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Cerefolin®NAC

Description

Cerefolin®NAC 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 [6(S)-5-MTHF] (Metafolin®) 5.6 mg
Methylcobalamin 2 mg
N-acetylcysteine 600 mg

Other Ingredients:

Microcrystalline Cellulose, Opadry™ tm Blue 07F90856 (Hypromellose, Talc, Titanium Dioxide, Polyethylene Glycol, FD&C Blue #2-Aluminum Lake, Saccharin Sodium), Magnesium Stearate (Vegetable Source).

Cerefolin®NAC caplets do not contain sugar, lactose, yeast or gluten.

Pharmacology

L-methylfolate or 6(S)-5-methyltetrahydrofolate [6(S)-5-MTHF], is the primary biologically active isomer of folate1 and the 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 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-MTHF7.

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 concentrations8,9, and increases total antioxidant capacity (TAC)10, thus correcting the characteristic pattern of changes in cognitively impaired patients with hyperhomocysteinemia.11,12,13

Pharmacokinetics14,15

Absorption and Elimination: L-methylfolate is a water soluble molecule which is primarily excreted via the kidneys.14 In a study of subjects with coronary artery disease (n=21), peak plasma levels were reached in 1-3 hours following ORAL/PARENTERAL administration.15 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.14 Plasma protein binding studies showed that L-methylfolate is 56% bound to plasma proteins.15

Indications and Usage

Cerefolin®NAC is indicated for the distinct nutritional requirements of individuals under a physician's treatment for early memory loss25 with particular emphasis for those individuals diagnosed with or at risk for neurovascular oxidative stress13,16,17 and/or hyperhomocysteinemia18; mild to moderate cognitive impairment with or without vitamin B12 deficiency8,12,19, vascular dementia11,12,20 or Alzheimer's disease11,12,16,21.

Treatment with Cerefolin®NAC should always be under the supervision of a Physician.

Contraindications

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

Precautions

General:
Folic acid when administered as a single agent in doses above 0.1mg 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 deficiency22,23. Folate therapy alone is inadequate for the treatment of a B12 deficiency. The 2 mg of methylcobalamin contained in Cerefolin®NAC has been shown to provide an adequate amount of cobalamin to address this p.recaution24. 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 Cerefolin®NAC. Do not administer Cerefolin®NAC 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. Cerefolin®NAC should be used with caution in those with a history of peptic ulcer disease since NAC may disrupt the gastric mucosal barrier.

Patient Information

Cerefolin®NAC is a medical food 26 for use only under the direction and supervision of a licensed physician.

Reactions To Drugs

Cerefolin®NAC added to other Drugs: High dose folic acid may result in decreased first-generation anticonvulsant and pyrimethamine serum levels. 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 L-methylfolate. Nevertheless, caution should be used when prescribing Cerefolin®NAC among patients who are receiving treatment with first generation anticonvulsants or pyrimethamine. NAC along with nitrates may cause headaches. Use of NAC with carbamazepine may cause reduced serum levels of carbamazepine. Capecitabine (Xeloda®) toxicity may increase with the addition of leucovorin (5-formyltetrahydrofolate) (folate).

Drugs added to Cerefolin®NAC: 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, para-aminosalicylic 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. The net effect of drug interactions with folate are summarized in Table 1.

Drugs Folate plasma level with adjuvant drugs Drug plasma level with adjuvant high dose folate
Anticonvulsants– first generation: carbamazepine, fosphenytoin, phenytoin, phenobarbital, primidone, valproic acid, valproate27,28*
Other Anticonvulsants**; lamotrigine29 –
Methotrexate –
Alcohol (excess amounts) –
Sulfasalazine –
Cholestyramine –
Colchicine –
Colestipol –
Isltretinoin –
L-Dopa –
Methylprednisone –
NSAIDs (high dose): ibuprofen, naproxen, indomethacin, sulindac –
Oral Contraceptives –
Pancreatic enzymes: pancrelipase, pancratin –
Pentamidine –
Pyrimethamine
Smoking –
Triamterene –
Trimethoprim –

* High doses of folate may result in decreased serum levels of these drugs thereby possibly reducing their effectiveness and/or increasing the frequency of seizures in susceptible patients.27,28

** Information on other second-generation anticonvulsants impact on folate levels is limited and can not be ruled out. Divalproex sodium30, topiramate31, gabapentin32, pregabalin33, levetiracetam34, tiagabine35 zonisamide36, have not reported the potential to lower folate in their respective prescribing information.

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.

Dosage and Administration

Usual adult dose is one caplet daily or as directed by a physician. Cerefolin®NAC is not recommended for use with children under the age of twelve.

Cerefolin®NAC must be administered under a doctor's supervision and therefore is available by prescription only.

How Supplied

Available as an oval coated blue colored caplet. Debossed with "PAL" on one side and "600" on the other. Commercial product is supplied in bottles of 90 or 500 caplets. Sample product is supplied in a carton containing five blisters with one caplet in each blister or in a bottle containing seven tablets.

Commercial Product (90 caplets) 0525-0510-90 Prescription Only
Commercial Product (500 caplets) 0525-0510-50 Prescription Only
Sample Product Blister (5 caplets) 0525-0510-05 Professional Samples - Not for sale
Sample Product Bottle (7 caplets) 0525-0510-05 Professional Samples - Not for sale

Storage

Store at controlled room temperature 15°C to 30°C (59°F to 86°F) (See USP). Protect from light and moisture. Dispense commercial product (90 caplets) in original light-resistant container. Dispense sample product in original blister or bottle.

Patents

Some or all of the following patents may apply:

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

References

  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.
  8. 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.
  9. 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.
  10. 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.
  11. McCaddon A and Davies G: Co-administration of N-acetylcysteine, vitamin B12 and folate in cognitively impaired hyperhomocysteinaemic patients. International Journal of Geriatric Psychiatry 2005;20(10):998-1000.
  12. 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.
  13. 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.
  14. 5-Methyltetrahydrofolate.(Monograph), Alternative Medicine Review, 2006. 11(4):330-337
  15. 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.
  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 A(beta) (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; GlaxoSmithKline.
  30. Depakote® (divalproex 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

Metafolin® is a registered trademark of Merck KGaA, Germany. Certain rights to CEREFOLIN®NAC were granted under a license from COBALZ Limited, Chester, United Kingdom, CH1 1NZ.

Manufactured For
PAMLAB, L.L.C. Covington, LA
70433

Revised 9/07
PC-0060-03