Label: L-METHYL-MC-NAC- levomefolate calcium, methylcobalamin, and acetylcysteine tablet, coated

  • NDC Code(s): 76439-361-90
  • Packager: Virtus Pharmaceuticals
  • Category: MEDICAL FOOD
  • DEA Schedule: None
  • Marketing Status: MEDICAL FOOD

Drug Label Information

Updated September 17, 2015

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  • DESCRIPTION

    L-Methyl-MC-NAC Tablets is an orally administered prescription medical food for the dietary management of certain metabolic processes identified with early memory loss.

    Each oval coated blue colored caplet contains:

    Dietary Ingredients:
    L-methylfolate Calcium 6 mg
    Methylcobalamin 2 mg
    N-Acetylcysteine 600 mg

    Ingredients

    N-acetylcysteine Microcrystalline Cellulose, Opadry II Blue 07F90856 (Hypromellose, Talc, Titanium Dioxide, Polyethylene Glycol, FD&C Blue #2-Aluminum Lake, Saccharin Sodium), Magnesium Stearate (Vegetable Source), L-methylfolate Calcium, Methylcobalamin, and Carnauba Wax.

    L-Methyl-MC-NAC Tablets do not contain sugar, lactose, yeast or gluten.

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  • PHARMACOLOGY

    L-methylfolate or 6(S)-5-methyltetrahydrofolate [6(S)-5-MTHF], is the primary biologically active isomer of folate 1 and the form of folate in circulation 2. It is also the form which is transported across membranes into peripheral tissues 3, particularly across the blood brain barrier 4. In the cell, 6(S)-5-MTHF is used in the methylation of homocysteine to form methionine and tetrahydrofolate (THF) 1. THF is the immediate acceptor of one carbon units for the synthesis of thymidine-DNA, purines (RNA and DNA) and methionine 5. Folic acid, the synthetic form of folate, must undergo enzymatic reduction by methylenetetrahydrofolate reductase (MTHFR) to become biologically active 6. Certain genetic mutations of MTHFR result in a cell's inability to convert folic acid to 6(S)-5-MTHF 7.

    Methylcobalamin (Methyl-B12) is one of two forms of biologically active vitamin B12. Methyl-B12 is the principal form of circulating vitamin B12, hence the form which is transported into peripheral tissue. Methyl-B12 is absorbed by a specific intestinal mechanism which uses intrinsic factor and by a diffusion process in which approximately 1% of the ingested dose is absorbed. Cyanocobalamin and hydroxycobalamin are forms of the vitamin that require conversion to Methyl-B12 via the intermediate glutathionyl- B12.

    N-acetylcysteine (NAC) is a precursor to glutathione (GSH) one of the body's most potent natural antioxidants. NAC is converted to GSH intracellularly. The presence of appropriate amounts of intracellular GSH helps to maintain the ability of the neurovascular tissue to metabolize vitamin B12 and to reduce or eliminate oxidative stress in these tissues. NAC significantly lowers plasma homocysteine concentrations9,10, and increases total antioxidant capacity (TAC)11, thus correcting the characteristic pattern of changes in cognitively impaired patients with hyperhomocysteinemia 12,13,14.

    Pharmacokinetics 8,15

    Absorption and Elimination

    L-methylfolate is a water soluble molecule which is primarily excreted via the kidneys 15. In a study of subjects with coronary artery disease (n=21), peak plasma levels were reached in 1-3 hours following ORAL/PARENTERAL administration 8. Peak concentrations of L-methylfolate were found to be more than seven times higher than folic acid (129 ng ml-1 vs. 14.1 ng ml-1) following ORAL/PARENTERAL administration. The mean elimination half-life is approximately 3 hours after 5mg of oral L-methylfolate, administered daily for 7 days. The mean values for Cmax, Tmax, and AUC0-12 were 129 ng ml-1, 1.3 hr., and 383 respectively.

    Distribution

    Red blood cells (RBCs) appear to be the storage depot for folate, as RBC levels remain elevated for periods in excess of 40 days following discontinuation of supplementation 15. Plasma protein binding studies showed that L-methylfolate is 56% bound to plasma proteins8.

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  • INDICATIONS AND USAGE

    L-Methyl-MC-NAC Tablets is indicated for the distinct nutritional requirements of individuals under a physician's treatment for early memory loss 25 with particular emphasis for those individuals diagnosed with or at risk for neurovascular oxidative stress 14,16,18 and/or hyperhomocysteinemia 18; mild to moderate cognitive impairment with or without vitamin B12 deficiency 9,13,19, vascular dementia 12,13,21 or Alzheimer's disease 12,13,16,21.

    L-Methyl-MC-NAC Tablets should always be used under medical supervision.

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  • CONTRAINDICATIONS

    There have been rare reports of hypersensitivity (allergic-like reactions) to L-Methyl-MC-NAC Tablets. Therefore, a known hypersensitivity to any components in the product is a contraindication to its use for any indication.

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  • PRECAUTIONS

    General

    Folic acid when administered as a single agent in doses above 0.1 mg daily, may obscure the detection of B12 deficiency (specifically, the administration of folic acid may reverse the hematological manifestations of B12 deficiency, including pernicious anemia, while not addressing the neurological manifestations). L-methylfolate may be less likely than folic acid to mask vitamin B12 deficiency 22,23. Folate therapy alone is inadequate for the treatment of a B12 deficiency. The 2 mg of methylcobalamin contained in L-Methyl-MC-NAC Tablets has been shown to provide an adequate amount of cobalamin to address this precaution 24. NAC should be avoided by nursing mothers. NAC clearance is reduced in those with chronic liver disease as well as in pre-term newborns. Headaches may be intensified in those taking NAC and nitrates for the treatment of angina. While the incidence of renal stones is low, those that do form renal stones, particularly cysteine stones should avoid L-Methyl-MC-NAC Tablets. Do not administer L-Methyl-MC-NAC Tablets to critically ill patients. NAC and its sulfhydryl metabolites could produce a false-positive result in the nitroprusside test for ketone bodies used in diabetes. L-Methyl-MC-NAC Tablets should be used with caution in those with a history of peptic ulcer disease since NAC may disrupt the gastric mucosal barrier.

    Patient Information

    L-Methyl-MC-NAC Tablets is a medical food 26 for use only under medical supervision and direction.

    Drug Interactions

    L-Methyl-MC-NAC Tablets added to other Drugs

    High dose folic acid may result in decreased serum levels for pyrimethamine and first-generation anticonvulsants (carbamazepine, fosphenytoin, phenytoin, phenobarbital, primidone, valproic acid, valproate). 27,28 This may possibly reduce first generation anticonvulsants effectiveness and/or increase the frequency of seizures in susceptible patients. 27,28 While the concurrent use of folic acid and first generation anticonvulsants or pyrimethamine may result in decreased efficacy of anticonvulsants, no such decreased effectiveness has been reported with the use of 6(S)-5-Methyltetrahydrofolic acid (as L-methylfolate). Nevertheless, caution should be used when prescribing L-Methyl-MC-NAC Tablets among patients who are receiving treatment with first generation anticonvulsants or pyrimethamine. Pyridoxal 5'-phosphate should not be given to patients receiving the drug levodopa, because the action of levodopa is antagonized by pyridoxal 5'-phosphate. However, pyridoxal 5'-phosphate may be used concurrently in patients receiving a preparation containing both carbidopa and levodopa. Capecitabine (Xeloda®) toxicity may increase with the addition of leucovorin (5-formyltetrahydrofolate) (folate).

    Drugs added to L-Methyl-MC-NAC Tablets

    Antibiotics may alter the intestinal microflora and may decrease the absorption of methylcobalamin. Cholestyramine, colchicines or colestipol may decrease the enterohepatic re-absorption of methylcobalamin. Metformin, paraaminosalicylic acid and potassium chloride may decrease the absorption of methylcobalamin. Nitrous oxide can produce a functional methylcobalamin deficiency. Several drugs are associated with lowering serum folate levels or reducing the amount of active folate available. First generation anticonvulsants (carbamazepine, fosphenytoin, phenobarbital, primidone, valproic acid, valproate) 27,28 and lamotrigine30 (a second-generation anticonvulsant) may decrease folate plasma levels. Information on other second-generation anticonvulsants impact on folate levels is limited and cannot be ruled out. Diavalproex sodium,30 topiramate,31 gabapentin,32 pregabalin,33 levetiracetam,34 tiagabine,35 zonisamide,36 have not reported the potential to lower folate in their respective prescribing information. Methotrexate, alcohol (in excess), sulfasalazine, cholestyramine, colchicine, colestipol, L-dopa, methylprednisone. NSAIDs (high dose), pancreatic enzymes (pancrelipase, pancratin), pentamidine, pyrimethamine, smoking, triamterene, and trimethoprim may decrease folate plasma levels. Warfarin can produce significant impairment in folate status after a 6-month therapy.

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  • ADVERSE REACTIONS

    While allergic sensitization has been reported following both oral and parenteral administration of folic acid, allergic sensitization has not been reported with the use of oral L-methylfolate. Mild transient diarrhea, polycythemia vera, itching, transitory exanthema and the feeling of swelling of the entire body have been associated with methylcobalamin. Nausea, vomiting, headache, other gastrointestinal symptoms, and rash (with or without mild fever) have been associated with NAC. There are rare reports of renal stone formation with NAC.

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  • DOSAGE AND ADMINISTRATION

    Usual adult dose is one caplet daily under medical supervision.

    L-Methyl-MC-NAC Tablets is not recommended for use with children under the age of twelve.

    L-Methyl-MC-NAC Tablets must be administered under medical supervision.

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  • HOW SUPPLIED

    Available as an oval coated blue colored caplet. Debossed with "V361" on one side and blank on the other. Commercial product is supplied in bottles of 90 caplets.

    Commercial Product (90 caplets) 76439-361-901

    Use under medical/physician supervision


    1
    Virtus Pharmaceuticals, LLC does not represent these product codes to actual National Drug Codes (NDCs). NDC format codes are product codes adjusted according to standard industry practice to meet the formatting requirements of pharmacy and health insurance computer systems.

    Storage

    Store at controlled room temperature 15°C to 30°C (59°F to 86°F) (See USP). Protect from light and moisture.

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  • PATENTS

    Some or all of the following patents may apply:

    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.

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  • REFERENCES

    1 Donaldson, K. and K. JC., Naturally occurring forms of folic acid. II. Enzymatic conversion of methylenetetrahydrofolic acid to prefolic A-methyltetrahydrofolate. J Biol Chem, 1962. 237: p. 1298-304.

    2 Sweeney, M.R., J. McPartlin, and J. Scott, Folic acid fortification and public health: report on threshold doses above which unmetabolised folic acid appear in serum. BMC Public Health, 2007. 7: p. 41

    3 Wagner, C., Cellular folate binding proteins; function and significance. Annu Rev Nutr, 1982. 2: p. 229-48.

    4 Spector, R. and A.V. Lorenzo, Folate transport in the central nervous system. Am J Physiol, 1975. 229(3): p. 777-82.

    5 Selhub, J., Folate, vitamin B12 and vitamin B6 and one carbon metabolism. J Nutr Health Aging, 2002. 6(1): p. 39-42.

    6 Wright, A.J., J.R. Dainty, and P.M. Finglas, Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK. Br J Nutr, 2007: p. 1-9.

    7 Chen, Z., A.C. Karaplis, S.L. Ackerman, I.P. Pogribny, S. Melnyk, S. Lussier-Cacan, M.F. Chen, A. Pai, S.W. John, R.S. Smith, T. Bottiglieri, P. Bagley, J. Selhub, M.A. Rudnicki, S.J. James, and R. Rozen, Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum Mol Genet, 2001. 10(5): p. 433-43.

    8 Willems FF, Boers GH, Blom HJ, et al. Pharmacokinetic Study on the Utilization of 5-methyltetrahydrofolate and Folic Acid in Patients with Coronary Artery Disease. Br J Pharmacol 2004;141:825-830.

    9 Lehmann M, Regland B, Blennow K, and Gottfries CG: Vitamin B12-B6- Folate Treatment Improves Blood- Brain Barrier Function in Patients with Hyperhomocysteinaemia and Mild Cognitive Impairment. Dementia and Geriatric Cognitive Disorders 2003; 16:145-150.

    10 Hultberg, B., Andersson, A., Masson, P., Larson, M., and Tunek, A. Plasma Homocysteine and Thiol Compound Fractions After Oral Administration of N-Acetylcysteine. Scand.J.Clin.Lab Invest 1994;54(6):417-22.

    11 Ventura, P., Panini, R., Abbati, G., Marchetti, G., and Salvioli, G. Urinary and Plasma Homocysteine and Cysteine Levels During Prolonged Oral N-Acetylcysteine Therapy. Pharmacology 2003;68(2):105-14.

    12 McCaddon A and Davies G: Coadministration of N-acetylcysteine, vitamin B12 and folate in cognitively impaired hyperhomocysteinaemic patients. International Journal of Geriatric Psychiatry 2005; 20(10):998- 1000.

    13 McCaddon A and Davies G: Clinical effects of co-administering N-acetylcysteine, vitamin B12 and folate in cognitively impaired hyperhomocysteinaemic patients. Haematologica Reports 2005:1(3):49-50. Poster presentation at the 5th Homocysteine Conference in Milan, Italy June 26th – June 30th 2005.

    14 Guidi I, Galimberti D, Lonati S, Novembrino C, Bamonti F, Tiriticco M, Fenoglio C, Venturelli E, Baron P, Bresolin N and Scarpini E: Oxidative imbalance in patients with mild cognitive impairment and Alzheimer's disease. Neurobiology of Aging 2006; 27(2):262-269.

    15 5-Methyltetrahydrofolate. (Monograph), Alternative Medicine Review, 2006. 11(4):330-337

    16 Adair JC, Knoefel JE and Morgan N: Controlled trial of N-acetylcysteine for patients with probable Alzheimer's disease. Neurology 2001;57:1515-1517.

    17 Boyd-Kimball D, Sultana R, Abdul HM and Butterfield DA: ∂-Glutamylcysteine Ethyl Ester-Induced Up-Regulation of Glutathione Protects Neurons Against Aβ (1-42)-Mediated Oxidative Stress and Neurotoxicity: Implications for Alzheimer's Disease. Journal of Neuroscience Research 2005;79:700- 706.

    18 Wiklund O, Fager G, Andersson A, Lundstam U, Masson P and Hultberg B: N-acetylcysteine treatment lowers plasma homocysteine but not serum lipoprotein(a) levels. Atherosclerosis 119 (1996) 99-106.

    19 PDR® For Nutritional Supplements, 2001;ISBN: 1-56363-364-7: 477-86.

    20 Nilsson K, Gustafson L, and Hultberg B: Improvement of cognitive functions after cobalamin/folate supplementation in elderly patients with dementia and elevated plasma homocysteine. International Journal of Geriatric Psychiatry 2001; 16:609-614.

    21 Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PWF, and Wolf PA: Plasma Homocysteine As A Risk Factor For Dementia And Alzheimer's Disease. New England Journal of Medicine 2002:Vol346, No. 7:476-483.

    22 B Akoglu, M Schrott, H Bolouri, A Jaffari, E Kutschera, WF Caspary and D Faust: The Folic Acid Metabolite L-5- Methyltetrahydrofolate Effectively Reduces Total Serum Homocysteine Level in Orthotopic Liver Transplant Recipients: A Double-Blind Placebo- Controlled Study. European Journal of Clinical Nutrition (2007), 1–6

    23 Scott JM, Weir DG: The Methylfolate Trap. A Physiological Response in Man to Prevent Methyl Group Deficiency in Kwashiokor and an Explanation for Folic-Acid-Induced Exacerbation of Subacute Combined Degeneration in Pernicious Anemia; Lancet. 1981 2:337-340

    24 Kuzminski AM, Del Giacco EJ, Allen RH, et al.: Effective Treatment Of Cobalamin Deficiency With Oral Cobalamin. Blood 1998; 92:1191- 1198.

    25 Durga J et al. Effect of a 3 year folic acid supplementation on cognitive function in older adults in the FACIT trial; a randomized, double blind, controlled trial. The Lancet 2007;369:208- 216.

    26 United States Food and Drug Administration Title 21 Code of federal Regulations 101.9(j)(8).

    27 PDR For Nutritional Supplements, (n.19) pp. 157-67.

    28 Leucovorin Calcium (folinic acid) For Injection Prescribing Information: December 2003; Mayne Pharma (USA) Inc.

    29 Lamictal® (lamotrigine) Prescribing Information:August 2005; GlaxoSmith- Kline.

    30 Depakote® (Diavalproex sodium) Prescribing Information:January 2006; Abbott Laboratories.

    31 Topamax® (topiramate) Prescribing Information:June 2005; ORTHO-McNEIL NEUROLOGICS, INC.

    32 Neurontin® (gabapentin) Prescribing Information:December 2005; Parke- Davis.

    33 Lyrica® (pregabalin) Prescribing Information:March 2006; Parke-Davis.

    34 Keppra® (levetiracetam) Prescribing Information: March 2007; UCB, Inc.

    35 Gabitril (tiagabine) Prescribing Information: March 2005: Cephalon, Inc.

    36 Zonegran® (zonisamide) Prescribing Information: December 2004: Elan Pharma International Ltd.; licensed to Eisai Inc

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  • SPL UNCLASSIFIED SECTION

    Distributed by:
    Virtus Pharmaceuticals, LLC
    Tampa, FL 33619
    PC0295-00
    Revised 11/14

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  • PRINCIPAL DISPLAY PANEL - 90 Tablet Bottle Label

    VIRTUS
    PHARMACEUTICALS

    76439-361-90

    L-METHYL-MC NAC

    TABLETS

    RX
    90 Tablets

    Made in the USA

    PRINCIPAL DISPLAY PANEL - 90 Tablet Bottle Label
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  • INGREDIENTS AND APPEARANCE
    L-METHYL-MC-NAC 
    levomefolate calcium, methylcobalamin, and acetylcysteine tablet, coated
    Product Information
    Product Type MEDICAL FOOD Item Code (Source) NHRIC:76439-361
    Route of Administration ORAL
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    LEVOMEFOLATE CALCIUM (UNII: A9R10K3F2F) (LEVOMEFOLIC ACID - UNII:8S95DH25XC) LEVOMEFOLATE CALCIUM 6 mg
    METHYLCOBALAMIN (UNII: BR1SN1JS2W) (METHYLCOBALAMIN - UNII:BR1SN1JS2W) METHYLCOBALAMIN 2 mg
    ACETYLCYSTEINE (UNII: WYQ7N0BPYC) (ACETYLCYSTEINE - UNII:WYQ7N0BPYC) ACETYLCYSTEINE 600 mg
    Inactive Ingredients
    Ingredient Name Strength
    CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
    HYPROMELLOSES (UNII: 3NXW29V3WO)  
    TALC (UNII: 7SEV7J4R1U)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    POLYETHYLENE GLYCOLS (UNII: 3WJQ0SDW1A)  
    FD&C BLUE NO. 2 (UNII: L06K8R7DQK)  
    ALUMINUM OXIDE (UNII: LMI26O6933)  
    SACCHARIN SODIUM (UNII: SB8ZUX40TY)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    CARNAUBA WAX (UNII: R12CBM0EIZ)  
    Product Characteristics
    Color BLUE Score no score
    Shape OVAL Size 19mm
    Flavor Imprint Code V361
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NHRIC:76439-361-90 90 in 1 BOTTLE
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    MEDICAL FOOD 02/09/2015
    Labeler - Virtus Pharmaceuticals (969483143)
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