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:

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.

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.

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.

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.

To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.

Available as an oval coated blue colored caplet. Debossed with "V361" on one side and blank on the other. Supplied in bottles of 90 caplets  (NDC  42291-362-90).

Use under medical/physician supervision

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.

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

Manufactured for:
AvKARE, Inc.
Pulaski, TN  38478

Mfg. Rev. 11/14  
AV 04/16 (P)

AvKARE

NDC 42291-362-90

L-METHYL-MC NAC

TABLETS

90 Tablets

Must be used under the supervision of a physician.

Description: Each blue colored coated caplet contains:
L-methylfolate Calcium .............................................................................................. 6 mg
Methylcobalamin ........................................................................................................ 2 mg
N-Acetylcysteine .................................................................................................... 600 mg

Ingredients:
N-Acetylcysteine, Microcrystalline, Cellulose, Opadry TM 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. Sugar, lactose, yeast, and gluten free.

See package insert for complete product information.

Identity: L-Methyl-MC-NAC Tablets is an orally administered medical food for use only under medical supervision for the dietary management of certain metabolic processes identified with early memory loss.
This product has been manufactured in a facility that also manufactures products containing milk and soy. Individuals with allergic tendencies to these substances should use discretion.

L-Methyl-MC-NAC is not recommended for use in children under the age of twelve.
Store at controlled room temperature 15°-30°C (59°-86°F). [See USP]. Protect from light and moisture. Dispense in a tight, light-resistant container.

If you are pregnant or nursing a baby, please ask a health professional.

KEEP THIS OUT OF REACH OF CHILDREN.

All prescriptions using this product shall be pursuant to state statutes as applicable.
This is not an Orange Book product.

Call your medical practitioner about side effects.

You may report side effects by calling 1-855-361-3993

Manufactured for:
AvKARE, Inc.
Pulaski, TN 38478

Mfg. Rev. 11/14         AV 04/16 (P)


N3   42291 36290   1