamin B6 in patients with hyperhomocysteinemia and a history
of stroke. In the Vitamin Intervention for Stroke Prevention (VISP) randomized, controlled
trial, patients who had had a stroke and whose plasma total homocysteine (homocysteine,
homocystine, and mixed cysteine homocysteine disulfide) level exceeded the 25th percentile
for the North American stroke population (9.5 micromoles/liter (mcmol/L) for men and 8.5
mcmol/L for women) were stratified according to age (below or above 70 years) and sex
before randomization to receive vitamin supplements. All subjects received the daily reference
intakes of vitamins recommended by the Food and Drug Administration, except for folic acid,
pyridoxine, and cobalamin. A highdose group (n=1853) was given pyridoxine 25 milligrams
(mg), cobalamin 0.4 mg, and folic acid 2.5 mg per day. A lowdose group (n=1827) was
given pyridoxine 200 micrograms (mcg), cobalamin 6 mcg, and folic acid 20 mcg. The study
was intended to last for 2 years after randomization but was terminated one year after
recruitment of the last patient because the chance of showing a difference between
treatments during the remaining followup was close to nil. Mean plasma homocysteine was
reduced in the lowdose group by 0.3 mcmol/L and in the highdose group by 2.2 mcmol/L at
1 month and remained relatively constant in both groups thereafter. Ischemic stroke recurred
in 8.1% of the lowdose group and in 8.4% of the highdose group over the study period.
The 2year risk ratio for ischemic stroke was 1 (95% confidence interval (CI), 0.81.3). For
CHD events, the high dose group had a 0.5% lower probability of CHD events; the 2 year
risk ratio was 0.9 (0.7 to 1.2). The highdose group had a 1% lower probability for death (2
year risk ratio = 0.9 (0.7 to 1.1)). Among patients whose baseline homocysteine levels
exceeded 14 mcmol/L, 2year risk ratios were 0.9 (0.7 to 1.3) for stroke, 0.9 (0.6 to 1.3) for
CHD events, 0.9 (0.6 to 1.3) for death, and 1 (0.9 to 1.2) for the combined end point with all
3 outcomes [56].

Colorectal cancer, Secondary prevention; Prophylaxis
1) Overview

Efficacy: Adult, Ineffective




2) Summary:
In a meta analysis of 3 randomized and pseudorandomized trials supplementation with folic
acid did not have an effect in recurrence of colorectal adenomas at 3 years; however, it
showed increase risk when used beyond 3 years [2].

Folic acid 1 milligram (mg)/day does not reduce the risk of recurrent colorectal adenomas
compared to placebo in patients with a previous history of colorectal adenomas [3]

3) Adult:
a) In a metaanalysis of 3 controlledtrials, patients receiving folic acid supplementation
showed no increased risk for adenomatous lesion when used for less than 3 years, but there
was an increased risk when used for longer than 3 years. All 3 randomized controlled or
pseudocontrolled studies (n=7488) included patients (age range, 1 to 80 years) receiving folic
acid 2.5 to 0.5 mg compared with those who received no folic acid for the primary or
secondary risk of adenoma or advanced adenomatous lesions, including colorectal cancer.
After a followup of 3 to 5 years, the risk of recurrent adenomas was not increased in patients
who supplemented with folic acid for less than 3 years (odds ratio (OR) 1.09; 95% confidence
interval (CI) 0.93 to 1.28); however there was increased in patients who supplemented with
folic acid beyond 3 years (OR 1.35; 95% CI 1.06 to 1.70). The risk for the occurrence of an 11/30
folic acid beyond 3 years (OR 1.35; 95% CI 1.06 to 1.70). The risk for the occurrence of an
advanced lesion was the highest (OR 1.50; 95% CI 1.06 to 2.10) [2].

1) The results of a doubleblind, 2factor, phase III clinical trial showed that folic acid 1
milligram (mg)/day does not reduce the risk of recurrent colorectal adenomas compared to
placebo as secondary prevention in patients with a previous history of colorectal adenomas.
For inclusion into the study, patients (n=1021) had to meet at least 1 of the following criteria:
1 histologically confirmed adenoma removed within 3 months before recruitment, 1
histologically confirmed adenoma removed within 16 months before recruitment and a
lifetime history of 2 or more adenomas, or a histologically confirmed adenoma of at least 1
centimeter (cm) in diameter removed within the last 16 months prior to recruitment. Patients
were excluded if they had any of the following: medical condition that could be worsened by
aspirin or folic acid; any condition commonly treated with folic acid, aspirin or nonsteroidal
antiinflammatory agents; invasive large intestine cancer; malabsorption syndromes; or a
history of familial polyposis syndrome. Patients were randomly assigned to receive folic acid 1
mg/day (n=516) or placebo (n=505); all patients were randomized a second time to receive
either aspirin 81 mg/day, aspirin 325 mg/day, or placebo. Within 3 months of enrollment, all
patients were required to have colonoscopies and removal of all polyps. Two followup
colonoscopies were performed at 2 separate cycles: the first colonoscopy was at 3 years; the
second was 3 or 5 years later. After the first followup colonoscopy (n=987), adenomas
occurred in 44.1% (221/501) of patients in the folic acid group compared to 42.4% (206/486)
of patients in the placebo group (unadjusted relative risk (RR), 1.04; 95% confidence interval
(CI), 0.90 to 1.20; p=0.58). Fiftyseven patients (11.4%) in the folic acid group developed at
least one advanced lesion compared to fortytwo patients (8.6%) in the placebo group
(unadjusted RR, 1.32; 95% CI, 0.9 to 1.92; p=0.15). After the second followup colonoscopy
(n=607), adenomas occurred in 41.9% of the folic acid group (n=127) and 37.2% of the
placebo group (n=113) (unadjusted RR, 1.13; 95% CI, 0.93 to 1.37; p=0.23). In this second
followup, the incidence of (at least one) advanced lesion was 11.6% for folic acid (n=35)
and 6.9% for placebo (n=21) (unadjusted RR, 1.67; 95% CI, 1.00 to 2.80; p=0.05). Likewise,
due to 24 cases of prostate cancer in the folic acid group (versus 8 cases in placebo), the risk
if noncolorectal cancers was significantly higher in the folic acid subjects compared to placebo
(p=0.02). Adenoma rates among patients with endpoint data from both followup periods
were 71.3% in the folic acid group and 65.5% in the placebo group (RR, 1.09; 95% CI, 0.98
to 1.21; p=0.12). Incidence of advanced lesions among patients with endpoint data from
both followup periods were 23.1% and 17.1% for the folic acid group and placebo group,
respectively, (RR, 1.35; 95% CI, 0.98 to 1.86; p=0.07). Control of possible confounders, such
as gender, age, length of followup, alcohol consumption, body mass index, clinical center,
baseline number of lifetime adenomas, baseline plasma folate levels, or aspirin allocation, did
not yield changes to any results [3].

Diarrhea
1) Overview

Efficacy: Pediatric, Evidence is inconclusive

Recommendation: Pediatric, Class III

Strength of Evidence: Pediatric, Category B


2) Summary:
Folic acid supplementation did not reduce duration of acute watery diarrhea in children [37]

3) Pediatric:
a) Folic acid given as an adjunct to fluid and electrolyte therapy gave no clinical benefit to
children with acute watery diarrhea. In a randomized, doubleblind study, 106 children
between the ages of 6 and 23 months and with acute watery diarrhea of less than 72 hours
duration were given either folic acid 5 mg or placebo every 8 hours for 5 days. There was no
difference between groups in stool output, intake of oral rehydration solution, or in duration of
diarrhea. When data were analyzed separately for rotaviruspositive and rotavirusnegative 12/30
diarrhea. When data were analyzed separately for rotaviruspositive and rotavirusnegative
children, results were still not different between the folic acidsupplemented and the placebo
groups [37].

Disorder of cardiovascular system; Prophylaxis
1) Overview





2) Summary:
In the Heart Outcomes Prevention Evaluation (HOPE) study, lowering of homocysteine levels
with a daily combination supplement of folic acid, vitamin B12, and vitamin B6 did not reduce
the risk of the composite endpoint of death from cardiovascular causes, myocardial infarction,
and stroke compared with placebo in highrisk patients [54].

In the Norwegian Vitamin (NORVIT) trial, lowering homocysteine levels with folic acid and
vitamin B12, with or without vitamin B6, did not lower the risk of myocardial infarction (MI)
and stoke compared with placebo in patients with history of an acute MI [55].

High doses of folic acid, vitamin B12, and vitamin B6 did not reduce the risk of stroke or
coronary heart disease events compared with low doses of folic acid, vitamin B12, and vitamin
B6 in patients with hyperhomocysteinemia and a history of stroke in the Vitamin Intervention
for Stroke Prevention (VISP) trial [56].

3) Adult:
a) In the Heart Outcomes Prevention Evaluation (HOPE) study, lowering of homocysteine
levels with a daily combination supplement of folic acid, cyanocobalamin (vitamin B12) and
pyridoxine (vitamin B6) supplement did not reduce the risk of the composite endpoint of death
from cardiovascular causes, myocardial infarction, and stroke compared with placebo in high
risk patients. Patients studied were men and women 55 years of age or older with a history of
vascular disease (coronary, cerebrovascular, peripheral vascular) or diabetes and additional
risk factors for atherosclerosis. Patients taking more than 0.2 mg of folic acid per day in a
vitamin supplement were excluded from the study. The HOPE trial was a 5year, multicenter,
doubleblind clinical trial (n=5522). Patients were randomized to receive a combination tablet
including: folic acid 2.5 mg, pyridoxine 50 mg, and cyanocobalamin 1 mg or matching placebo
once daily. The mean homocysteine levels in the active treatment group decreased to 0.3
milligrams per liter (mg/L) from baseline and the placebo group increased to 0.1 mg/L from
baseline. The composite primary endpoint of death from cardiovascular causes, myocardial
infarction, and stroke was not significantly different between treatment groups. In this study,
519 (18.8%) primary outcome events occurred in the active treatment group compared to 547
(19.8%) occurrences in the placebo group (relative risk (RR), 0.95; 95% confidence interval
(CI), 0.84 to 1.07; p=0.41). There were no significant differences between the two study
groups in rates of cardiovascular related deaths or myocardial infarctions when the individual
components of the composite endpoint were analyzed separately. There were statistically
significant fewer strokes in the active treatment group (n=111; 4%) compared to placebo
(n=147; 5.3%) (RR, 0.75; 95% CI, 0.59 to 0.97; p=0.03); however, the number of strokes
was much less than the number of cardiovascular events. Also, the confidence intervals
around the estimated risk reduction for strokes were wide and were not adjusted for the
multiplicity of outcomes compared. In addition, there was no difference between study groups
on the number of total ischemic events (RR, 1.03; 95% CI, 0.94 to 1.13; p=0.57). However,
there was a significant difference in the number of patients hospitalized for unstable angina in
the active treatment group compared to the placebo group (RR, 1.24; 95% CI, 1.04 to 1.49;
p=0.02) [54].

b) In the Norwegian Vitamin (NORVIT) trial, lowering homocysteine levels with folic acid and
cyanocobalamin (vitamin B12), with or without pyridoxine (vitamin B6), did not lower the risk
of myocardial infarction (MI) and stoke compared with placebo in patients with history of an
acute MI. In addition, there was a trend toward a harmful effect from this combination
supplement. The study included men and women who were between 30 to 85 years of age
who had a previous acute myocardial infarction 7 days before randomization. Patients with
comorbid diseases associated with a life expectancy of less than four years, prescribed
treatment with Bvitamins or untreated vitamin B deficiency were not allowed to participate in
the study. In this multicenter, 3year, randomized, doubleblind study (n=3500), patients were
randomized in a twobytwo factorial design to receive one of four treatments including: folic
acid 0.8 mg, cyanocobalamin 0.4 mg, and pyridoxine 40 mg (referred to as the combination
therapy), or folic acid 0.8 mg and cyanocobalamin 0.4 mg, or pyridoxine 40 mg, or placebo.
The mean homocysteine levels decreased by 27% in the two groups of patients who received
folic acid and cyanocobalamin. In patients who received pyridoxine only, the mean
homocysteine level did not change significantly from baseline. Treatment with folic acid and
cyanocobalamin, with or without pyridoxine, was not associated with a reduced risk of
nonfatal and fatal MI and nonfatal or fatal stoke (primary endpoint). The rate ratio for the
combination therapy versus placebo was 1.22 (95% CI, 1 to 1.5; p=0.05), a trend toward an
increased events rate. Pyridoxine supplementation 40 mg per day was associated with a 17%
increase in the risk of myocardial infarction (p=0.05), and the combination therapy was
associated with a 30% increase risk of myocardial infarction (p=0.05); however, these
analyses were not adjusted for multiple comparisons and could have been explained by
chance [55].

c) High doses of folic acid, cobalamin (vitamin B12), and pyridoxine (vitamin B6) did not
reduce the risk of stroke or coronary heart disease (CHD) events compared with low doses of
folic acid, vitamin B12, and vitamin B6 in patients with hyperhomocysteinemia and a history of
stroke. In the Vitamin Intervention for Stroke Prevention (VISP) randomized, controlled trial,
patients who had had a stroke and whose plasma total homocysteine (homocysteine,
homocystine, and mixed cysteine homocysteine disulfide) level exceeded the 25th percentile
for the North American stroke population (9.5 micromoles/liter (mcmol/L) for men and 8.5
mcmol/L for women) were stratified according to age (below or above 70 years) and sex
before randomization to receive vitamin supplements. All subjects received the daily reference
intakes of vitamins recommended by the Food and Drug Administration, except for folic acid,
pyridoxine, and cobalamin. A highdose group (n=1853) was given pyridoxine 25 milligrams
(mg), cobalamin 0.4 mg, and folic acid 2.5 mg per day. A lowdose group (n=1827) was given
pyridoxine 200 micrograms (mcg), cobalamin 6 mcg, and folic acid 20 mcg. The study was
intended to last for 2 years after randomization but was terminated one year after recruitment
of the last patient because the chance of showing a difference between treatments during the
remaining followup was close to nil. Mean plasma homocysteine was reduced in the lowdose
group by 0.3 mcmol/L and in the highdose group by 2.2 mcmol/L at 1 month and remained
relatively constant in both groups thereafter. Ischemic stroke recurred in 8.1% of the lowdose
group and in 8.4% of the highdose group over the study period. The 2year risk ratio for
ischemic stroke was 1 (95% confidence interval (CI), 0.81.3). For CHD events, the high dose
group had a 0.5% lower probability of CHD events; the 2 year risk ratio was 0.9 (0.7 to 1.2).
The highdose group had a 1% lower probability for death (2year risk ratio = 0.9 (0.7 to
1.1)). Among patients whose baseline homocysteine levels exceeded 14 mcmol/L, 2year risk
ratios were 0.9 (0.7 to 1.3) for stroke, 0.9 (0.6 to 1.3) for CHD events, 0.9 (0.6 to 1.3) for
death, and 1 (0.9 to 1.2) for the combined end point with all 3 outcomes [56].

Druginduced gingival hyperplasia, Phenytoininduced
1) Overview

Efficacy: Adult, Evidence is inconclusive; Pediatric, Evidence is inconclusive

Recommendation: Adult, Class III; Pediatric, Class III



2) Summary:
Somewhat effective in patients with subnormal serum folate but not in patients with normal
folate [59][60]

3) Adult:
a) Supplemental folic acid does not appear to reduce phenytoininduced gingival hyperplasia.
In a randomized, doubleblind, parallel study with 20 severely retarded institutionalized
epileptic adults, all of whom exhibited phenytoininduced gingival hyperplasia, daily
supplementation of folic acid 3 milligrams (mg) for 16 weeks had no more effect on
hyperplasia, gingival health, or plaque index than did a placebo [59]. All subjects had normal
serum folate levels, even at the beginning of the study.

b) Oral systemic folic acid was not effective in reducing phenytoininduced gingival
hyperplasia in patients with normal serum folate levels; however, use of a folatecontaining
mouthwash was effective. A doubleblind, placebocontrolled trial was conducted to evaluate
the effects of both systemic and topical folic acid administration on gingival hyperplasia.
Fifteen mentally handicapped subjects ranging in age from 11 to 29 years with gingival
hyperplasia were included. All subjects had taken phenytoin for at least 3 years and had
normal serum folate levels. The study participants received baseline dental hygiene
counseling, and were then randomized into 3 groups. Group 1 received two 1 mg tablets of
folic acid orally twice a day and a 5 mL of placebo mouthwash twice daily. Group 2 received 2
placebo tablets twice daily and 5 mL of a mouthwash containing 1 mg/mL folate twice daily.
Group 3 received 2 placebo tablets twice daily and 5 mL of placebo mouthwash twice daily.
Probing depths and plaque and gingival indices were assessed at baseline and at 3 and 6
months. There were no significant differences among the groups with respect to plaque index
or gingival inflammation throughout the study. Only the group receiving the folic acid
mouthwash improved significantly from baseline on the gingival hyperplasia index (p less than
0.05). The authors postulated that folic acid applied topically may reduce hyperplasia by
reducing the pathological oral flora or perhaps by reducing inflammation via binding of plaque
derived endotoxin to folate [60]. Brown et al hypothesized that topical folate administration
may have provided a greater local folic acid concentration through passive diffusion than
through the systemic route [59].
4) Pediatric:
a) In children with phenytoininduced gingival hyperplasia, there were no differences in
outcome between the groups receiving 5 mg folic acid/day for a year and placebo. Serum
folate values were all in the normal range at the beginning of the study. The same study
included a group of mentally retarded adults, whose plasma phenytoin levels were above the
normal range. In those subjects whose serum folate levels were subnormal at the start of the
study, some improvement in the gingival hyperplasia was observed. The authors urge the
monitoring of serum folate levels in patients taking anticonvulsive therapy [61].

1) Overview


Recommendation: Adult, Class IIa; Pediatric, Class IIa



2) Summary:
Indicated for folic acid deficiency [5][5]

3) Adult:
a) Supplementation of exogenous folate, whether given orally or parentally, is effective in the
treatment of folic acid deficiency [5][5].

Folic acid deficiency Sex hormones adverse reaction
1) Overview





2) Summary:
Can correct folate deficiency induced by use of oral contraceptives [64][65][64]

3) Adult:
a) Ingestion of oral contraceptives may result in folic acid deficiency which on occasion may
be manifested by megaloblastic anemia and thrombocytopenia. Administration of folic acid can
correct the folic acid deficiency and thereby promptly reverse any abnormalities associated
with the folic acid deficiencies [64][65]. The minimum optimal dose of oral folic acid is 2
milligrams/day [64].

Fragile X syndrome
1) Overview

Efficacy: Pediatric, Evidence is inconclusive

Recommendation: Pediatric, Class III

Strength of Evidence: Pediatric, Category B


2) Summary:
Overall, folic acid has not been shown to be effective, although some patients respond
(Gillberg et al, 1986; Madison et al, 1986a; Rosenblatt et al, 1985; FrosterIskenius et al,
1986; Brown et al, 1984)

Response may be greatest in prepubertal patients [57]

3) Pediatric:
a) Folic acid had a positive effect on behavior and IQ in some patients but not in most in a
small study. In a doubleblind, crossover study, 25 males with fragileX syndrome, ranging in
age from 1 to 31 years, were treated with either folic acid 5 milligrams or placebo twice daily
for 6 months. Each treatment group was then crossed over to the opposite treatment for
another six months. Parents and caretakers evaluated patients for improvements in speech,
language, apraxia, and behavior. Evaluations by the parents or caretakers were conducted
prior to and following the study, and prior to crossover of medication. The parents or
caretakers found improvements in attentiveness, activity level, cooperativeness, and
concentrating ability during the study. Of the 25 patients enrolled in the study, 3 patients were
not included in the analysis; 1 patient was unevaluable at all 3 assessment periods and the
other 2 patients who were in the pubertal or postpubertal groups did not complete the study
in order to continue on folic acid therapy. When comparing the overall effects on IQ, no
statistically significant difference was detected between the folic acid and placebo treatments
(p = 0.77). When comparing the effects of folic acid in prepubertal patients, behavior and IQ
significantly improved compared to placebo (p = 0.016 and p = 0.028, respectively) [57].

b) Six fragileX patients, aged 3 to 15 years, and four matched patients without fragileX
syndrome, aged 5 to 9 years, were treated with either folic acid 10 milligrams daily or placebo
in an ABA or BAB fashion. Each study phase was four months in duration. Assessments were16/30
in an ABA or BAB fashion. Each study phase was four months in duration. Assessments were
conducted prior to and following the study, as well as one month prior to the end of each
fourmonth study period. Response to therapy was evaluated by videotapes of the patients
and by interviews with parents or caretakers regarding patient improvement during the study.
Although the videotaped sessions demonstrated either deterioration or no improvement during
folic acid administration, all of the parents or caretakers perceived improvement in
hyperactivity, attention, cooperation, speech, and language, but only 1 of the 10 parents or
caretakers interviewed was able to correctly identify the sequence of drug administration. The
results of this study are negative even when analyzing subpopulations of prepubertal males
and adolescent males. The investigators reported no significant change in memory or IQ in
either group. The incomplete reporting of methods and results confounds interpretation of this
study [58].

c) Overall, folic acid has not been shown to be effective, although some patients respond.
Studies differ with regard to cognitive responses, sample sizes, and age groups. Of 29 patients
studied in a number of trials, (Gillberg et al, 1986; Madison et al, 1986a; Rosenblatt et al,
1985; FrosterIskenius et al, 1986; Brown et al, 1984) only two patients appeared to respond
to folic acid therapy: an 18yearold male (Brown et al, 1984) and a 5yearold female
(FrosterIskenius et al, 1986).

Gingivitis
1) Overview





2) Summary:
Topical folic acid improves gingival inflammation in adults who are not taking phenytoin and
may help children with subclinical folate deficiency (Pack, 1984)(Thompson & Pack, 1982)[66]

3) Adult:
a) Topical folic acid significantly improved gingival inflammation in nonpregnant adults in a
randomized, doubleblind, placebocontrolled study. Over a period of 4 weeks, male and
female subjects (n=60) rinsed twice daily for 1 minute with 5 milliliters of mouthwash
containing folic acid 5 milligrams or no folate. Folic acid treatment resulted in significantly
greater decrease in mean number of gingival color change sites and bleeding sites compared
to controls (p less than 0.001) (Pack, 1984).

b) Topical folic acid significantly improved gingival inflammation during pregnancy. In two
doubleblind studies, one of 14 days length and one of 28 days length, groups of patients
using a folate mouthwash, rinsing twice daily for 1 minute, and receiving a placebo tablet
exhibited significantly less gingival hyperplasia than pregnant women using placebo
mouthwash and folic acid tablets (5 milligrams/day) or both placebo mouthwash and tablets.
No effect of treatment on dental plaque was detected (Thompson & Pack, 1982)[66].

c) Rinsing with a folic acid solution improved gingival inflammation in a randomized, double
blind, placebocontrolled study. Subjects (n=30) aged 21 to 32 years rinsed twice daily with
either 5 milliliters of a 0.1% folic acid solution or placebo for 60 days. Folic acid caused a
significant (p less than 0.05) improvement in a gingival index and a bleeding index, but not a
plaque index compared to placebo. No significant increase in serum folic acid was found after
treatment in the experimental group (Vogel et al, 1978).

d) Oral folic acid improved one of two indices of gingival inflammation in a randomized,
doubleblind, placebocontrolled study. Subjects (n=30) aged 19 to 58 received either folic
acid 2000 micrograms or placebo twice daily for 30 days. Evaluation by a gingival index,
plaque index and by gingival exudate flow revealed significant improvement from treatment
only in gingival exudate flow compared to initial values and to placebo (p less than 0.05) 17/30
only in gingival exudate flow compared to initial values and to placebo (p less than 0.05)
(Vogel et al, 1976).

Homocystinemia
1) Overview

Efficacy: Adult, Evidence favors efficacy; Pediatric, Evidence favors efficacy

Recommendation: Adult, Class IIa; Pediatric, Class IIb

Strength of Evidence: Adult, Category A; Pediatric, Category B


2) Summary:
Plasma homocysteine is predictor of mortality in coronary artery disease (Nygard et al, 1997)

Folic acid lowers plasma homocysteine [9][10]

Folic acid with vitamin B12 more effective than folic acid alone for lowering plasma
homocysteine [11]

3) Adult:
a) Vitamin treatment (folic acid 5 milligrams (mg) and pyridoxine 250 mg daily) for 2 years, in
comparison to placebo treatment, decreased plasma homocysteine and decreased rate of
abnormal exercise electrocardiography tests (a coronary outcome variable) but had no effect
on ankle brachial pressure indices and peripheral artery or carotid artery outcomes. This
randomized, doubleblind, placebocontrolled trial was conducted in 156 healthy siblings of
patients with premature arterial disease [12].

b) A metaanalysis of 12 trials examining the effects of supplemental folic acid on blood
homocysteine levels showed that supplements of 0.5 to 5 milligrams (mg) folic acid could be
expected to reduce blood homocysteine by a quarter to a third. Absolute and proportional
reductions were greatest in persons with high pretreatment homocysteine and low
pretreatment folic acid. Addition of vitamin B12 reduced blood homocysteine by another 7%.
Vitamin B6 did not lower homocysteine any further. The average concentration of blood
homocysteine in Western populations is 12 micromoles/L [9].

c) Supplementation with B vitamins (folic acid, vitamin B12, and vitamin B6) reduced elevated
plasma homocysteine levels in men, but antioxidant vitamins (vitamin E, ascorbic acid, and
betacarotene) were without effect. The top third of men with respect to plasma homocysteine
was selected from a force of Belfast workers in the age range 30 to 49 years. The
homocysteine level of this target population (n=101) was greater than or equal to 8.3
micromoles/L. Subjects were randomized to receive 1 of 4 treatments for 8 weeks: Bgroup
vitamins alone (folic acid 1 milligram(mg)/day, pyridoxine 7.2 mg/day, and cyanocobalamin
0.02 mg/day); antioxidants alone (ascorbic acid 150 mg/day, alphatocopherol 67 mg/day,
and betacarotene 9 mg/day); Bvitamins and antioxidant vitamins; or placebo. At baseline,
fasting homocysteine was inversely correlated with folate (r=0.37, p less than 0.01) and
cobalamin (r=0.25, p less than 0.01). There were no correlations with pyridoxine, vitamin E,
ascorbic acid, or betacarotene. Over 8 weeks, the Bvitamins reduced homocysteine
concentration by 27.9% (p less than 0.001), whereas antioxidant vitamins raised it by 5.1%
(not significant). There was no interaction between the Bvitamins and antioxidant vitamins.
The folate response was 36% higher in subjects homozygous for the nonthermolabile allele of
5,10methylene tetrahydrofolate reductase (MTHFR) than in those homozygous for the
thermolabile allele; however, group sizes were too small to determine statistical significance
[10].

d) A combination of folic acid and vitamin B12 is more effective for lowering plasma
homocysteine (Hcy) than is folic acid alone. In a randomized, doubleblind study, 150 women
aged 20 to 34 years were given placebo for 4 weeks and then one of the following treatments
for 4 weeks: folic acid 400 micrograms/day (mcg/day); folic acid 400 mcg/day plus vitamin
B12 (cyanocobalamin) 6 mcg/day; or folic acid 400 mcg/day plus vitamin B12 400 mcg/day. At
B12 (cyanocobalamin) 6 mcg/day; or folic acid 400 mcg/day plus vitamin B12 400 mcg/day. At
the start of the study, the majority of the women had normal status with respect to folic acid
and vitamin B12 and had plasma homocysteine levels within the normal range. Nevertheless,
after 4 weeks of supplementation, plasma Hcy was significantly reduced in all groups
compared to baseline values (p less than 0.001). Reductions in the 3 groups were 11%, 15%
and 18%, respectively. The difference between the group receiving folic acid only and the
group receiving folic acid plus 400 mcg vitamin B12 was significant (p less than 0.05).
Individual changes were greatest in those who had higher starting levels of plasma Hcy and in
those with lower levels of folic acid [11]. A subsequent study in 53 healthy volunteers showed
that, while homocysteine concentration depends mainly on folate status, supplementation with
folate above a certain level (200 to 400 mcg daily) shifts the dependency from folate to
vitamin B12. Hence, the authors suggested that supplementation with both folate and vitamin
B12 would have a greater lowering effect on the risk of vascular disease than would folate
alone [13].

e) Longterm supplementation with folic acid, vitamin B12, and pyridoxine gave sustained
reduction of elevated plasma homocysteine levels in predialysis chronic renal failure patients.
Patients (n=78) were given folic acid 5 milligrams (mg) 3 times per week, vitamin B12 one mg
3 times per week, and pyridoxine 250 mg 2 times per week for 1 to 6 years. An average
reduction of 33% (p less than 0.001) was evident by 3 months of treatment. At the end of
followup (either the beginning of hemodialysis or December 1997), average plasma
homocysteine was 40% below baseline values, although renal function had continued to
decline [14].

f) Folic acid fortification of cereals at levels recommended by the United States Food and Drug
Administration (FDA) reduces plasma homocysteine levels but perhaps not sufficiently to affect
people with ischemic heart disease. In a doubleblind crossover study, 75 subjects with
ischemic heart disease were given 30gram (g) portions of an unfortified breakfast cereal
(placebo) or a fortified one to be consumed daily for 5 weeks. This was followed by a 5week
washout period during which subjects consumed their usual diet, and then another 5week
period during which they consumed the other cereal. Subjects were divided into 3 groups;
each group received a different fortified cereal with folic acid 127 micrograms (mcg), 499 mcg,
or 665 mcg per 30 g of cereal. All fortified cereals also contained pyridoxine 1.8 milligrams and
cyanocobalamin 6.1 mcg per 30 g. The cereal containing 127 mcg folic acid per 30 g reduced
plasma homocysteine by 3.7%. Cereals with 499 and 665 mcg folic acid per 30 g reduced
homocysteine by 11% and 14%, respectively (p=0.001). Plasma folic acid increased
proportionately to the level of folic acid in the cereal. The level of folic acid recommended by
the FDA is intended to reduce the occurrence of neural tube defects; it many be too low to
significantly reduce homocysteinemia [15].

g) When consumed daily, folic acidfortified cereals reduced plasma homocysteine levels by
approximately 10%, on average. In a double blind study, 94 healthy volunteers consumed a
portion of a provided breakfast cereal daily for 24 weeks. Cereals were unfortified or fortified
either with folic acid to provide about 200 micrograms per portion or folic acid (same
concentration) plus other vitamins. Serum folate and red cell folate rose, and plasma
homocysteine declined (p less than 0.001 for all parameters) over the study period in subjects
eating fortified cereals. Changes in the two fortifiedcereal groups were not different. There
were no changes over time in the placebo group. The higher the baseline homocysteine level,
the greater was the folate effect. Plasma homocysteine levels of the study population were
considered to be within the normal range at the start of the study [16].

h) Supplementation of uremic hemodialysis patients with oral 5methyltetrahydrofolate
(MTHF) 15 milligrams/day for 2 months lowered serum homocysteine concentrations and
raised the ratio of adenosylmethionine to adenosylhomocysteine, which is inversely related to
the degree of inhibition of transmethylation reactions (involved in such processes as
membrane protein repair). Before MTHF treatment, the average plasma homocysteine
concentration of the 14 patients was 68 micromolar (mcM); after treatment it was 18.9 mcM.
In 6 of the patients, homocysteine was reduced to less than 15 mcM, within the acceptable
range. The adenosylmethionine/adenosylhomocysteine ratio increased form 1.5 to 2.9 over
the 2 months of treatment [17]. In contrast, hyperhomocysteinemia persisted in 2 populations
of hemodialysis patients who received either 1 mg or 5 mg folic acid daily. Plasma
homocysteine levels were 27.3 and 28.9 micromoles/liter, respectively, showing that folic acid
at 1 or 5 mg daily, routinely prescribed in many hemodialysis units, is insufficient to reduce
homocysteine to levels associated with average cardiovascular risk [18].

i) Folic acid supplementation of dialysis patients reduced elevated plasma homocysteine levels
but failed to improve endothelial function in a 52week study. In the first phase of the study,
30 patients on peritoneal dialysis (PD) randomly received either folic acid 5 milligrams (mg)
per day or folic acid 5 mg plus betaine 4 grams per day for 12 weeks. In both groups, serum
folate rose, and plasma homocysteine fell dramatically to 16.8 and 21.5 micromoles/liter in the
2 groups, respectively. Betaine had no additional effect beyond that of folate on plasma
homocysteine. In the second phase, 28 of the patients were rerandomized to groups
receiving folic acid 1 mg or folic acid 5 mg daily for 40 more weeks. There were no further
significant changes in plasma homocysteine in either group. Endothelial function, as measured
by endotheliumdependent, flowmediated vasodilatation in the forearm (which parallels
endothelial function of the coronary arteries) and by levels of endotheliumderived proteins
(high levels of which are indicative of vascular damage), did not change in either group over
the 52week period [19].

j) A single measurement of serum homocysteine (Hcy) is not a reliable predictor of vascular
disease. In a study (n=79) to determine whether measurement of changes in serum Hcy
during folate supplementation could provide a method for detecting subclinical folate
deficiency, investigators found that variations of serum Hcy from day to day within an
individual not receiving folate supplementation can be greater than the average change within
a group receiving folate supplementation. This does not discredit epidemiological studies that
associate elevated serum Hcy levels with cardiovascular disease. However, it warns that to
extrapolate these findings to an individual may require repeated Hcy analyses [20].
4) Pediatric:
a) Children with sickle cell disease (SCD) have plasma folate levels comparable to those of
normal children but higher plasma homocysteine levels, which can be reduced by folate
supplementation. Fortysix Jamaican children with SCD were given vitamins B12 and B6 for
one week (to assure that deficiencies of those vitamins did not affect results when folic acid
was supplemented) and then folic acid for the next week (2 milligrams (mg) per day for
children 6 and under, and 4 mg per day for children over 6). At the end of a week of folic acid
supplementation, plasma homocysteine had declined 53%. Although folate supplementation is
not necessary for the prevention of macrocytic anemia in this population, and plasma folate
levels are the same as in normal children, folate intake is apparently suboptimal for the
regulation of homocysteine [21].

Impaired cognition; Prophylaxis
1) Overview





2) Summary:
There is no evidence in Englishlanguage literature that folic acid supplementation or vitamin B
supplementation alone or in combination affects cognitive function in normal or cognitively
impaired patients according to a systematic review of randomized, controlled trials [1]

3) Adult:
a) There is no evidence in Englishlanguage literature that folic acid supplementation or
vitamin B supplementation alone or in combination affects cognitive function in normal or
cognitively impaired patients according to a systematic review of randomized, controlled trials.
Articles included were from randomized controlled trials of cyanocobalamin or
hydroxycobalamin (vitamin B12), pyridoxine hydrochloride (vitamin B6) and/or folic acid
supplementation, excluding multivitamins, in a wide variety of dosages, routes and
populations. The studies included had cognitive function outcomes, such as diagnosis or
degree of Alzheimer disease, other agerelated neurocognitive disorders, cognitive impairment
or cognitive function tests. Fourteen trials met this study criteria; however, the majority of 20/30
or cognitive function tests. Fourteen trials met this study criteria; however, the majority of
these trials were of poor quality and were limited in terms of clinical relevance. Across studies,
there were three trials of vitamin B6 and six trials in vitamin B12 that found no overall effect
on cognitive function. One of the three folic acid studies found a benefit in patients with
cognitive impairment with low baseline folate levels (less than 3 ng/mL or 6.8 mmol/L). All six
trials of vitamin B combination studies had no effect on cognitive function. In three of the
studies reviewed, patients in the placebo arm had greater improvement in a small number of
cognitive tests compared to patients receiving either folic acid or combination B therapy [1].
Memory impairment
1) Overview





2) Summary:
Results from a pilot study suggest that folic acid supplementation may be of benefit in
treatment of geriatric cognitive deficit [62]

Further studies are needed

3) Adult:
a) Thirty elderly patients with diminished cognitive function and folate levels below 3 ng/mL
were enrolled in a doubleblind, placebocontrolled pilot study to evaluate the efficacy of folic
acid supplementation. The preliminary results demonstrated that patients treated with folic
acid for 60 days showed a significant improvement of both memory and attention efficiency
when compared with the placebo group [62].

1) Overview

Efficacy: Adult, Effective

Recommendation: Adult, Class I



2) Summary:
Supplemental folic acid during the periconceptional period reduces the incidence of neural
tube defects (NTDs) [41][38][42][43]

Folate from supplemental folic acid more effective than folate from food sources for reducing
NTDs [44]. Similar results were reported by others [45]

High doses of supplemental folic acid (6 mg/day) reduced the occurrence of cleft lip and cleft
palate; 0.8 mg/day did not [46]

Supplemental folic acid reduced the incidence of imperforate anus in children born to women
in China [47]

The incidence of Lipomyelomeningocele has not been reduced by folic acid fortification of
foods in Nova Scotia (McNeely & Howes, 2004)
foods in Nova Scotia (McNeely & Howes, 2004)

3) Adult:
a) Neural Tube Defects
1) An analysis of published data showed that, for every increase of 0.1 milligram (mg) folic
acid intake per day, serum folate increases approximately 1 nanogram/milliliter (ng/mL) in
women of childbearing age and approximately 2.5 ng/mL in older people. Furthermore, a
doubling of serum folate roughly halves the risk of bearing a child with a neural tube defect
(NTD). For women with the average serum folate of women of childbearing age in the United
Kingdom (5 ng/mL), increasing folic acid intake by 0.4 mg/day (the level recommended
during the periconceptional period in the United States) reduces risk of an NTD birth by 36%.
An increased folic acid intake of 5 mg/day reduces risk by 85%. On this basis, the authors
recommend that women intending to become pregnant take supplemental folic acid 5
mg/day. The model developed in this study to predict relative risk of an NTD birth from
supplemental folic acid intake was verified by a close match between the model's prediction
and actual findings by the United States Public Health Service after the introduction of the
food fortification program in 1996 [41].

2) Folic acid should be administered at least 1 month before and during the first 3 months of
pregnancy. The Centers for Disease Control, American Academy of Pediatrics, and various
other committees recommend that all women of childbearing age who are capable of
becoming pregnant receive 0.4 milligrams/day. The reduction in neural tube defects has been
60% to 70% in patients receiving folic acid therapy [38][42]. Patients with a previous history
of a neural tube defect during pregnancy should receive 4 milligrams/day starting 1 month
before pregnancy and throughout the first 3 months of pregnancy [39][40]; (Mulinare, 1993;
Anon, 1992). The occurrence of neural tube defects (spina bifida, anencephaly, or
encephalocele) in the United States was 0.6 case per 1000 live births in 1989. The ethnic
groups with the highest rates include Welsh, Irish, and Sikhs. The recurrence rate for women
with a previous history of an infant born with a neural tube defect is 20 cases per 1000 live
births (2%). However, in high risk populations, the recurrence rate may be up to 50 cases per
1000 live births (5%).

3) The occurrence of neural tube defects was decreased by approximately 60% in 3051
pregnant mothers treated with 0.4 milligram of FOLIC ACID during the periconceptional
period (28 days before the last menstrual period through 28 days after the last menstrual
period) [43].

4) A significant reduction in risk for first time occurrence of neural tube defects was observed
in 18,508 pregnant women consuming folic acidcontaining multivitamins compared to no folic
acid consumption [44]. Similar results were reported by others [45].

b) Other Birth Defects
1) Periconceptional use of folic acid reduced the rate of occurrence of imperforate anus
among infants born to Chinese women participating in a large, epidemiologic study (n greater
than 223,000). Women who were already pregnant or who were preparing for marriage were
asked to purchase pills containing folic acid 400 micrograms (mcg) without other vitamins and
to take one per day through the end of the first trimester of pregnancy. Among those women
who took folic acid, the rate of occurrence of imperforate anus was 1.6 per 10,000 births of at
least 20 weeks' gestation; the rate among nonpilltakers was 3.1 per 10,000. When adjusted
for maternal age (a factor in the occurrence of imperforate anus), the relative risk for
imperforate anus among folic acid pilltakers was 0.59 (95% confidence interval: 0.33 to
1.07) [47].

2) Periconceptional supplementation with folic acid, approximately 6 milligrams (mg) per day,
reduced the occurrence of cleft lip (CL) with or without cleft palate (CP), whereas
supplementation with a multivitamin pill containing folic acid 0.8 mg did not. A prospective
cohort study of supplemented (0.8 mg per day) and unsupplemented women in Hungary
(more than 10,000 births) showed no difference in occurrence CL and CP between the
groups. A Hungarian casecontrol study (more than 50,000 births), however, showed that
frequent use of highdose folic acid (in general 6 mg per day) was associated with a lower
occurrence of CL and CP. The critical period for primary and secondary palate development is
during the first and second months of gestation. There was no difference between cases and
controls in the occurrence of supplementation with folic acid after 4 months of pregnancy
[46].

3) Folic acid 5 milligrams/day significantly increased predelivery hemoglobin in pregnant
women with betathalassemia minor compared with those receiving folic acid 0.25
milligram/day [48].

1) Overview


Recommendation: Adult, Class IIb; Pediatric, Class IIb



2) Summary:
Folic acid is a dietary supplement [24]

3) Adult:
a) The folate coenzymes involved in deoxyribonucleic acid (DNA) synthesis, and are required
for normal cell division. The upper intake level of folate from fortified food or as a supplement
for adults is 1 milligram per day [24]. Higher doses may be required in the presence of
alcoholism, hemolytic anemia, anticonvulsant therapy, smoking, pregnant adolescents, or
socioeconomic conditions [6].

Restenotic lesion of coronary artery; Prophylaxis
1) Overview

Efficacy: Adult, Ineffective




2) Summary:
Supplementation with folate, vitamin B6, and vitamin B12 resulted in more restenosis than did
placebo in patients with coronary artery stents[53]

3) Adult:
a) In comparison to placebo, supplementation with folic acid, vitamin B6, and vitamin B12
(referred to as folate therapy) increased the risk of instent restenosis in patients with
coronary stents. In a randomized, doubleblind, placebocontrolled trial, 636 patients with
successful coronary stents received either placebo (n=320) or an intravenous bolus of folic
acid 1 milligram (mg), vitamin B6 5 mg, and vitamin B12 1 mg, followed by daily oral folic acid
1.2 mg, vitamin B6 48 mg, and vitamin B12 60 micrograms (n=316) for 6 months. At the 6
month followup, the minimal luminal diameter was significantly smaller in the folate group
than in the placebo group (1.59 vs 1.74 millimeters, p=0.008), and the folate group had a
higher frequency of smaller diameters (p=0.004). Restenosis, defined as stenosis of more than
50% of the luminal diameter, occurred in 34.5% of patients in the folate group and in 26.5%
of patients in the placebo group (relative risk 1.3; 95% confidence interval, 1 to 1.69;
p=0.05). By 250 days of followup, 15.8% of the folate group and 10.6% of the placebo group
had required a second revascularization procedure (p=0.05). Plasma homocysteine was
reduced in the folate group but not in the placebo group and was significantly lower at 6
month followup in the folate group than in the placebo group (p less than 0.001), suggesting
that plasma homocysteine level is not a predictor of restenosis [53].

1) Overview



Strength of Evidence: Adult, Category A


2) Summary:
Evidence
Folic acid supplementation significantly reduced the risk of abnormal serum transaminase
levels by 81% in a metaanalysis of randomized placebocontrolled trials evaluating the
protective effect of lowdose folate supplementation in adults receiving methotrexate (25
mg/week or less) for rheumatoid arthritis (N=6; 174 subjects receiving folic acid). Additionally,
significantly fewer patients receiving folic acid withdrew from methotrexate therapy. Although
not statistically significant, there was a trend toward a lower incidence of stomatitis and a
24% reduction in the risk of developing gastrointestinal side effects. No differences in disease
activity were detected for folic acid compared with placebo [63].

Dose Adjustments
Adult Dosage
Normal Dosage
Intramuscular route

Intravenous route

Oral route
Homocystinemia
a) Folic acid alone at a dose of 0.5 milligrams (mg) per day was effective in
reducing both fasting homocysteine concentrations and the increase in
homocysteine caused by a methionine load. Folic acid 5 mg was no more effective
than 0.5 mg [22].

b) In patients with documented coronary artery disease and elevated plasma
homocysteine, folic acid 400 micrograms (mcg) daily for 90 days lowered plasma
homocysteine as effectively (by 30%) as did 1 milligram (mg) per day or 5mg/day.
All treatments provided vitamin B6 12.5 mg and vitamin B12 500 mcg daily [23].
a) Neural Tube Defect, prophylaxis (against first occurrence)
1) Daily dosing of folic acid 400 micrograms was more effective than folic acid
2800 micrograms/week for achieving red blood cell folate levels considered to be
protective against neural tube defects (905 nanomoles/liter). Fifty percent of 37
women receiving the weekly dose and 75% of 35 women receiving the daily dose
had red blood cell folate levels above 905 nanomoles/liter by 12 weeks. At 6
weeks, only 23% of the daily folic acid group had red blood cell folate levels above
905 nanomoles/liter, possibly suggesting that women desiring to become pregnant
should begin taking folic acid earlier than the currently recommended 4 weeks
[49].

2) For the prevention of neural tube defects, all women of childbearing age who
are capable of becoming pregnant should take 0.4 milligrams of folic acid daily.
This dose is usually found in any multivitamin [38][39][40]. Folic acid should be
administered at least 1 month before pregnancy and for the first 3 months of
pregnancy [40]; (Mulinare, 1993). Doses from 0.5 milligrams to 1 milligram/day
are often administered during pregnancy. Prenatal vitamins contain 0.8 milligrams
to 1 milligram of folic acid [39].

3) An analysis of published data showed that, for every increase of 0.1 milligram
(mg) folic acid intake per day, serum folate increases approximately 1
nanogram/milliliter (ng/mL) in women of childbearing age and approximately 2.5
ng/mL in older people. Furthermore, a doubling of serum folate roughly halves the
average serum folate of women of childbearing age in the United Kingdom (5
ng/mL), increasing folic acid intake by 0.4 mg/day (the level recommended during
the periconceptional period in the United States) reduces risk of an NTD birth by
36%. An increased folic acid intake of 5 mg/day reduces risk by 85%. On this
basis, the authors recommend that women intending to become pregnant take
supplemental folic acid 5 mg/day [41].

4) Folic acid supplements, folic acid intake from fortified cereals, and vitamin C
supplements were found to predict red cell folate levels in women (n=189)
intending to become pregnant. Only women taking folic acid supplements
(typically 400 micrograms/day) had red cell folate levels of 906 nmol/L (400
ng/mL) that is considered by some to be optimal for prevention of neural tube
defects. In nonusers of supplements, 500 micrograms of folate per day from
foods and fortified cereals may be necessary to achieve equivalent red cell folate
levels. One woman in 8 had a red cell folate level below 200 nanograms/milliliter,
indicative of negative folate balance. Supplemental iron was negatively related to
red cell folate level. With folic acid supplement users, zinc was also inversely
related to red cell folate level [50].

5) Supplemental intake of folate (400 mcg/day) as folic acid (ie, synthetic form) or
in folic acidfortified foods raised red blood cell folate to levels thought to be
protective against neural tube defects, whereas eating 400 mcg folate per day
from foods naturally rich in folate did not. It is presumed that the explanation lies
in the greater bioavailability of folic acid, as compared to the polyglutamate form
of folate that occurs naturally in foods [51].

b) Neural Tube Defect, prophylaxis (against recurrence)
1) Women with history of a pregnancy resulting in a neural tube defect should
receive 4 milligrams/day starting 1 month before pregnancy and throughout the
first 3 months of pregnancy [38][39][40]; (Mulinare, 1993). However, the
Canadian College of Medical Geneticists recommends a range of 0.8 milligrams to
5 milligrams/day [52]. Doses as high as 10 milligrams/day have not shown any
acute or chronic toxicity [42].

a) The recommended daily allowance of folate is 400 micrograms (mcg) for men,
400 mcg for women, 600 mcg for pregnant women, and 500 mcg for lactation
women [24].

a) Offlabel dosage: 1 mg/day orally OR 5 mg/week orally [63]

Subcutaneous route

Dosage in Geriatric Patients
A) HYPERHOMOCYSTEINEMIA
1) Supplements of folic acid 600 micrograms per day (with dietary intake, providing
approximately 900 micrograms total folic acid intake per day) were estimated to be sufficient
to ensure that 95% of the elderly population would be without cardiovascular risk (ie, plasma
homocysteine lower than 10 micromoles/liter) from folate deficiency. This conclusion was
based on a randomized, placebocontrolled, doserange study with 368 adults, aged 6575
years. The recommendation is based on an assumption of adequate vitamin B12 intake [69].

Dosage Adjustment During Dialysis
A) In patients with a satisfactory level of nutrition, supplemental folate is not necessary to
ensure adequate erythropoiesis [70][71][72]. However, homocysteine, a risk factor for
atherosclerosis, accumulates in the blood of dialysis patients and is inversely related to folate
status. If plasma homocysteine is above the normal range (5 to 15 micromoles/liter), one
recommendation is to supplement folate at a level of 5 mg/day. Reductions in homocysteine of
25% to 30% can be expected within 4 to 6 weeks. If after 8 weeks homocysteine is still
elevated, the dose can be increased stepwise by 5 mg/day to a maximum of 15 mg/day [73].
Pediatric Dosage
Normal Dosage
Intramuscular route
0.1 mg/d [5].

b) The recommended intramuscular dose for preterm infants is 100 micrograms
daily from day 7 to discharge from hospital [8].
0.1 mg/d [5].

Intravenous route
0.1 mg/d [5].
0.1 mg/d [5].

Oral route
0.1 mg/d [7].
0.1 mg/d [7].

a) The recommended daily allowance of folate is 65 to 80 micrograms (mcg) for
children 1 year of age and younger, 150 mcg for children aged 1 to 3 years, 200
mcg for children aged 4 to 8 years, 300 mcg for children aged 9 to 13 years, and
400 mcg for children aged 14 to 18 years [24].

Subcutaneous route
0.1 mg/d [5].
0.1 mg/d [5].

Administration
A) Oral route
1) Store oral folic acid at controlled room temperature, 15 to 30 degrees C (59 to 86 degrees F)
(Prod Info Folvite(R), 1990).
B) Parenteral route
1) Store parenteral folic acid at controlled room temperature, 15 to 30 degrees C (59 to 86 degrees
F) (Prod Info Folvite(R), 1990).

C) Extemporaneous Formulation Oral route
1) A folic acid solution, may be prepared using 6 milliliters of folic acid injection 5
milligrams/milliliter (Folvite(R); Lederle) and a sufficient quantity of distilled water to bring the
volume to 30 milliliters. The final concentration will be 1 milligram/milliliter. This mixture should be
labeled "refrigerate" and "protect from light" and is stable for 3 months [181].

Comparative Efficacy
Leucovorin
Hyperhomocysteinemia
a) Oral folinic acid (the active form of folic acid) was not better than an equimolar
amount of folic acid for reducing hyperhomocysteinemia in hemodialysis patients. Forty
eight chronic, stable hemodialysis patients, who had been supplemented daily with folic
acid 1 milligram (mg), vitamin B6 10 mg, and vitamin B12 0.012 mg, were matched in
age, sex and screening plasma homocysteine level and randomly assigned in paired
blocks to receive either folic acid 15 mg/day or Lfolinic acid 20 mg/day (equimolar to 15
mg folic acid) for 12 weeks. All patients received vitamin B6 50 mg/day and vitamin B12
one mg/day. There were no significant differences between groups in the percentage
reductions (21% and 22%) of plasma homocysteine over the 12week study. Final
average plasma homocysteine levels were 15.9 and 16.9 micromoles/liter (above the
normal level, 12 micromoles/liter) for Lfolinic acid and folic acid, respectively. Ninety
percent of the patients exhibited mild hyperhomocysteinemia refractory to treatment with
either regimen [149].

Methotrexate adverse reaction
a) In comparison with placebo, both folic acid and folinic acid (leucovorin) reduced the
occurrence of elevated liver enzymes in patients being treated with methotrexate for
rheumatoid arthritis and reduced the rate of discontinuation of methotrexate treatment.
In a randomized, doubleblind study, 411 patients were given placebo, oral folic acid 1
milligram (mg) per day, or oral folinic acid 2.5 mg/week for 48 weeks. Methotrexate was
started at 7.5 mg orally once a week, with the possibility of increasing the dose at the
rate of 2.5 mg every 6 weeks, to a maximum of 25 mg/week, for insufficient response. If
the dose exceeded 15 mg/week, the folate dose was doubled. Discontinuation of
methotrexate treatment due to adverse events occurred in a significantly higher
percentage of patients in the placebo group (38%) than in the folic acid group (17%) or
the folinic acid group (12%). The difference between the folate groups was not
significant. The incidence of elevated serum alanine amino transferase (ALT) was
significantly greater in the placebo group than in the folate groups (p less than 0.0001).
There was no significant difference among groups for the occurrence of other adverse
reactions. During treatment, there was no difference among groups in disease activity.
Among patients who did not discontinue methotrexate, the final methotrexate dosage
was significantly lower (14.5 mg/week) in the placebo group than in the folic acid group
(18 mg/week; p less than 0.001) and the folinic acid group (16.4 mg/week; p=0.017).
The authors considered this negative effect of folates on efficacy to be minor and the
slightly higher methotrexate doses to be associated with no increases in toxicity, at least
in the short term. It is possible that the higher methotrexate doses could be associated
with greater toxicity in the long term [150].

Pyridoxine
Hyperhomocysteinemia
a) Folic acid reduced fasting homocysteine concentrations in patients with
hyperhomocysteinemia, whereas pyridoxine alone was without effect. Pyridoxine reduced
the increase in homocysteine after methionine loading, but was no more effective than
folic acid. In a nonrandomized study, patients with hyperhomocysteinemia in the fasting
state and/or after a methionine load (n=117) were treated daily with pyridoxine 200
milligrams (mg), folic acid 5 mg, a combination of folic acid 0.5 mg and pyridoxine 100
mg, or folic acid 0.5 mg alone for 8 weeks. Treatment assignment was not randomized
and followed the evolution of current clinical practice throughout the period of subject
recruitment. Some patients underwent more than one treatment regimen. Pyridoxine 200
mg was the only regimen that did not reduce fasting homocysteine. Effective treatments
did not differ from one another. All treatments were equally effective in reducing the rise
in homocysteine caused by a methionine load. Therefore, folic acid 0.5 mg was the
lowest effective therapy for reducing both fasting homocysteine concentrations and the
increase due to a methionine load [148].

Place In Therapy
A) Folic acid is indicated for the treatment of folic acid deficiency.
B) Folic acid is given to women intending to become pregnant and in the early months of pregnancy
to reduce the risk of neural tube defects and other birth defects (imperforate anus, cleft lip).
Last Modified: March 16, 2017
©2017 Truven Health Analytics LLC

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