L-METHYL-B6-B12 Tablets

L-Methyl-B6-B12 Tablets is an orally administered medical food for the dietary management of endothelial dysfunction in patients with diabetic peripheral neuropathy.

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), Lmethylfolate Calcium, Magnesium Stearate, Methylcobalamin, and Carnauba Wax.

L-methylfolate or 6(S)-5-methyltetrahydrofolate [6(S)-5-MTHF], is the primary biologically active diastereoisomer of folate¹ and the primary form of folate in circulation.² It is also the form which is transported across membranes into peripheral tissues³, 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 About 70% of food folate and cellular folate is comprised of 6(S)-5-MTHF. Folic acid, the synthetic form of folate, must undergo enzymatic reduction by methylenetetrahydrofolate reductase (MTHFR) to become biologically active.⁶ Genetic mutations of MTHFR result in a cell's inability to convert folic acid to 6(S)-5- MTHF.⁷

Pyridoxal-5'-phosphate (PLP) is the active form of vitamin B₆ and is used as the prosthetic group for many of the enzymes where this vitamin is involved. PLP is readily absorbed by the intestine by a process which is preceded by dephosphorylation to form pyridoxal. The phosphate group is regained during passage through the intestine. Pyridoxine, the parent compound of PLP and the most frequently used form of vitamin B₆, requires reduction and phosphorylation before becoming biologically active. The PLP in L-Methyl-B6- B12 Tablets contains 25mg of pyridoxal (the active component of PLP).

Methylcobalamin (Methyl-B₁₂) is one of the 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 the intestine by a specific mechanism which uses the 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 methylcobalamin.

L-Methyl-B6-B12 Tablets are indicated for the distinct nutritional requirements of patients with endothelial dysfunction^9-11 who present with loss of protective sensation¹² and neuropathic pain^13-15 associated with diabetic peripheral neuropathy.

L-Methyl-B6-B12 Tablets are indicated for the distinct nutritional requirements of patients with endothelial dysfunction and/or hyperhomocysteinemia¹⁶ who present with lower extremity ulceration(s).^17-19

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

There have been rare reports of hypersensitivity (allergic-like reactions) to L-Methyl-B6-B12 Tablets. Therefore, a known hypersensitivity to any of the 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 L-Methylfolate Calcium. Paresthesia, somnolence, nausea and headaches have been reported with pyridoxal 5'-phosphate. Mild transient diarrhea, polycythemia vera, itching, transitory exanthema and the feeling of swelling of the entire body has been associated with methylcobalamin.

The recommended dose is one tablet twice daily (B.I.D.) or as directed. L-Methyl-B6-B12 Tablets must be used under medical supervision.

L-Methyl-B6-B12 Tablets 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 ninety (90) tablets.

Commercial Product (90 tablets)
76439-362-90¹

Use under medical/physician supervision.

Use under medical/physician supervision.

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.

¹ Donaldson, K. and K. JC., Naturally occurring forms of folic acid. II. Enzymatic conversion of methylenetetrahydrofolic acid to prefolic A-methyl-tetrahydrofolate. 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.

⁸5-Methy l tet rahydrofola te. (Monograph), Alternative Medicine Review, 2006. 11(4):330-337

⁹ Verhaar M. C., Wever Robert M.F., Kastelein John J.P., van Dam Thea, Koomans Hein A, Rabelink Ton J. 5- Methyltetrahydrofolate, the Active Form of Folic Acid, Restores Endothelial Function in Familial Hypercholesterolemia. Circulation 1998; 97:237-241.

¹⁰ van Etten R.W., de Koning E.J.P., Verhaar M.C., Gaillard A.J.M., Rabelink T.J. Impaired NO-dependent vasodilation in patients with Type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate. Diabetologia 2002; 45:1004- 1010.

¹¹ Romerio S. C., Linder L., Nyfeler J., Wenk M., Litynsky P., Asmis R., Haefeli W. E. Acute hyperhomocysteinemia decreases NO bioavailability in healthy adults. Atherosclerosis 2004; 176:337-344.

¹² Walker MJ Jr, Morris LM. Increased cutaneous sensibility in patients with diabetic neuropathy utilizing a pharmacological approach-clinical case evidence. Clinical case Update: Vascular Disease Management 2007; 2(1):1-8.

¹³ Jacobs, Allen M. Abstracts of New Cardiovascular Horizons Meeting. Orally Administered Lmethylfolate, Methylcobalamin, and pyridoxal 5' –phosphate Reduces the Symptoms of Diabetic Peripheral Neuropathy. Oral Presentations 2008.

¹⁴ Jacobs, Allen M. Abstracts of New Cardiovascular Horizons Meeting. L-methylfolate, methylcobalamin, and pyridoxal 5' –phosphate supplementation to pregabalin partial responders for the treatment of painful diabetic neuropathy. Oral Presentations 2008.

¹⁵ Li G. Effect of Mecobalamin on Diabetic Neuropathies. Beijing Methycobal Clinical Trial Collaborative Group. Zhonghua Nei Ke Za Zhi 1999;38(1):14-17.

¹⁶ Ambrosch A. et al. Relation between homocysteinemia and diabetic neuropathy in patients with Type 2 diabetes mellitus. Diabet Med. 2001;18:185-192.

¹⁷ Veves A., Akbari C.M., Primavera J., Donaghue V.M., Zacharoulis D., Chrzan J.S., DeGirolami U., LoGerfo F.W., Freemen R. Endothelial Dysfunction and the Expression of Endothelias Nitric Oxide Synthetase in Diabetic Neuropathy, Vascular Disease and Foot Ulceration. Diabetes 1998;47:457-463.

¹⁸ Boykin J. V. Jr., Ischemic Vascular Disease, Nitric Oxide Deficiency, and Impaired Wound Healing. Vascular Disease Management 2007; 2(1) 1-8.

¹⁹ Boykin J. V. Jr., Byalis C, Homocysteine-A Stealth Mediator of Impaired Wound Healing: A Preliminary Study. Wounds 2006;18(4): 101-116.

²⁰ 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

²¹ 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

²² United States Food and Drug Administration Title 21 Code of federal Regulations 101.9(j)(8).

²³ PDR^® For Nutritional Supplements, 2001; ISBN: 1- 56363-364-7:157-167.

²⁴ Leucovorin Calcium (folinic acid) For Injection Prescribing Information: December 2003; Mayne Pharma (USA) Inc.

²⁵ Lamictal^® (lamotrigine) Prescribing Information: August 2005; Glaxo-SmithKline.

²⁶ Depakote^® (divalproex sodium) Prescribing Information: January 2006; Abbott Laboratories.

²⁷ Topamax^® (topiramate) Prescribing Information: June 2005; ORTHO-McNEIL NEUROLOGICS, INC.

²⁸ Neurontin^® (gabapentin) Prescribing Information: December 2005; Parke-Davis.

²⁹ Lyrica^® (pregabalin) Prescribing Information: March 2006; Parke- Davis.

³⁰ Keppra^® (levetiracetam) Prescribing Information: March 2007; UCB, Inc.

³¹ Gabitril (tiagabine) Prescribing Information: March 2005: Cephalon, Inc.

³² Zonegran^® (zonisamide) Prescribing Information: December 2004: Elan Pharma International Ltd.; licensed to Eisai Inc

Manufactured for:

Virtus Pharmaceuticals, LLC
Tampa, FL 33619

PC0293-00
Revised 11/14

VIRTUS
PHARMACEUTICALS

76439-362-90

L-METHYL-B6-B12

TABLETS

R_x
90 Tablets