Levomefolate, also known as L-methylfolate, is the biologically active form of folic acid, vitamin B9. Levomefolate is able to cross the blood brain barrier where it is necessary for the formation of important monoamines (serotonin, norepinephrine, and dopamine). Levomefolate is commonly found as an ingredient in multivitamin products as a source of folate, including in many prenatal vitamins. Levomefolate products are also marketed in medical foods and dietary supplements that are used as adjunctive therapy in the management of patients with mood disorders with suboptimal folate concentrations. A medical food is a prescription-only item, prescribed when a patient has special nutrient needs associated with a disease or health condition. The FDA does not currently have specific safety or efficacy evaluation standards for medical foods, which are not regulated as drugs.The FDA has assigned a 'GRAS' status to levomefolate; dietary supplements in the U.S. receive the GRAS designation when public consumption is Generally Recognized as Safe. Levomefolate may be useful in patients with depression who have not fully responded to antidepressant therapy or have documented low concentrations of levomefolate and in those patients with genetic mutations in methylene tetrahydrofolate reductase (MTHFR), the enzyme necessary for the conversion of folic acid to levomefolate. Thus, levomefolate may be used for folate supplementation in patients regardless of MTHFR C677T polymorphism genotype.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer levomefolate orally at the same time daily or as directed by the prescriber. May give with or without food.
Levomefolate is generally well tolerated. In two randomized controlled trials assessing the effectiveness of adjunct levomefolate for SSRI-resistant major depression, a total of 223 patients were randomized to receive 7.5 to 15 mg/day of levomefolate or placebo. Side effects reported in patients receiving levomefolate were comparable in type and frequency to those reported in patients receiving placebo. One patient receiving levomefolate 15 mg/day withdrew from the study due to the development of manic symptoms; causality was not specified.
Levomefolate (L-methylfolate) appears to be well-tolerated and the incidence of any reported reactions is generally similar to placebo. Allergic reactions have rarely been reported with the use of oral levomefolate as well as oral and parenteral folic acid, including anaphylactoid reactions, rash, and pruritus.
Levomefolate is contraindicated in patients with a known levomefolate hypersensitivity or hypersensitivity to any product component. For example, some levomefolate products (i.e., Denovo capsules) contain FD and C Yellow No. 5 (tartrazine) and should not be used in patients with a history of tartrazine dye hypersensitivity. Rare reports of hypersensitivity (allergic-type reactions) have been reported with the use of oral levomefolate as well as oral and parenteral folic acid.
Patients at risk for vitamin B12 deficiency should consult with their care team before taking levomefolate. Folic acid, when administered in daily doses above 0.1 mg, may obscure the detection of vitamin B12 deficiency (specifically, folate supplementation may reverse the hematological manifestations of B12 deficiency, including pernicious anemia, while not addressing the neurological manifestations). Levomefolate may be less likely than folic acid to mask vitamin B12 deficiency. Folate therapy alone is inadequate for the treatment of a vitamin B12 deficiency.
A major depressive episode may be the initial presentation of bipolar disorder. Use levomefolate with caution in patients with bipolar disorder. It is generally believed, although not established in controlled trials, that treating such an episode with an antidepressant alone may increase the likelihood of a precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Levomefolate is not an antidepressant, but may enhance the antidepressant effects of known antidepressants. Patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder since mood elevation in this population is possible. Patients should communicate immediately with their care team the emergence of agitation, irritability, unusual changes in behavior, or suicidality.
Levomefolate supplements are classified as medical foods and dietary supplements; the ingredients of medical food products are Generally Recognized as Safe (GRAS) by the FDA; formal pregnancy studies are not required by the FDA for these products. Levomefolate, also known as L-methylfolate, is commonly found in prenatal vitamins and certain dietary supplements in a much lower dose (approximately 1 mg/day PO) compared to the dose used for marketed levomefolate products as adjunct supplements for mental health. The safety and efficacy of levomefolate use in pregnant women at higher doses (7.5 to 15 mg per day) in products marketed for mental health have not been established. Levomefolate extended-release tablets are contraindicated for use in pregnancy per the product label. Pregnant patients should consult with their care team prior to use of the levomefolate glucosamine extended-release tablets, which are marketed as a medical food for dietary support of patients with a distinctive nutritional requirement associated with depression. Levomefolate is the biologically active form of folate found in the circulation. Folate is important in prenatal care because deficiencies of dietary folic acid can lead to anemia or peripheral neuropathy in the mother and congenital abnormalities in the fetus. Dietary supplementation with folic acid around the time of conception has been known to reduce the risk of neural tube defects. Folic acid is also thought to reduce the risk of preterm birth and congenital heart disease.
Levomefolate supplements are classified as medical foods and dietary supplements; formal lactation information is not available but in general levomefolate is compatible with breast-feeding. The ingredients of medical food products are Generally Recognized as Safe (GRAS) by the FDA. Levomefolate, also known as L-methylfolate, is commonly found in prenatal vitamins and most dietary supplements in a much lower dose (approximately 400 mcg to 1 mg per day PO) compared to products marketed for adjunctive support of mental health (7.5 to 15 mg per day) as medical foods. Patients who are breast-feeding should consult with their care team prior to use of the levomefolate glucosamine extended-release tablets, which are marketed as a medical food for dietary support of patients with a distinctive nutritional requirement associated with depression. Prenatal vitamins are often continued postpartum in women for added nutritional support during breast-feeding.
For the adjunctive management of depression:
-as an adjunct to antidepressant therapy in patients with suboptimal levomefolate concentrations:
NOTE: Levomefolate may be used regardless of MTHFR C677T polymorphism genotype.
Oral dosage (immediate-release capsules and tablets):
Adults: 7.5 to 15 mg PO once daily. Levomefolate (L-methylfolate) is indicated as adjunct support for patients with major depressive disorder who are on an antidepressant and have suboptimal levomefolate concentrations in the cerebrospinal fluid, plasma, and/or red blood cells. In a double-blind, placebo-controlled trial of patients with depression and low folate levels, patients (n = 24) were randomized to receive placebo or methylfolate 15 mg PO daily as an adjunct to their antidepressant therapy (either tricyclic antidepressant or monoamine oxidase inhibitor) for 6 months. Depression symptoms were evaluated using the Hamilton Depression Rating Scale and a standardized clinical rating scale. Patients who received methylfolate in combination with an antidepressant had significant improvement in depressive symptoms compared to those taking placebo (p less than 0.01 at 3 months; p less than 0.001 at 6 months). L-methylfolate was well-tolerated with no serious adverse events reported.
Oral dosage (extended-release tablets):
Adults: Take 25,500 mcg DFE (previously stated as 15 mg) PO once daily. Levomefolate (L-methylfolate) is indicated as adjunct support for patients with major depressive disorder who are on an antidepressant and have suboptimal levomefolate concentrations in the cerebrospinal fluid, plasma, and/or red blood cells.
For adjunctive use in patients with schizophrenia stable on an antipsychotic and with suboptimal levomefolate concentrations:
NOTE: Levomefolate may be used regardless of MTHFR C677T polymorphism genotype.
Oral dosage (immediate-release capsules and tablets):
Adults: 7.5 to 15 mg PO once daily. Levomefolate (L-methylfolate) is indicated for patients who have suboptimal levomefolate levels in the cerebrospinal fluid, plasma, and/or red blood cells and have schizophrenia who present with negative symptoms and/or cognitive impairment, with particular emphasis as adjunctive support for individuals who have stabilized on antipsychotics. In a double-blind, placebo-controlled trial of patients with schizophrenia and low folate levels, patients (n = 17) were randomized to receive placebo or methylfolate 15 mg PO daily as an adjunct to their antipsychotic therapy for 6 months. Symptoms of schizophrenia were evaluated using a validated clinical rating scale. Patients who received methylfolate in combination with an antipsychotic had significant improvement in symptoms compared to those who received placebo (p less than 0.01 at 3 months; p less than 0.001 at 6 months). L-methylfolate was well-tolerated with no serious adverse events reported.
For nutritional supplementation to meet requirements for folic acid intake:
Oral dosage:
Adults: Common adult dose range for dietary supplementation is 400 to 1,000 mcg PO once daily. 400 mcg of (6S)-5-methyltetrahydrofolate (5-MTHF) glucosamine (also known as levomefolate glucosamine) provides 680 mcg DFEs (dietary folate equivalents); 1,000 mcg supplies 1,700 mcg DFEs. Follow the directions on the specific dietary supplement product label.
Maximum Dosage Limits:
-Adults
15 mg/day PO immediate-release capsules and tablets; 25,500 mcg DFE/day PO extended release tablets.
-Geriatric
15 mg/day PO immediate-release capsules and tablets; 25,500 mcg DFE/day PO extended-release tablets.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustment are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustment are needed.
*non-FDA-approved indication
Acetaminophen; Ibuprofen: (Minor) L-methylfolate should be used cautiously in patients taking high doses of ibuprofen. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with high doses of ibuprofen. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Alogliptin; Metformin: (Minor) Levomefolate and metformin should be used together cautiously. Plasma concentrations of levomefolate may be reduced during treatment of type 2 diabetes with metformin. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Canagliflozin; Metformin: (Minor) Levomefolate and metformin should be used together cautiously. Plasma concentrations of levomefolate may be reduced during treatment of type 2 diabetes with metformin. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Capecitabine: (Moderate) Monitor for an increase in capecitabine-related adverse reactions if coadministration with L-methylfolate is necessary. Capecitabine is an orally administered prodrug of fluorouracil; leucovorin enhances the binding of fluorouracil to thymidylate synthase, increasing exposure to fluorouracil. L-methylfolate is the biologically active form of folic acid, which is converted to folinic acid in vivo; leucovorin is the calcium salt of folinic acid. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil.
Carbamazepine: (Moderate) High doses of folate may cause decreased serum concentrations of carbamazepine resulting in a decrease in effectiveness and, possibly, an increase in the frequency of seizures in susceptible patients. In addition, L-methylfolate plasma levels may be decreased when administered with carbamazepine. Although no decrease in effectiveness of anticonvulsants has been reported with the concurrent use of L-methylfolate, caution still should be exercised with the coadministration of these agents and patients should be monitored closely for seizure activity.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Minor) L-methylfolate should be used cautiously in patients taking high doses of ibuprofen. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with high doses of ibuprofen. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Cholestyramine: (Major) L-methylfolate and cholestyramine should be used together cautiously. Cholestyramine administration may decrease L-methylfolate plasma concentrations. Patients taking both drugs should take L-methylfolate 1 hour before or 4 to 6 hours after a dose of cholestyramine.
Colestipol: (Major) L-methylfolate and colestipol should be used together cautiously. Colestipol administration may decrease L-methylfolate plasma concentrations. Patients taking both agents should take L-methylfolate 1 hour before or 4 to 6 hours after a dose of colestipol.
Dapagliflozin; Metformin: (Minor) Levomefolate and metformin should be used together cautiously. Plasma concentrations of levomefolate may be reduced during treatment of type 2 diabetes with metformin. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Diphenhydramine; Ibuprofen: (Minor) L-methylfolate should be used cautiously in patients taking high doses of ibuprofen. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with high doses of ibuprofen. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Diphenhydramine; Naproxen: (Minor) L-methylfolate should be used cautiously in patients taking high doses of naproxen. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with high doses of naproxen. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Empagliflozin; Linagliptin; Metformin: (Minor) Levomefolate and metformin should be used together cautiously. Plasma concentrations of levomefolate may be reduced during treatment of type 2 diabetes with metformin. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Empagliflozin; Metformin: (Minor) Levomefolate and metformin should be used together cautiously. Plasma concentrations of levomefolate may be reduced during treatment of type 2 diabetes with metformin. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Ertugliflozin; Metformin: (Minor) Levomefolate and metformin should be used together cautiously. Plasma concentrations of levomefolate may be reduced during treatment of type 2 diabetes with metformin. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Floxuridine: (Moderate) L-methylfolate is the biologically active form of folic acid; leucovorin is a reduced form of folic acid. Coadministration of leucovorin with 5-FU may potentiate the adverse effects associated with 5-FU. Since floxuridine is metabolized to 5-FU, a similar interaction may occur with concomitant administration of floxuridine and L-methylfolate.
Fluorouracil, 5-FU: (Moderate) L-methylfolate is the biologically active form of folic acid; leucovorin is a reduced form of folic acid. Coadministration of leucovorin with Fluorouracil, 5-FU may potentiate the adverse effects associated with 5-FU. Although no interaction between L-methylfolate and fluorouracil, 5-FU has been reported, caution still should be exercised with the coadministration of these agents.
Fluoxetine: (Minor) Levomefolate and fluoxetine should be used together cautiously. Fluoxetine is a noncompetitive inhibitor of levomefolate active transport in the intestines. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Fosphenytoin: (Moderate) Numerous studies indicate that folate status is impaired with the chronic use of diphenylhydantoin (phenytoin or fosphenytoin). Prolonged administration of phenytoin reportedly has resulted in a folate deficiency. In addition, folic acid replacement has resulted in an increase in metabolism of phenytoin and a decrease in phenytoin concentration in some patients, apparently through increased metabolism and/or redistribution of phenytoin in the brain and CSF. Although no decrease in effectiveness of anticonvulsants has been reported with the concurrent use of L-methylfolate, caution still should be exercised with the coadministration of these agents, and patients should be monitored closely for seizure activity.
Glipizide; Metformin: (Minor) Levomefolate and metformin should be used together cautiously. Plasma concentrations of levomefolate may be reduced during treatment of type 2 diabetes with metformin. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Glyburide; Metformin: (Minor) Levomefolate and metformin should be used together cautiously. Plasma concentrations of levomefolate may be reduced during treatment of type 2 diabetes with metformin. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Hydrocodone; Ibuprofen: (Minor) L-methylfolate should be used cautiously in patients taking high doses of ibuprofen. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with high doses of ibuprofen. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Ibuprofen: (Minor) L-methylfolate should be used cautiously in patients taking high doses of ibuprofen. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with high doses of ibuprofen. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Ibuprofen; Famotidine: (Minor) L-methylfolate should be used cautiously in patients taking high doses of ibuprofen. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with high doses of ibuprofen. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Ibuprofen; Oxycodone: (Minor) L-methylfolate should be used cautiously in patients taking high doses of ibuprofen. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with high doses of ibuprofen. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Ibuprofen; Pseudoephedrine: (Minor) L-methylfolate should be used cautiously in patients taking high doses of ibuprofen. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with high doses of ibuprofen. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Indomethacin: (Minor) L-methylfolate should be used cautiously in patients taking high doses of indomethacin. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with high doses of indomethacin. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Isotretinoin: (Minor) L-methylfolate and isotretinoin should be used together cautiously. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with isotretinoin. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Lamotrigine: (Minor) L-methylfolate concentrations may be reduced when administered concomitantly with lamotrigine. Patients should be monitored closely for decreased efficacy of L-methylfolate if these agents are used together.
Linagliptin; Metformin: (Minor) Levomefolate and metformin should be used together cautiously. Plasma concentrations of levomefolate may be reduced during treatment of type 2 diabetes with metformin. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Metformin: (Minor) Levomefolate and metformin should be used together cautiously. Plasma concentrations of levomefolate may be reduced during treatment of type 2 diabetes with metformin. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Metformin; Repaglinide: (Minor) Levomefolate and metformin should be used together cautiously. Plasma concentrations of levomefolate may be reduced during treatment of type 2 diabetes with metformin. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Metformin; Saxagliptin: (Minor) Levomefolate and metformin should be used together cautiously. Plasma concentrations of levomefolate may be reduced during treatment of type 2 diabetes with metformin. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Metformin; Sitagliptin: (Minor) Levomefolate and metformin should be used together cautiously. Plasma concentrations of levomefolate may be reduced during treatment of type 2 diabetes with metformin. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Methotrexate: (Minor) L-methylfolate should be used cautiously in patients taking methotrexate. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with methotrexate. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Methylprednisolone: (Minor) L-methylfolate and methylprednisolone should be used together cautiously. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with methylprednisolone. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Naproxen: (Minor) L-methylfolate should be used cautiously in patients taking high doses of naproxen. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with high doses of naproxen. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Naproxen; Esomeprazole: (Minor) L-methylfolate should be used cautiously in patients taking high doses of naproxen. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with high doses of naproxen. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Naproxen; Pseudoephedrine: (Minor) L-methylfolate should be used cautiously in patients taking high doses of naproxen. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with high doses of naproxen. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Nitrofurantoin: (Moderate) L-methylfolate and nitrofurantoin should be used together cautiously. Nitrofurantoin is a folate antagonist. Plasma concentrations of both medications may be reduced when used concomitantly.
Olanzapine; Fluoxetine: (Minor) Levomefolate and fluoxetine should be used together cautiously. Fluoxetine is a noncompetitive inhibitor of levomefolate active transport in the intestines. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Pentamidine: (Minor) L-methylfolate and pentamidine should be used together cautiously. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with pentamidine. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Phenobarbital: (Moderate) Numerous studies indicate that folate status is impaired with the chronic use of phenobarbital, presumably via inhibition of the intestinal absorption of folic acid. The studies available suffer from poor methodologic control and definitive conclusions cannot be drawn relative to adverse effects of phenobarbital on folate status. In addition, high doses of folate may result in decreased serum concentrations of phenobarbital resulting in a decrease in effectiveness and, possibly, an increase in the frequency of seizures in susceptible patients. Although no decrease in effectiveness of anticonvulsants has been reported with the concurrent use of L-methylfolate, caution still should be exercised with the coadministration of these agents and patients should be monitored closely for seizure activity.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Numerous studies indicate that folate status is impaired with the chronic use of phenobarbital, presumably via inhibition of the intestinal absorption of folic acid. The studies available suffer from poor methodologic control and definitive conclusions cannot be drawn relative to adverse effects of phenobarbital on folate status. In addition, high doses of folate may result in decreased serum concentrations of phenobarbital resulting in a decrease in effectiveness and, possibly, an increase in the frequency of seizures in susceptible patients. Although no decrease in effectiveness of anticonvulsants has been reported with the concurrent use of L-methylfolate, caution still should be exercised with the coadministration of these agents and patients should be monitored closely for seizure activity.
Phenytoin: (Moderate) Numerous studies indicate that folate status is impaired with the chronic use of diphenylhydantoin (phenytoin or fosphenytoin). Prolonged administration of phenytoin reportedly has resulted in a folate deficiency. In addition, folic acid replacement has resulted in an increase in metabolism of phenytoin and a decrease in phenytoin concentration in some patients, apparently through increased metabolism and/or redistribution of phenytoin in the brain and CSF. Although no decrease in effectiveness of anticonvulsants has been reported with the concurrent use of L-methylfolate, caution still should be exercised with the coadministration of these agents, and patients should be monitored closely for seizure activity.
Pioglitazone; Metformin: (Minor) Levomefolate and metformin should be used together cautiously. Plasma concentrations of levomefolate may be reduced during treatment of type 2 diabetes with metformin. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Primidone: (Moderate) High doses of folate may cause decreased serum concentrations of primidone resulting in a decrease in effectiveness and, possibly, an increase in the frequency of seizures in susceptible patients. In addition, L-methylfolate plasma levels may be decreased when administered with primidone. Although no decrease in effectiveness of anticonvulsants has been reported with the concurrent use of L-methylfolate, caution still should be exercised with the coadministration of these agents and patients should be monitored closely for seizure activity.
Pyrimethamine: (Moderate) L-methylfolate and pyrimethamine should be used together cautiously. Pyrimethamine is a folate antagonist. Plasma concentrations of both medications may be reduced when used concomitantly.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Minor) L-methylfolate and trimethoprim should be used together cautiously. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with trimethoprim. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Sulfasalazine: (Minor) L-methylfolate should be used cautiously in patients taking sulfasalazine. Sulfasalazine exhibits antifolate activity and can inhibit the absorption and lower the plasma concentrations of L-methylfolate. Patients receiving sulfasalazine should be monitored for decreased efficacy of L-methylfolate therapy.
Sulindac: (Minor) L-methylfolate should be used cautiously in patients taking high doses of sulindac. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with high doses of sulindac. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Sumatriptan; Naproxen: (Minor) L-methylfolate should be used cautiously in patients taking high doses of naproxen. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with high doses of naproxen. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Triamterene: (Minor) L-methylfolate and triamterene should be used together cautiously. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with triamterene. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Triamterene; Hydrochlorothiazide, HCTZ: (Minor) L-methylfolate and triamterene should be used together cautiously. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with triamterene. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Trimethoprim: (Minor) L-methylfolate and trimethoprim should be used together cautiously. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with trimethoprim. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Valproic Acid, Divalproex Sodium: (Moderate) High doses of folate may cause decreased serum concentrations of valproic acid, divalproex sodium resulting in a decrease in effectiveness and, possibly, an increase in the frequency of seizures in susceptible patients. In addition, L-methylfolate plasma levels may be decreased when administered with valproic acid. Although no decrease in effectiveness of anticonvulsants has been reported with the concurrent use of L-methylfolate, caution still should be exercised with the coadministration of these agents and patients should be monitored closely for seizure activity.
Warfarin: (Moderate) L-methylfolate and warfarin should be used together cautiously. Significant impairment of folate status may occur after 6 months of therapy with warfarin. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Folate is the general term that refers to a variety of chemical forms of folic acid. Levomefolate, also known as 6(S)-5-methyltetrahydrofolate and L-methylfolate, is the biologically active form of folate found in the circulation. Folic acid is the synthetic form of folate found in artificially enriched foods, as well as in prescription and over-the-counter vitamins. Dihydrofolate is the dietary form of folate found naturally in foods. Both folic acid and dihydrofolate must undergo enzymatic reduction by methylenetetrahydrofolate reductase (MTHFR) to levomefolate; levomefolate is then transported across cell membranes by receptor-mediated endocytosis. Levomefolate readily crosses the blood brain barrier where it modulates the formation of the monoamines serotonin, norepinephrine, and dopamine. Having defective or less functional forms of any of the enzymes necessary for the conversion of dietary folate to levomefolate (e.g., C677T variant of MTHFR) could result in inadequate concentrations of levomefolate in the central nervous system, which, theoretically, could affect the synthesis of monoamine neurotransmitters. Depression has been associated with an imbalance of these monoamines, and, furthermore, low folate concentrations have been reported in up to 56% of patients with depression. Levomefolate supplementation may increase monoamine synthesis and augment antidepressant therapy in patients with depression.
Levomefolate also is involved in the formation of methionine from homocysteine. Adequate folic acid intake can normalize high homocysteine levels by increasing remethylation of homocysteine to methionine. Elevated homocysteine concentrations in the CNS is associated with depression, dementia, and the negative symptoms of schizophrenia. In addition, hyperhomocysteinemia is recognized as an independent risk factor for arthrosclerosis of the coronary, cerebral, and peripheral vasculature and may also be important in the pathogenesis of inflammatory bowel disease, diabetic retinopathy, and rheumatic diseases.
Levomefolate is administered orally. Levomefolate is 56% bound to plasma proteins and is distributed to and stored in red blood cells. Levomefolate is a water soluble molecule that is primarily excreted by the kidneys. After the administration of levomefolate 5 mg PO daily for 7 days, the mean elimination half-life was found to be approximately 3 hours.
-Route-Specific Pharmacokinetics
Oral Route
In a study of patients with coronary artery disease (n = 21), peak plasma concentrations were reached 1-3 hours after oral administration. Peak plasma concentrations of levomefolate were found to be more than 7 times higher than folic acid (129 ng/ml vs. 14.1 ng/ml) after oral or parenteral administration.