Label: L-METHYL-B6-B12- levomefolate calcium, pyridoxal phosphate anhydrous, and methylcobalamin tablet, coated

  • NHRIC Code(s): 76439-362-50
  • Packager: Virtus Pharmaceuticals OpCo II
  • Category: MEDICAL FOOD
  • DEA Schedule: None
  • Marketing Status: MEDICAL FOOD

Drug Label Information

Updated February 12, 2016

If you are a consumer or patient please visit this version.

  • DESCRIPTION

    L-Methyl-B6-B12 is a medical food for the clinical dietary management of the metabolic imbalances associated with hyperhomocysteinemia that cannot be managed by diet modification alone. Dispense by prescription. Use under medical supervision.

    Each round coated purple colored tablet contains:
    Pyridoxal 5'-phosphate35 mg
    L-methylfolate Calcium3 mg
    Methylcobalamin2 mg

    Dietary Ingredients

    Dibasic Calcium Phosphate Dihydrate, Microcrystalline Cellulose 90, PYRIDOXAL-5'-PHOSPHATE, Microcrystalline Cellulose HD 90, Opadry II Purple 40L10045 (Polydextrose, Titanium Dioxide, Hypromellose 3cP, Hypromellose 6cP, Glycerol Triacetate, Hypromellose 50cP, FD&C Blue #2, FD&C Red #40 and Polyglycol 8000), Microcrystalline Cellulose 50, Opadry II Clear Y-19-7483 (Hypromellose 6cP, Maltodextrin, Hypromellose 3cP, Polyglycol 400 and Hypromellose 50cP), L-METHYLFOLATE CALCIUM, Magnesium Stearate, METHYLCOBALAMIN, and Carnauba Wax.

    Contains FD&C Blue #2 and FD&C Red #40.

  • Indications

    Hyperhomocysteinemia of any etiology.

  • Intended Use

    Medical foods are intended for the patient who has a limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foodstuffs or certain nutrients, or who has other special medically determined nutrient requirements, the dietary management of which cannot be achieved by the modification of the normal diet alone1.

    L-Methyl-B6-B12 is a specially formulated medical food for the dietary support of patients with hyperhomocysteinemia. It also is helpful in managing patients with high total homocysteine concentrations associated with malabsorption of vitamin B12 or suboptimal intake of B vitamins.

    L-Methyl-B6-B12 Tablets should always be used under medical supervision.

  • Background

    Folic acid itself does not occur in nature; it is synthetic and lacks coenzyme activity. To be beneficial in human metabolism, orally administered folic acid must be absorbed through the brush border of the intestine and transferred to the liver where it is reduced to tetrahydrofolate (THF) form within the cell. L-5-methyl-tetrahydrofolate (5MTHF) is the predominant form of dietary folate and the only species normally found in the systemic circulation. Although 5MTHF does not occur in natural foodstuffs, it has been specially synthesized and formulated and is commercially available as the calcium salt.

    5MTHF is at least as effective as folic acid in improving folate status as measured by blood concentration of folate and by functional indicators of folate status, such as plasma homocysteine. 5MTHF may have advantages over folic acid because it may reduce folate's potential for masking vitamin B12 deficiency; 5MTHF also may be associated with a reduced interaction with drugs that inhibit dihydrofolate reductase.2

    Homocysteine (HCy) is an intermediary in amino acid metabolism. It is not a building block of protein itself, but is an integral part of methionine metabolism.3 Hyperhomocysteinemia (HHCy) is frequently associated with folate deficiency, and 5MTHF works in concert with vitamin B12 as a methyl-group donor in the remethylation of homocysteine to methionine.4,5 In this way 5MTHF can act to reduce the amount of serum homocysteine.4

    HHCy has been associated with a myriad of medical conditions, including those concerning folate deficiency,5 endothelial dysfunction,6-10 oxidative stress of endothelial cells,11,12 vascular dysfunction,5,13 pre-eclampsia,14,15 coronary artery disease,6,8,13 microvascular angina,12 cardiovascular disease,7,16,17 wound healing,18 microvascular endothelium,19 and cerebral endothelium.20 Most of these reports include discussions of a nitric acid synthase (NOS) mechanism for the pathophysiology, in which HHCy impairs NOS function.5-8,10-20

    HCy impairs the nitric oxide synthase pathway,17 and antagonizes Nitric Oxide (NO) production,12,16,18 and disrupts NO signaling.20 HCy promotes oxidative stress in endothelial cells via an NOS-dependent mechanism.11 Oxidative stress lowers the bioavailability of NO, presumably by impairing NOS.12,16 NO has been considered to be a mediator of the repair of oxidative stress damage.18 In particular, the endothelial cells of the cardiovascular and central nervous system tissues rely on NO for wound repair, and endothelium and microvascular integrity12,18. When NOS activity is impaired by HCy, both a lack and an excess of NO can have important pathological implications.16

    In one study, 5-MTHF had beneficial effects on endothelial function and decreased vascular superoxide production by improving NOS "coupling."10

    5-MTHF uniquely counteracts the harmful effects of HHCy and provides nutritional support for patients who have medical conditions related to oxidative stress and impaired activity of inducible or endothelial NOS.

    Vitamin B6 plays an active role in the maintenance of normal HCy levels.21

    Vitamin B12 is a cofactor in the conversion of homocysteine to methionine (which in turn is required for the synthesis of S-adenosylmethionine, a universal methyl donor).22,23

    Active and ongoing medical supervision is required for the clinical management of patients with HHCy.

  • CONTRAINDICATIONS

    L-METHYL-B6∙B12 is contraindicated in patients with known hypersensitivity to any of the components contained in this product.

    Discontinue use if patient exhibits signs of hypersensitivity such as tachycardia, urticaria, or shortness of breath.

  • PRECAUTIONS

    Folic acid, when administered in daily doses above 0.1 mg, may obscure the detection of vitamin B12 deficiency, including pernicious anemia. L-METHYL-B6-B12 may be less likely than folic acid to mask vitamin B12 deficiency.2

    INTERACTIONS WITH DRUGS

    Major interactions occur when L-methylfolate is co-administered with 5-fluorouracil or any of its prodrugs (e.g., capecitabine, tegafur) and prescribed in combination with leucovorin. Co-administration with folate therapy may potentiate the pharmacologic effects of 5-fluorouracil (5-FU). The exact mechanism of interaction is unknown. Although enhancement of 5-FU cytotoxicity may be used to advantage in some cancer patients, increased toxicity should also be considered; a lower dosage of 5-FU or the prodrug may be required.24-31

    Patients should be monitored closely for potential toxicities of 5-FU such as neutropenia, thrombocytopenia, stomatitis, gastrointestinal hemorrhage, severe diarrhea, vomiting, cutaneous reactions, and neuropathy. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil concomitantly with folates. [Leucovorin is a mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid (THF)].28,30

    Additionally, L-METHYL-B6-B12 has been known to show moderate interactions with:

    Antiepileptic drugs

    Folic acid

    Co-administration with folate therapy may reduce the anticonvulsant effects of phenytoin, phenobarbital, primidone, and succinimides. The exact mechanism of interaction is unknown. Available data pertain primarily to phenytoin. Some investigators suggest that folic acid may serve as a cofactor in the metabolism of phenytoin, thus clearance is increased in the presence of folic acid. In one study, administration of folic acid for 14 days reduced the serum levels of phenytoin in normal subjects without significantly altering the bound fraction. Urinary excretion of phenytoin and its metabolite, meta-hydroxydiphenylhydantoin, was increased. In another study, three of four folate-deficient male patients receiving phenytoin monotherapy for epilepsy demonstrated a 7.5% to 47.6% decrease in total phenytoin plasma concentration following the addition of folic acid 1 mg/day for 180 or 300 days. Ratios of urinary metabolites to parent drug increased in these patients, suggesting an increase in phenytoin oxidative metabolism. The interaction is further supported by case reports describing subtherapeutic phenytoin levels and/or breakthrough seizures following the addition of folate therapy, including one case involving folinic acid (leucovorin). Limited data are available for phenobarbital and primidone. In one study, the addition of folic acid 15 mg/day increased the frequency and severity of seizures in 13 of 26 folate-deficient epileptic patients receiving two or more anticonvulsant drugs, including phenytoin, phenobarbital, and primidone. Nine of them required discontinuation of folic acid therapy. No data are available for other hydantoins.32-48

    Vitamin B6

    Some antiepileptic medications, including valproic acid, carbamazepine, and phenytoin, increase the catabolism rate of vitamin B6 vitamers, resulting in low plasma PLP concentrations and hyperhomocysteinemia.49,50 High homocysteine levels in antiepileptic drug users can increase the risk of epileptic seizures and vascular events like stroke, and reduce the ability to control seizures in patients with epilepsy. Additionally, patients usually take antiepileptic drugs for periods of years, which increases their risk of chronic vascular toxicity.

    Conversely, some studies have shown that supplementing with pyridoxine 1200 mg/day for 12 to 120 days can reduce serum concentrations of phenytoin and phenobarbital.51,52 It is not known whether lower doses of pyridoxine have this effect.

    Antibiotics

    A broad spectrum antibiotic used to treat tuberculosis in combination with pyridoxal phosphate. Cycloserine increases urinary excretion of pyridoxine.53 Urinary loss of pyridoxine may exacerbate seizures and neurotoxicity associated with cycloserine.

    Monoamines

    Selective serotonin reuptake inhibitors (SSRls), serotonin and norepinephrine reuptake inhibitors (SNRls) as well as dopamine may be affected by L-methylfolate. L-methylfolate regulates the synthesis of serotonin, dopamine, and norepinephrine.54

    Interference with homocysteine metabolism. Metformin, methotrexate, nicotinic acid, and fibric acid derivatives (used in certain dyslipidemias) can reduce plasma folate and B6 levels and raise plasma homocysteine levels.55,56

    Arsenic Trioxide

    Arsenic trioxide, an antineoplastic drug indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterized by the presence of a specific genetic defect. Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block.57 Theoretically, use of arsenic trioxide during intensive vitamin B12 therapy for the treatment of megaloblastic anemia may potentiate the risk of cardiac arrhythmias (e.g. ventricular tachycardia and torsade de pointes) because of the hypokalemia that may develop during the early phase of vitamin B12 therapy (due to increasing potassium requirements as normal erythropoiesis is established.57

    Chloramphenicol

    Chloramphenicol, a bacteriostatic antibiotic, may interfere with vitamin B12 activity. A few case reports suggested that chloramphenicol might interfere with the red blood cell response to vitamin B12 in some patients.58,59

    It is worth noting that chloramphenicol is no longer widely prescribed in the U.S. since it is required to carry the boxed warning "Bone marrow hypoplasia including aplastic anemia and death has been reported following topical application of chloramphenicol. Chloramphenicol should not be used when less potentially dangerous agents would be expected to provide effective treatment." Most NDAs approved for chloramphenicol have been discontinued.

    Proton Pump Inhibitors and H2 Receptor Antagonists

    Proton pump inhibitors, such as omeprazole and lansoprazole, are indicated for the treatment of gastroesophageal reflux disease and peptic ulcer disease. These drugs can interfere with the absorption of vitamin B12 release from food by slowing the release of gastric acid.60-62 It is unclear whether these drugs affect vitamin B12 status.63-66

    Histamine H2 receptor antagonists, such as cimetidine, famotidine, and ranitidine, are indicated for the treatment of peptic ulcers. These drugs can interfere with the absorption of vitamin B12 from food by slowing the release of hydrochloric acid into the stomach.60-62 There is no evidence that H2 receptor antagonists promote vitamin B12 deficiency, even after long-term use.66

    Paresthesia, somnolence, nausea and headaches have been reported with pyridoxal 5' phosphate. Chronic administration of 1 to 6 grams oral pyridoxine per day for 12-40 months can cause severe and progressive sensory neuropathy.69-73 Symptom severity appears to be dose dependent, and symptoms usually stop when vitamin B6 is discontinued as soon as the symptoms are noticed.

    Other side effects from excessive B6 intake include painful, disfiguring dermatological lesions; photosensitivity, and gastrointestinal symptoms (e.g. nausea and heartburn).22,70,74

    Orally administered vitamin B12 has no reported side effects.72,73

  • Dosage and Administration

    The recommended dose is one tablet twice daily or as directed. L-Methyl-B6-B12 tablets must be used under medical supervision.

  • How Supplied

    L-Methyl-B6-B12 is available as a round coated purple colored tablet, debossed with "V362" on one side and blank on the other. Commercial product is supplied in bottles of five hundred (500) tablets.

    Commercial Product (500 tablets) 76439-362-50

    Storage

    Store at controlled room temperature 15°C to 30°C (59°F to 86°F) Protect from light and moisture. Dispense in tight, light-resistant container.

  • Patents

    Some or all of the following patents may apply:

    U.S. Patent No. 4,940,658
    U.S. Patent No. 5,563,126
    U.S. Patent No. 5,795,873
    U.S. Patent No. 5,997,915
    U.S. Patent No. 6,011,040
    U.S. Patent No. 6,207,651
    U.S. Patent No. 6,254,904
    U.S. Patent No. 6,297,224
    U.S. Patent No. 6,528,496
    and other pending patent applications.

  • References

    1
    United States Food and Drug Administration Title 21 Code of Federal Regulations 101.90(j)(8).
    2
    Pietrzik K, Bailey L, Shane B. Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet (201O) Aug 49(8): 535-548.
    3
    Blom HJ, Smulders Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis (2011) 34: 75-81.
    4
    Akoglu B, Schrott M, Bolouri H, et al. The folic acid metabolite 1-5-methyltetrahydrofolate effectively reduces total serum homocysteine level in orthotopic liver transplant recipients: a double blind placebo-controlled study. Eur J of ClinNutrition (2008) 62:796-801.
    5
    Bhargava S, Tyagi SC. Nutriepigenetic regulation by folate-homocysteine-methionine axis: a review. Mol Cell Biochem (2014) Feb: 387 (1-2) 56-61.
    6
    He L, Zeng H, Feng J, et al. Am J Physiol Endocrinol Metab (2010) Dec 299(6): E1061-1065.
    7
    Yan TT, Li Q, Zhang XH, et al. Homocysteine ipaired endothelial function through compromised vascular endothelial growth factor/Akt/endothelial nitric oxide synthase signaling. Clin Exp. Pharmacol Physiol (201O) Nov 37(11): 1071-1077.
    8
    Yi X, Zhou Y, Jiang D, et al. Efficacy of folic acid supplementation on edothelial function and plasma homocysteine concentration in coronary artery disease: a meta-analysis of randomized controlled trials. Experimental and Therapeutic Medicine (2014) 7: 1100-1110.
    9
    Heydrick SJ, Weiss N, Thomas SR, et al. L-homocysteine and L-homocystine stereospecifically induce endothelial nitric oxide synthase-dependent lipid peroxidation in endothelial cells. Free Radic Biol Med (2004) Mar (1): 36(5): 632-640.
    10
    Laskowska M, Laskowska K, Terbosh M, et al. A comparison of maternal serum levels of endothelial nitric oxide synthase, asymmetric dimethylarginine, and homocysteine in normal and preeclamptic pregnancies. Med Sci Monit (2013) 19:430-437.
    11
    Pimentel AM, Pereira NR, Costa CA, et al. L-Arginine-nitric oxide pathway and oxidative stress in plasma and platelets of patients with pre-eclampsia. Hypertens Research (2013) Sep 36(9): 783-788.
    12
    Bilsborough W, Green OJ, Mamotte CO, et al. Endothelial nitric oxide synthase gene polymorphism, homocysteine, cholesterol and vascular endothelial function. Atherosclerosis (2003) Jul 169(1): 131-138.
    13
    Porro B, Eligini S, Veglia F, et al. Nitric Oxide Synthetic Pathway in Patients with Microvascular Angina and its Relations with Oxidative Stress. Oxidative Medicine and Cellular Longevity 2014 article id. 726539.9 pages.
    14
    Rochette L, Lorin J, Zeller M, et al. Nitric Oxide synthase inhibition and oxidative stress in cardiovascular diseases: possible therapeutic targets? Pharmacol Ther (2013) Dec 140(3): 239-257.
    15
    Stühlinger M and Stanger 0. Asymmetric dimethyl-L-arginine (ADMA): a possible link between homocyst(e)ine and endothelial dysfunction. Curr Drug Metab (2005) Feb; 6(1):3-14.
    16
    Boykin JV, Baylis C. Homocysteine - a stealth mediator of impaired wound healing: a preliminary study. Wounds (2006) 18(4): 101-116.
    17
    Mayo JN, Chen CH, Liao FF, et al. Homocysteine disrupts outgrowth of microvascular endothelium by an iNOS-dependent mechanism. Microcirculation (2014) Aug 21(6):541-550.
    18
    Mayo JN, Beard, RS, Price TO, et al. Nitrative stress in cerebral endothelium is mediated by mGluR5 in hyperhomocysteinemia. J Cerebral Blood Flow & Metabolism (2012) 32: 825-834.
    19
    Stühlinger M, Tsao P, Her J-H, et al. Homocysteine Impairs the Nitric Oxide Synthase Pathway. Role of Asymmetric Dimethylarginine. (2001) Circulation 104:2569-2575.
    20
    Antoniades C, Shirodaria C, Warrick N, et al. 5-methyltetrahydrofolate rapidly improves endothelial function and decreases superoxide production in human vessels. Effects on Vascular Tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. Circulation (2006) 114: 1193-1201.
    21
    Mackey A, Davis S, Gregory J. Vitamin B6. In: Shils M, Shike M, Ross A, Caballero B, Cousins R, eds. Modern nutrition in health and disease. 10th ed. Baltimore, md: Lippincott Williams & Wilkins; 2005.
    22
    Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press, 1998.
    23
    Clarke R. B-Vitamins And Prevention Of Dementia. Proc Nutr Soc 2008;67:75-81.
    24
    Clippe C, Freyer G, Milano G, Trillet-Lenoir V "Lethal toxicity of capecitabine due to abusive folic acid prescription?" Clin Oncol (R Coll Radiol) 15 (2003): 299-300.
    25
    EMEA. European Medicines Agency "EPARs. European Union Public Assessment Reports. Available from: URL: http://www.ema.europa.eu/ema/index .jsp?curl=pages/ includes/medicines/medicines_landingpage.jsp&mid."
    26
    "Product Information. Xeloda (capecitabine)." Roche Laboratories, Nutley, NJ.
    27
    Nobile MT, Rosso R, Sertoli MR, Rubagotti A, Vidili MG, Guglielmi A, Venturini M, Canobbio L, Fassio T, Gallo L, et al "Randomised comparison of weekly bolus 5-fluorouracil with or without leucovorin in metastatic colorectal carcinoma." Eur J Cancer 28a (1992):1823-7.
    28
    "Product Information. Levoleucovorin (levoleucovorin)." Spectrum Chemical, Gardena, CA.
    29
    Schalhorn A, Kuhl M "Clinical pharmacokinetics of fluorouracil and folinic acid." Semin Oncol 19 (1992): 82-92.
    30
    "Product Information. Wellcovorin (leucovorin)." Glaxo Wellcome, Research Triangle Park, NC.
    31
    Mainwaring P, Grygiel JJ "Interaction of 5-fluorouracil with folates." Aust N Z J Med 25 (1995): 60.
    32
    Katz M "Potential danger of self-medication with folic acid." N Engl J Med 289 (1973):1095.
    33
    Furlanut M, Benetello P, Avogaro A, Dainese R "Effects of folic acid on phenytoin kinetics in healthy subjects." Clin Pharmacol Ther 24 (1978): 294-7.
    34
    Berg MJ, Fincham RW, Ebert BE, Schottelius DD "Phenytoin pharmacokinetics: before and after folic acid administration." Epilepsia 33 (1992): 712-20.
    35
    Canadian Pharmacists Association "e-CPS. Available from: URL: http://www.pharmacists.ca/function/Subscriptions/ecps.cfm?link=eCPS_quikLink."
    36
    Berg MJ, Fischer LJ , Rivey MP, Vern BA, Lantz RK, Schottelius DD "Phenytoin and folic acid interaction: a preliminary report." Ther Drug Monit 5 (1983): 389-94.
    37
    Seligmann H, Potasman I, Weller B, Schwartz M, Prokocimer M "Phenytoin-folic acid interaction: A lesson to be learned." Clin Neuropharmacol 22 (1999): 268-72.
    38
    Lewis DP, Van Dyke DC, Willhite LA, Stumbo PJ, Berg MJ "Phenytoin-folic acid interaction. " Ann Pharmacother 29 (1995): 726-35.
    39
    MacCosbe PE, Toomey K "Interaction of phenytoin and folic acid." Clin Pharm 2 (1983): 362-9.
    40
    Berg MJ, Rivey MP, Vern BA, Fischer LJ, Schottelius DD "Phenytoin and folic acid: individualized drug-drug interaction."Ther Drug Monit 5 (1983): 395-9.
    41
    Ch'ien LT, Krumdieck CL, Scott CW Jr, Butterworth CE Jr "Harmful effect of megadoses of vitamins: electroencephalogram abnormalities and seizures induced by intravenous folate in drug-treated epileptics." Am J Clin Nutr 28 (1975): 51-8.
    42
    Robenberg IH "Drugs and folic acid absorption." Gastroenterology 63 (1972): 353-7.
    43
    Yuen GJ "Interaction of phenytoin and folic acid: an alternative explanation." Clin Pharm 3(1984): 116,119.
    44
    Carl GF, Smith ML "Phenytoin-folate interactions: differing effects of the sodium salt and the free acid of phenytoin." Epilepsia 33 (1992): 372-5.
    45
    Berg MJ, Stumbo PJ, Chenard CA, Fincham RW, Schneider PJ, Schottelius D "Folic acid improves phenytoin pharmacokinetics." J Am Diet Assoc 95 (1995): 352-6.
    46
    Steinweg DL, Bentley ML "Seizures following reduction in phenytoin level after orally administered folic acid." Neurology 64 (2005): 1982.
    47
    Ministerio de Sanidad y Consumo. Gobierno de España "AEMPS. Agencia Espanola de Medicamentos y Productos Sanitarios. Available from: URL: https://sinaem4.agemed. es/consaem/fichasTecnicas.do?metodo=detalleForm."
    48
    Veldhorst-Janssen NM, Boersma HH, de Krom MC, van Rijswijk RE "Oral tegafur/folinic acid chemotherapy decreases phenytoin efficacy." Br J Cancer 90 (2004): 745.
    49
    Clayton PT. B6-responsive disorders: a model of vitamin dependency. J Inherit Metab Dis 2006;29:317-26.
    50
    Apeland T, Froyland ES, Kristensen 0, Strandjord RE, Mansoor MA. Drug-induced pertubation of the aminothiol redox-status in patients with epilepsy: improvement by B-vitamins. Epilepsy Res 2008;82:1-6.
    51
    Bender DA. Non-nutritional uses of vitamin B6. Br J Nutr 1999;81: 7-20.
    52
    Hansson 0, Sillanpaa M. Letter: Pyridoxine and serum concentration of phenytoin and phenobarbitone. Lancet 1976;1:256.
    53
    Bailey RL, Gahche JJ, Lentino CV, Dwyer JT, Engel JS, Thomas PR, et al. Dietary supplement use in the United States, 2003-2006. J Nutr 2011;141:261-6.
    54
    Stahl, SM. "L-methylfolate: a vitamin for your monoamines." J Clin Psychiatry 69 (2008): 1352-3.
    55
    Desousa C, Keebler M, McNamara DB, Fonseca V. "Drugs affecting homocysteine metabolism: impact on cardiovascular risk.: Drugs 62 (2002): 605-16.
    56
    Wulffelé MG, Kooy A, Lehert P, Bets D, Ogtrerop JC, Borger vander Burg B, Donker AJ, Stehouwer CD. "Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized placebo-controlled trial." J Intern Med 254(2003): 455-63.
    57
    Drugs.com. Drug interactions between arsenic trioxide and Vitamin B12. Accessed 2 June 2014.
    58
    Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006;354:1567-77.
    59
    Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA.2008;299:2027-36.
    60
    Bradford GS and Taylor CT. Omeprazole and vitamin B12 deficiency. Ann Pharmacother 1999;33:641-3.
    61
    Kasper H. Vitamin absorption in the elderly. Int J Vitam Nutr Res 1999;69:169-72.
    62
    Howden CW. Vitamin B12 levels during prolonged treatment with proton pump inhibitors. J Clin Gastroenterol 2000;30:29-33.
    63
    Valuck RJ, Ruscin JM. A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults. J Clin Epidemiol 2004;57:422-8.
    64
    Ruscin JM, Page RL 2nd, Valuck RJ. Vitamin B(12) deficiency associated with histamine(2)-receptor antagonists and a proton-pump inhibitor. Ann Pharmacother 2002;36:812-6.
    65
    Den Elzen WP, Groeneveld Y, De Ruijter W, Souverijn JH, Le Cessie S, Assendelft WJ, et al. Long-term use of proton pump inhibitors (PPls) and vitamin B12 status in elderly individuals. Aliment Pharmacol Ther 2008;27:491-7.
    66
    Termanini B, Gibril F, Sutliff VE, Yu F, Venzon DJ, Jensen RT. Effect of long-term gastric acid suppressive therapy on serum vitamin B12 levels in patients with Zollinger-Ellison syndrome. Am J Med 1998;104:422-30.
    67
    Bauman WA, Shaw S, Jayatilleke K, Spungen AM, Herbert V. Increased intake of calcium reverses the B12 malabsorption induced by metformin. Diabetes Care 2000;23:1227-31 .
    68
    de Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, Bets D, Verburg J, Donker AJ, Stehouwer CD. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 201O May 20;340:c2181.
    69
    Simpson JL, Bailey LB, Pietrzik K, Shane B, Holzgreve W. Micronutrients and women of reproductive potential: required dietary intake and consequences of dietary deficiency or excess. Part 1–Folate, Vitamin B12, Vitamin B6. J Matern Fetal Neonatal Med 2010;23:1323-43.
    70
    Bendich A, Cohen M. Vitamin B6 safety issues. Ann NY Acad Sci 1990;585:321-30.
    71
    Gdynia HJ, Muller T, Sperfeld AD, Kuhnlein P, Otto M, Kassubek J, et al. Severe sensorimotor neuropathy after intake of highest dosages of vitamin B6. Neuromuscul Disord 2008;18:156-8.
    72
    Perry TA, Weerasuriya A, Mouton PR, Holloway HW, Greig NH. Pyridoxine-induced toxicity in rats: a stereological quantification of the sensory neuropathy. Exp Neurol 2004;190:133-44.
    73
    Bender DA. Non-nutritional uses of vitamin B6. Br J Nutr 1999;81:7-20.
    74
    McCormick D. Vitamin B6. In: Bowman B, Russell R, eds. Present Knowledge in Nutrition. 9th ed. Washington, DC: International Life Sciences Institute; 2006.
  • SPL UNCLASSIFIED SECTION

    Manufactured for:
    Virtus Pharmaceuticals OPCO II, LLC
    Nashville, TN 37217
    1-855-255-6076

    Rev. 10/15

  • PRINCIPAL DISPLAY PANEL - 500 Tablet Bottle Label

    VIRTUS
    PHARMACEUTICALS OPCO II

    76439-362-50

    L-METHYL-B6-B12

    TABLETS

    MEDICAL FOOD

    Rx
    500 Tablets

    PRINCIPAL DISPLAY PANEL- 500 Tablet Bottle Label
  • INGREDIENTS AND APPEARANCE
    L-METHYL-B6-B12 
    levomefolate calcium, pyridoxal phosphate anhydrous, and methylcobalamin tablet, coated
    Product Information
    Product TypeMEDICAL FOODItem Code (Source)NHRIC:76439-362
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    LEVOMEFOLATE CALCIUM (UNII: A9R10K3F2F) (LEVOMEFOLIC ACID - UNII:8S95DH25XC) LEVOMEFOLATE CALCIUM3 mg
    PYRIDOXAL PHOSPHATE ANHYDROUS (UNII: F06SGE49M6) (PYRIDOXAL PHOSPHATE ANHYDROUS - UNII:F06SGE49M6) PYRIDOXAL PHOSPHATE ANHYDROUS35 mg
    METHYLCOBALAMIN (UNII: BR1SN1JS2W) (METHYLCOBALAMIN - UNII:BR1SN1JS2W) METHYLCOBALAMIN2 mg
    Inactive Ingredients
    Ingredient NameStrength
    DIBASIC CALCIUM PHOSPHATE DIHYDRATE (UNII: O7TSZ97GEP)  
    POLYDEXTROSE (UNII: VH2XOU12IE)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    HYPROMELLOSE 2910 (3 MPA.S) (UNII: 0VUT3PMY82)  
    HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6)  
    TRIACETIN (UNII: XHX3C3X673)  
    HYPROMELLOSE 2910 (50 MPA.S) (UNII: 1IVH67816N)  
    FD&C BLUE NO. 2 (UNII: L06K8R7DQK)  
    FD&C RED NO. 40 (UNII: WZB9127XOA)  
    MALTODEXTRIN (UNII: 7CVR7L4A2D)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    CARNAUBA WAX (UNII: R12CBM0EIZ)  
    Product Characteristics
    ColorPURPLEScoreno score
    ShapeROUNDSize10mm
    FlavorImprint Code V362
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NHRIC:76439-362-50500 in 1 BOTTLE
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    MEDICAL FOOD05/15/2015
    Labeler - Virtus Pharmaceuticals OpCo II (969483143)