Pharmacology
Folic acid polyglutamates from food sources are enzymatically hydrolyzed in the gastrointestinal tract to monoglutamates prior to absorption, which occurs mainly in the proximal small intestine. In the presence of malabsorption syndrome, folic acid from oral supplements will still be absorbed, whereas absorption of folic acid from food sources may be impaired.
Following absorption of 1 mg or less, folic acid is converted in the liver and plasma to its metabolically active form tetrahydrofolic acid, which is then distributed into all body tissues. Normal serum folate concentrations range from 11 to 34 nmol/mL. The liver contains about 50% of total body folate stores. Larger doses of folic acid may escape metabolism by the liver and appear in the blood mainly as folic acid.
Following oral administration of single 0.1 to 0.2 mg doses of folic acid in healthy 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. After doses of about 2.5 to 5 mg, about 50% of a dose is excreted in urine and after a 15 mg dose, up to 90% may be recovered in urine. Small amounts of orally administered folic acid have been recovered from feces.
Indications
Folic acid is used in the treatment of megaloblastic and macrocytic anemias caused by folate deficiency. It is also used in the treatment of megaloblastic anemias of pregnancy, infancy and childhood, as well as megaloblastic anemias associated with primary liver disease, alcoholic cirrhosis, intestinal strictures, anastomoses or sprue. In large doses, folic acid is used in the treatment of tropical sprue.
There is strong evidence that prophylactic therapy with folic acid, prior to and during pregnancy, can reduce the risk of fetal neural tube defects. Health Canada recommends that all women of child bearing potential, whether planning pregnancy or not, should maintain an adequate daily intake of folic acid (see Dosage).
Folic acid is not effective in reversing the effects of folic acid reductase inhibitors such as methotrexate, for which leucovorin calcium (folinic acid) must be used. However, folic acid is used during long-term, low-dose methotrexate therapy to prevent methotrexate toxicity, particularly oral ulceration and gastrointestinal irritation, to treat or prevent folate deficiency and to prevent hyperhomocysteinemia.
Precautions
Folic acid therapy in folate deficient individuals may decrease serum levels of phenytoin.
Drugs that can cause folate deficiency include phenytoin, isoniazid, primidone, barbiturates, oral contraceptives, ethanol, sulfasalazine, cycloserine, glutethamide, methotrexate, pyrimethamine, trimethoprim and triamterene.
When cholestyramine and folic acid are administered together, there may be a reduction or delay in folic acid absorption. If concomitant therapy is required, folic acid should be administered at least 1 hour before or 4 to 6 hours after cholestyramine.
Folic acid is actively excreted in human breast milk. Adverse effects in breast-fed infants have not been documented with intake of normal daily requirements of folic acid during lactation.
Pregnant women are more prone to develop folate deficiency which can lead to complications and fetal abnormalities (see Pharmacology).
Contraindications
Folic acid is contraindicated in patients with hypersensitivity to folic acid products.
Warnings
See Precautions.
Adverse Effects
Folic acid is relatively nontoxic but has rarely caused allergic reactions including erythema, pruritus and/or urticaria. High doses (e.g., 15 mg/day) have rarely been associated with various gastrointestinal symptoms and CNS effects such as altered sleep patterns, difficulty concentrating, irritability, overactivity, excitement, mental depression, confusion and impaired judgement.
Overdose
For management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.
Dosage
To prevent deficiency, adequate dietary intake of folic acid is preferred over supplementation whenever possible. Food sources include asparagus, spinach, legumes (e.g., beans, lentils), avocados, cantaloupe, fortified cereal and grain products, and liver.
Treatment of Deficiency: Oral: The usual therapeutic dose of folic acid for adults and children is 0.25 to 1 mg daily; however, some patients may require higher doses. Within the first 48 hours of treatment, the bone marrow begins to become normoblastic. Reticulocytosis begins within 2 to 5 days. To maintain a normoblastic marrow, lower daily maintenance doses of folic acid are used: adults and children 4 years and over, 0.4 mg; children up to 4 years, 0.3 mg; infants, 0.1 mg. Higher maintenance doses may be required in certain patients such as alcoholics, patients with hemolytic anemia or chronic infections, or pregnant women taking certain anticonvulsants (e.g., valproic acid or carbamazepine).
Higher doses have been recommended for the treatment of tropical sprue: 3 to 15 mg daily.
Prophylaxis of Neural Tube Defects (NTD): Health Canada recommends that all women who could become pregnant should take a multivitamin containing 0.4 mg of folic acid every day starting at least 3 months before pregnancy and throughout the first 3 months of pregnancy.
Women with a history of pregnancy complicated by NTD are considered at high risk for recurrence and are advised to consider taking 4 mg folic acid daily when not using reliable birth control (or at least 2 to 4 weeks prior to conception), continuing until 10 to 12 weeks after last menstrual period.
Women with no previous history of NTD-affected pregnancy but who may be at increased risk due to 1st degree relative (child, sibling or parent) with NTD, or for medical reasons such as type I diabetes or therapy with valproic acid or carbamazepine, are advised to consider taking 1 to 5 mg folic acid daily while not using reliable birth control, continuing for 10 to 12 weeks after last menstrual period. Higher doses (4 to 5 mg daily) should not be taken as a multivitamin because of the risk of intake of harmful amounts of other components such as vitamins A and D.
Prevention of Methotrexate Toxicity (see Indications): 0.4 to 1 mg daily.
Parenteral: When the oral route is not feasible, an equivalent dose of folic acid may be given by iv, sc or deep im injection. However, most patients with malabsorption syndrome are still able to absorb oral folic acid supplements.
Products with strengths less than 1 mg are available without a prescription.
