Folic Acid

B03B - Vitamin B12 and folic acid ATC A11AA03 Small molecule approved 1982 Oral Parenteral Natural product

JFDA label: Mamera Caplet

Mechanism of Action

Folic acid is necessary for formation of a number of coenzymes in many metabolic systems, particularly for purine and pyrimidine synthesis; required for nucleoprotein synthesis and maintenance in erythropoiesis; stimulates WBC and platelet production in folate deficiency anemia. Folic acid enhances the metabolism of formic acid, the toxic metabolite of methanol, to nontoxic metabolites (off-label use).

Indications

Approved

Megaloblastic and macrocytic anemias due to folate deficiency

Off-label

Adjunctive cofactory therapy in methanol toxicity (alternative to leucovorin calcium)
Neural tube defects

Contraindications

Source: Lexicomp

Hypersensitivity to folic acid or any component of the formulation Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (1)

Not Known Flushing (slight)

Nervous system disorders (1)

Not Known Malaise (general)

Immune system disorders (1)

Not Known Hypersensitivity reaction

Skin and subcutaneous tissue disorders (3)

Not Known Erythema · pruritus · skin rash

Respiratory, thoracic and mediastinal disorders (1)

Not Known Bronchospasm

Dosing

Source: Lexicomp

Megaloblastic and macrocytic anemias due to folate deficiency: Manufacturer’s labeling: Oral, IM, IV, SubQ: Initial: 0.4 to 1 mg/day. Higher doses may be required in resistant cases. Maintenance dose: 0.4 mg/day Pregnant and lactating women: Maintenance dose: 0.8 mg/day Alternate recommendations (off-label dose): Oral: 1 to 5 mg once daily (Cook 2014); doses up to 15 mg once daily have also been recommended (Hoffbrand 2015). Prevention of neural tube defects (off-label use): Oral: Females of childbearing potential: 400 to 800 mcg/day (USPSTF 2017) Females at high risk, who have had a previous pregnancy with a neural tube defect, or with family history of neural tube defects: 4 mg/day (ACOG 2003)

(For additional information see "Folic acid: Pediatric drug information") Megaloblastic and macrocytic anemias due to folate deficiency: Oral, IM, IV, SubQ: Initial: 0.4 to 1 mg/day. Higher doses may be required in resistant cases. Maintenance dose: Infants: 0.1 mg/day Children Children ≥4 years, Adolescents, and Adults: Refer to adult dosing.

Refer to adult dosing. Vitamin B12 deficiency must be ruled out before initiating folate therapy due to frequency of combined nutritional deficiencies.

Warnings & Precautions

Source: Lexicomp

Anemia

Monotherapy: Not appropriate for monotherapy with pernicious, aplastic, or normocytic anemias when anemia is present with vitamin B12 deficiency.

Pernicious anemia

Doses >0.1 mg/day may obscure pernicious anemia with continuing irreversible nerve damage progression. Dosage form specific issues:

Aluminum

The parenteral product may contain aluminum; toxic aluminum concentrations may be seen with high doses, prolonged use, or renal dysfunction. Premature neonates are at higher risk due to immature renal function and aluminum intake from other parenteral sources. Parenteral aluminum exposure of >4 to 5 mcg/kg/day is associated with CNS and bone toxicity; tissue loading may occur at lower doses (Federal Register, 2002). See manufacturer’s labeling.

Benzyl alcohol and derivatives

Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling. Other warnings/precautions:

Resistance to treatment

May occur with depressed hematopoiesis, alcoholism, and deficiencies of other vitamins.

Pregnancy & Lactation

Pregnancy

FDA category A

Safe

400 mcg/day preconception to 12 weeks prevents most NTDs. 5 mg/day for high-risk women (previous NTD, anti-epileptics, diabetes, obesity)

Lactation

Folate is excreted in breast milk; concentrations are not affected by dietary intake unless the mother has a severe deficiency. Folate requirements increase in breast-feeding women (IOM 1998).

Chemistry & Properties

Formula	C19H19N7O6
Molecular weight	441.4 g/mol
IUPAC name	(2S)-2-[[4-[(2-amino-4-oxo-3H-pteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid
CAS	59-30-3
PubChem CID	135398658
InChIKey	`OVBPIULPVIDEAO-LBPRGKRZSA-N`
logP	-0.04 (XLogP -1.1)
Polar surface area	213.28 Å²
H-bond acceptors / donors	9 / 6
Drug-likeness (QED)	0.26
Lipinski violations	1

SMILES

Nc1nc(=O)c2nc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2[nH]1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	Yes

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP4 (Inhibitor)OAT1 (Inhibitor)OATP (Inhibitor)OATP1A2 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)OCT1 (Inhibitor)P-gp (Inhibitor)BCRP (Substrate)MRP (Substrate)MRP3 (Substrate)MRP4 (Substrate)OATP1B1 (Substrate)OATP1B3 (Substrate)OATP1C1 (Substrate)P-gp (Substrate)PCFT (Substrate)Transporter(unspecified) (Substrate)

Drug–drug interactions (32, DDInter)

Interacting drug	Severity	Management
Capecitabine	major
Fluorouracil	major
Carbamazepine	moderate
Cholestyramine	moderate
Colestipol	moderate
Eslicarbazepine	moderate
Ethosuximide	moderate
Ethotoin	moderate
Felbamate	moderate
Fosphenytoin	moderate
Lamotrigine	moderate
Mephenytoin	moderate
Methotrexate	moderate
Methsuximide	moderate
Methylphenobarbital	moderate
Oxcarbazepine	moderate
Pancrelipase	moderate
Phenobarbital	moderate
Phensuximide	moderate
Phenytoin	moderate
Primidone	moderate
Pyrimethamine	moderate
Rufinamide	moderate
Sulfadiazine	moderate
Sulfadoxine	moderate
Sulfamethizole	moderate
Sulfamethoxazole	moderate
Sulfisoxazole	moderate
Triamterene	moderate
Trimethoprim	moderate
Valproic acid	moderate
Sulfasalazine	minor

Registered Products (17)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
joriver Folic Acid	Tablet 5 mg	30 tab pack varies	JORDAN RIVER PHARMA.IND(JORIVER)/JORDAN	1.010
Filicine	Tablet 5 mg	30 tab pack varies	Trust Drug Store	1.310
Ironorm Capsules	Capsule 1.7 mg, 10 mg, 15 mg, 2 mg, 195 mg, 1.00 mg	25 cap pack varies	AL Razi Drug Store	2.060
Mamera Caplet	Tablet 1 mg, 30 mcg, 100 mg, 30 IU, 3000 IU, 200 IU, 3 mg, 3.4 mg, 20 mg, 20 mcg, 10 mg, 12 mcg, 200 mg, 25 mcg, 150 mcg, 25 mcg, 22.5 mg, 27 mg, 2 mg, 10 mg, 25 mg, 2.3 mg	30 tab	Jordan Sweden Medical & Sterilization Co.	2.420
Joswe Folic Acid	Tablet 5 mg	100 tab	Jordan Sweden Medical & Sterilization Co.	2.700
Fefol Spansule Cap.	Capsule 0.5 mg, 150 mg	30 cap pack varies	Meda AB	2.800
Stresstab With Zinc	Tablet 0.5 mg, 25 ng, 600 mg, 45 IU, 30 mg, 10 mg, 100 mg, 10 mg, 25 mcg, 23.9 mg, 0.9 mg, 25 mg	30 tab	Sukhtian Group	2.930
joriver Folic Acid	Tablet 5 mg	100 tab pack varies	JORDAN RIVER PHARMA.IND(JORIVER)/JORDAN	3.180
FOLIC ACID 5 TABS	Tablet (as hydrate)5 mg	100 F.C Tab	JAWEDA INT. DRUD STORE	4.000
Filicine	Tablet 5 mg	100 tab pack varies	Trust Drug Store	4.000
Pronatal	Tablet 0.6 mg, 2.6 mcg, 18 mg, 0.03 mg, 2 mg, 85 mg, 15 mg, 0.06 mg, 150 mg, 0.03 mg, 0.2 mg, 0.05 mg, 11 mg, 1.9 mg, 27 mg, 1 mg, 53 mg, 1.4 mg, 200 IU, 1.4 mg	30 tab	THE ARAB DRUG STORE P.S.C	5.570
Ironorm Capsules	Capsule 1.7 mg, 10 mg, 15 mg, 2 mg, 195 mg, 1.00 mg	100 cap pack varies	AL Razi Drug Store	7.690
Elevit Pronatal film-coated tablets	Film-Coated Tablet 0.80 mg, 4.00 mcg, 19.00 mg, 10.00 mg, 200 mcg, 100.00 mg, 1080 mcg, 12.5 mcg, 125.00 mg, 7.50 mg, 2.60 mg, 60.00 mg, 1.00 mg, 125 mg, 1.00 mg, 1.80 mg, 100.00 mg, 1.60 mg, 15.00 mg	30 tab	The Jordan Drugstore Co	8.330
Medivitan injection	Powder for Injection 1.05 mg, 1 mg, 5 mg	8 amp	Karmel Drug Store	11.770
joriver Folic Acid	Tablet 5 mg	1000 tab pack varies	JORDAN RIVER PHARMA.IND(JORIVER)/JORDAN	12.150
Fefol Spansule Cap.	Capsule 0.5 mg, 150 mg	250 cap pack varies	Meda AB	21.230
Filicine	Tablet 5 mg	1000 tab pack varies	Trust Drug Store	36.270