Folic Acid

INDICATIONS AND USAGE FOLIC ACID oral solution is indicated for the treatment of megaloblastic anemias due to folic acid deficiency in adult and pediatric patients. FOLIC ACID oral solution is a folate analog indicated for the treatment of megaloblastic anemias due to folic acid deficiency in adult and pediatric patients. ( 1 )

DOSAGE AND ADMINISTRATION Recommended starting dosage in adults and pediatric patients (regardless of age) is up to 1 mg orally daily. ( 2 ) Maintenance dosage ( 2 ) - Pediatric patients birth to 23 months: 0.1 mg orally daily - Pediatric patients 2 years to less than 4 years: up to 0.3 mg orally daily - Adults and pediatric patients 4 years and older: 0.4 mg orally daily - Pregnant and Lactating Women: 0.8 mg orally daily; but never less than 0.1 mg orally per day 2.1 Important Administration Information Instruct patients or caregivers to use an oral dosing syringe to correctly measure the prescribed amount of medication. Inform patients that oral dosing syringes may be obtained from their pharmacy. 2.2 Recommended Dosing Initial Dosing The recommended starting dosage of FOLIC ACID oral solution in pediatric and adult patients is up to 1 mg orally daily. FOLIC ACID oral solution can be taken with or without food. Rule out pernicious anemia prior to use of any doses greater than 0.4 mg (except during pregnancy and lactation). Maintenance Dosing When clinical symptoms have subsided and the blood picture has become normal, use a daily maintenance level as follows: - Pediatric patients aged birth to 23 months: 0.1 mg orally daily - Pediatric patients aged 2 years to less than 4 years: up to 0.3 mg orally daily - Pediatric patients aged 4 years and older and adult patients: 0.4 mg orally daily - Pregnant and Lactating Women: 0.8 mg orally daily; but never less than 0.1 mg orally per day Higher maintenance doses may be needed in the presence of alcoholism, hemolytic anemia, anticonvulsant therapy, or chronic infection. Monitor patients frequently for relapse and adjust dose accordingly.

WARNINGS AND PRECAUTIONS Folic acid in doses above 0.1 mg daily may obscure pernicious anemia in that hematologic remission can occur while neurologic manifestations remain progressive. This may result in severe nervous system damage before the correct diagnosis is made. ( 5.1 ) 5.1 Risk of Obscuring Diagnosis of Pernicious Anemia The use of single-agent FOLIC ACID oral solution (without the use of vitamin B12) is not recommended for the treatment of pernicious anemia and other megaloblastic anemias in which vitamin B 12 is deficient. Folic acid in doses above 0.1 mg daily may obscure pernicious anemia in that hematologic remission can occur while neurologic manifestations remain progressive. There is a potential danger in administering folic acid to patients with undiagnosed anemia, since folic acid may obscure the diagnosis of pernicious anemia by alleviating the hematologic manifestations of the disease while allowing the neurologic complications to progress. This may result in severe nervous system damage before the correct diagnosis is made. Adequate doses of vitamin B 12 may prevent, halt, or improve the neurologic changes caused by pernicious anemia.

CONTRAINDICATIONS FOLIC ACID oral solution is contraindicated in patients with a history of a hypersensitivity reaction to folic acid or any of the ingredients of QUIOFIC [see Description (11) ]. FOLIC ACID oral solution is contraindicated in patients with a history of a hypersensitivity reaction to folic acid or any of the ingredients of QUIOFIC. ( 4 )

DRUG INTERACTIONS Anticonvulsant action of phenytoin is antagonized by folic acid. ( 7 ) Multiple drug classes, including anticonvulsants, antibiotic/antimicrobial agents, folate antagonists, GI-binding agents, and oral contraceptives, may reduce folic acid absorption or folate levels. ( 7 ) 7.1 Impact of Folic Acid on Other Drugs Folic acid may interfere with gastrointestinal absorption of methotrexate. Folic acid therapy in folate-deficient individuals may decrease serum levels of phenytoin. Folic acid may also interfere with the absorption and effectiveness of antibiotic tetracycline. Folic acid supplements are usually avoided on the day of oral methotrexate administration. Generally, the time of administration of these drugs should be separated from folic acid. 7.2 Impact of Other Drugs on Folic Acid A wide range of medications can affect folic acid levels through multiple mechanisms, including impaired absorption, accelerated metabolism, and direct inhibition of folate pathways. Enzyme-inducing anticonvulsants such as phenytoin, primidone, carbamazepine, phenobarbital, and the broader anticonvulsant class increase hepatic folate metabolism, inhibit intestinal folate-processing enzymes, raise gastrointestinal pH, or displace folate from serum proteins, collectively leading to decreased folate availability. Valproate and sulfasalazine primarily reduce intestinal folate absorption or interfere with folate-dependent metabolic pathways, while isoniazid and cycloserine reduce folate utilization through metabolic disruption. Several antifolate agents, including trimethoprim, pyrimethamine, methotrexate, and triamterene, directly inhibit dihydrofolate reductase, decreasing the formation of active folate derivatives. Additional agents such as pentamidine, antacids, cholestyramine, colestipol, and H 2 blockers impair gastrointestinal folate uptake through pH elevation, transporter inhibition, or binding of dietary folate. Nitrous oxide indirectly decreases folate activity by inactivating vitamin B12 and downstream methylation pathways, while oral contraceptives increase folate turnover and urinary loss. While on FOLIC ACID oral solution treatment, if patients are concomitantly using any of the drugs or drug classes mentioned above, then monitor for reduced efficacy and adjust the dose of FOLIC ACID oral solution as needed.

ADVERSE REACTIONS Allergic sensitization has been reported following both oral and parenteral administration of folic acid. Folic acid is relatively nontoxic in man. Rare instances of allergic responses to folic acid preparations have been reported and have included erythema, skin rash, itching, general malaise, and respiratory difficulty due to bronchospasm. One patient experienced symptoms suggesting anaphylaxis following injection of the drug. Gastrointestinal side effects, including anorexia, nausea, abdominal distention, flatulence, and a bitter or bad taste, have been reported in patients receiving 15 mg folic acid daily for 1 month. Other side effects reported in patients receiving 15 mg daily include altered sleep patterns, difficulty in concentrating, irritability, overactivity, excitement, mental depression, confusion, and impaired judgment. Decreased vitamin B 12 serum levels may occur in patients receiving prolonged folic acid therapy. In an uncontrolled study, orally administered folic acid was reported to increase the incidence of seizures in some epileptic patients receiving phenobarbital, primidone, or diphenylhydantoin. Another investigator reported decreased diphenylhydantoin serum levels in folate-deficient patients receiving diphenylhydantoin who were treated with 5 mg or 15 mg of folic acid daily. CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088 OR LEADING PHARMA, LLC AT 1-844-740-7500.

CLINICAL PHARMACOLOGY Folic acid acts on megaloblastic bone marrow to produce a normoblastic marrow. In man, an exogenous source of folate is required for nucleoprotein synthesis and the maintenance of normal erythropoiesis. Folic acid is the precursor of tetrahydrofolic acid, which is involved as a cofactor for transformylation reactions in the biosynthesis of purines and thymidylates of nucleic acids. Impairment of thymidylate synthesis in patients with folic acid deficiency is thought to account for the defective deoxyribonucleic acid (DNA) synthesis that leads to megaloblast formation and megaloblastic and macrocytic anemias. Folic acid is absorbed rapidly from the small intestine, primarily from the proximal portion. Naturally occurring conjugated folates are reduced enzymatically to folic acid in the gastrointestinal tract prior to absorption. Folic acid appears in the plasma approximately 15 to 30 minutes after an oral dose; peak levels are generally reached within 1 hour. After intravenous administration, the drug is rapidly cleared from the plasma. Cerebrospinal fluid levels of folic acid are several times greater than serum levels of the drug. Folic acid is metabolized in the liver to 7,8-dihydrofolic acid and eventually to 5,6,7,8-tetrahydrofolic acid with the aid of reduced diphosphopyridine nucleotide (DPNH) and folate reductases. Tetrahydrofolic acid is linked in the N 5 or N 10 positions with formyl, hydroxymethyl, methyl, or formimino groups. N 5 -formyltetrahydrofolic acid is leucovorin. Tetrahydrofolic acid derivatives are distributed to all body tissues but are stored primarily in the liver. Normal serum levels of total folate have been reported to be 5 ng/mL to 15 ng/mL; normal cerebrospinal fluid levels are approximately 16 ng/mL to 21 ng/mL. Normal erythrocyte folate levels have been reported to range from 175 ng/mL to 316 ng/mL. In general, folate serum levels below 5 ng/mL indicate folate deficiency, and levels below 2 ng/mL usually result in megaloblastic anemia. After a single oral dose of 100 mcg of folic acid in a limited number of normal adults, only a trace amount of the drug appeared in the urine. An oral dose of 5 mg in 1 study and a dose of 40 mcg/kg of body weight in another study resulted in approximately 50% of the dose appearing in the urine. After a single oral dose of 15 mg, up to 90% of the dose was recovered in the urine. A majority of the metabolic products appeared in the urine after 6 hours; excretion was generally complete within 24 hours. Small amounts of orally administered folic acid have also been recovered in the feces. Folic acid is also excreted in the milk of lactating mothers.