Package Insert

DESCRIPTION

Zervalx™ is an orally administered prescription medical food for the dietary management of the following patient conditions:

  • preconception hyperhomocysteinemia; and/or,
  • intermediate- to higher- risk pregnancies which require an increased dietary folate intake; and/or,
  • hemolytic, megaloblastic, and/or sickle cell anemia complicated by folate deficiency; and/or
  • experiencing methotrexate induced plasma hyperhomocysteinemia.

Zervalx™ should always be used under the supervision of a physician.

Each round, coated, light yellow-colored tablet contains:

Dietary Ingredients:
L-methylfolate  [6(S)-5-MTHF] (Metafolin®)  1.0 mg

Chemical Structure:
L-methylfolate chemical structure

Other Ingredients:
Dibasic Calcium Phosphate Dihydrate, Silicified Microcrystalline Cellulose 90, Silicified Microcrystalline Cellulose HD 90, Opadry II Yellow 85F92413 (Polyvinyl Alcohol, Titanium Dioxide, PEG 3350, Talc, Riboflavin, FD&C Yellow #6 and FD&C Blue #2), Magnesium Stearate (Vegetable Source), and Carnauba Wax.

Zervalx™ tablets do not contain sugar, lactose, yeast or gluten.

CLINICAL PHARMACOLOGY

L-methylfolate or 6(S)-5-methyltetrahydrofolate [6(S)-5-MTHF], is the primary biologically active isomer of folate1 and the primary form of folate in circulation2. It is also the form which is transported across membranes into peripheral tissues3, particularly across the blood brain barrier4, in contrast to folic acid which does not. In cells, 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 methionine5. Folic acid, the synthetic form of folate, must undergo enzymatic reduction by methylenetetrahydrofolate reductase (MTHFR) to become biologically active6. Genetic mutations of MTHFR result in a cell's inability to convert folic acid to 6(S)-5-MTHF7.

Pharmacokinetics8,9:

Absorption and Elimination: L-methylfolate is a water soluble molecule which is primarily excreted via the kidneys9. 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.9 Plasma protein binding studies showed that L-methylfolate is 56% bound to plasma proteins.8

INDICATIONS AND USAGE

Zervalx™ is indicated for the distinct nutritional requirements of preconception and pregnant women who require increased folate concentrations, in the plasma and/or red blood cells (RBC), regardless of MTHFR C677T polymorphism genotype, with particular emphasis, for preconception and pregnant women over 35 years of age, and/or who are associated with intermediate- to higher- risk pregnancies.10,11,12,13 and/or who have preconception hyperhomocysteinemia14,15,16. Zervalx™ can be used prior to conception.17,18 throughout pregnancy, the postnatal period19 or while taking oral contraceptives to improve nutritional folate concentrations.20,21

Zervalx™ is indicated for the distinct nutritional requirements of patients, regardless of folate MTHFR 677C->T polymorphism genotype.22,23,24; who present with hemolytic, megaloblastic, and/or sickle cell anemia, complicated by folate deficiency25,26,27,28; and/or experience methotrexate induced plasma hyperhomocysteinemia28,29,30,31.

Use with Zervalx™ should always occur under the care of a physician.

CONTRAINDICATIONS

There have been rare reports of hypersensitivity (allergic-type reactions) to Zervalx™. Therefore, a known hypersensitivity to any of the components contained in this product is a contraindication to its use for any indication.

PRECAUTIONS

General:
Folic acid, when administered in daily doses above 0.1mg, 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.25,32 Folate therapy alone is inadequate for the treatment of a B12 deficiency.

Patient Information:
Zervalx™ is a prescription medical food33 for use only under the direction and supervision of a licensed physician.

Drug Interactions:
Zervalx™ added to other drugs: High doses of folic acid may result in decreased first-generation anticonvulsant and pyrimethamine serum levels.34 While the concurrent use of folic acid and first generation anticonvulsants or pyrimethamine may result in decreased efficacy of anticonvulsants34, no such decreased effectiveness has been reported with the use of L-methylfolate. Nevertheless, caution should be used when prescribing Zervalx™ among patients who are receiving treatment with first generation anticonvulsants or pyrimethamine.

Drugs added to Zervalx™: 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.

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, valproate34,35*
Other Anticonvulsants** –
Methotrexate –
Alcohol (excess amounts) –
Sulfasalazine –
Cholestyramine –
Colchicine –
Colestipol –
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.34,35

** Information on other second-generation anticonvulsants impact on folate levels is limited and can not be ruled out. Divalproex sodium36, topiramate37, gabapentin38, oral contraceptives39, pregabalin40, levetiracetam41, tiagabine42 zonisamide43, have not reported the potential to lower folate in their respective prescribing information.

ADVERSE REACTIONS

Allergic reactions have been reported following the use of both oral and parenteral folic acid, as well as the use of oral L-methylfolate.

DOSAGE AND ADMINISTRATION

The usual adult dose is one tablet daily with or without food or as directed by a physician. Zervalx™ must be administered under a doctor's supervision and therefore is available by prescription only.

HOW SUPPLIED

Zervalx™ is available as a round, coated, light yellow-colored tablet. Zervalx™ is debossed with "PAL" on one side and "1.0" on the other. Commercial product is supplied in bottles of 90 tablets. Sample product is supplied in a bottle with seven tablets per bottle.

Commercial Product (90 tablets) 0525-1010-90 Rx Only
Sample Product - Bottle (7 tablets) 0525-1010-70 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 tablets) 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. 5,059,595
U.S. Patent No. 5,538,734
U.S. Patent No. 6,011,040
U.S. Patent No. 6,271,374
U.S. Patent No. 6,441,168 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
  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. 5-Methyltetrahydrofolate.(Monograph), Alternative Medicine Review, 2006. 11(4):330-337
  10. Charles Deborah H. M., Ness Andy R., Campbell Doris, Smith George Davey, Whitley Elise, and Hall Marion H.: Folic acid supplements in pregnancy and birth outcome: re-analysis of a large randomized controlled trial and update of Cochrane review. Paediatric and Perinatal Epidemiology 2005; Vol 19:112-124.
  11. Cleary-Goldman Jane, Malone Fergal D., Vidaver John, Ball Robert H., Nyberg David A., Comstock Christine H., Saade George R., Eddleman Keith A., Klugman Susan, Dugoff Lorraine, Timor-Tritsch Ilan E., Craigo Sabrina D., Carr Stephen R., Wolfe Honor M., Bianchi Diana W., and D'Alton Mary for the FASTER Consortium. Obstetrics & Gynecology 2005; Vol. 105, No. 5:983-990.
  12. Relton Caroline L., Pearce Mark S., and Parker Louise: The influence of erythrocyte folate and serum vitamin B12 status on birth weight. British Journal of Nutrition 2005; Vol. 93:593-99.
  13. Tamura Tsunenobu and Picciano Mary Frances: Folate and human reproduction. Am J Clin Nutr 2006; 83:993-1016.
  14. Murphy M, Scott J, Arija V, Molloy A, Fernandez-Ballart J. Maternal homocysteine before conception and throughout pregnancy predicts fetal homocysteine and birth weight.
  15. Murphy MM, Fernandez-Ballart JD, Arija V, Scott J.M, Molloy AM, Canals J. Maternal homocysteine at preconception is negatively associated with cognitive achievement in children at 4 months and 6 years of age. Clinical Chemistry & Laboratory Medicine. 45(5):A23, May 2007
  16. Wilson RD, Johnson JA, Wyatt P, et al. Pre-conceptional vitamin/folic acid supplementation 2007: the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. J Obste Gynaeco Can. 2007 Dec; 29(12):1003-26.
  17. Sinclair K, Allegrucci C, Singh R, Gardner D, Sebastian, et al. DNA methylation, insulin resistance and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. PNAS 2007 vol. 104 no.9
  18. Lamers Yvonne, Prinz-Langenohl Reinhild, Bramswig Susanne, and Pietrzik Klaus: Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age. Am J Clin Nutr 2006; 84:156-61.
  19. Houghton Lisa A, Sherwood Kelly L, Pawlosky Robert, Ito Shinya, and O'Connor Deborah L: [6S]-5-methyltetrahydrofolate is at least as effective as folic acid in preventing a decline in blood folate concentrations during lactation. Am J Clin Nutr 2006;83:842-50
  20. Ryan-Harshman M, Aldoori W. Folic acid and prevention of neural tube defects. Can Fam Physician. 2008 Jan:54(1):36-8.
  21. Wald NJ, Law MR, Morris JK, Wald DS. Quantifying the effect of folic acid. Lancet. 2001 Dec 15;358(9298):2069-73.
  22. Botto Lorenzo D, and Yang Quanhe: 5,10-Methylenetetrahydrofolate Reductase Gene Variants and Congenital Anomalies: A HuGE Review. American Journal of Epidemiology 2000;Vol 151, No.9:862-77.
  23. Kirke Peadar N, Mills James L, Molloy Anne M, Brody Lawrence C, O'Leary Valerie B, Daly Leslie, Murray Sharon, Conley Mary, Mayne Philip D, Smith Owen, and Scott John M: Impact of the MTHFR C677T polymorphism on risk of neural tube defects: case-control study. BMJ 2004;Vol 328:1535-6.
  24. Molloy Anne M, Daly Sean, Mills James L, Kirke Peader N, Whitehead Alexander S, Ramsbottom Dorothy, Conley Mary R, Weir Donald G, and Scott John M: Thermolabile variant of 5,10-Methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations. The Lancet 1997; Vol 349:1591-93.
  25. 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
  26. Lowenthal EA, Mayo MS, Cornwell PE, Thornley-Brown D. Homocysteine elevation in sickle cell disease. J Am Coll Nutr. 2000 Oct;19(5):608-12.
  27. Caruso R, Campolo J, et al. Effect of homocysteine lowering by 5 methyltetrahydrofolate on redox status in hyperhomocysteinemia. J. Cardiovasc Pharmaco. 2006 Apr; 47(4):549-55.
  28. Hardman J, Limbird L (Editors-in-Chief) Goodman and Gilman's The Pharmacological Basis of Therapeutics Ninth Edition. Chapter 53: Hematopoietic Agents; p 1334-36.
  29. van Ede AE, Laan RF, Blom HJ, et al. The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients. Arthritis Rheum. 2001 Nov; 44(11):2525-30.
  30. Urano W, Taniguchi A, Yamanaka H, et al. Polymorphisms in the methylenetetrahydrofolate reductase gene were associated with both the efficacy and the toxicity of methotrexate used for the treatment of rheumatoid arthritis, as evidenced by single locus and haplotype analyses. Pharmacogenetics. 2002 Apr; 12(3):183-90.
  31. van Ede AE, Laan RF, Rood MJ, et al. Effect of folic or folinic acid supplementation of the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multi-center, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2001 Jul; 44(7):1515-24
  32. 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
  33. United States Food and Drug Administration Title 21 Code of Federal Regulations 101.9(j) (8).
  34. PDR® For Nutritional Supplements, 2001;ISBN: 1-56363-364-7:157-167.
  35. Leucovorin Calcium (folinic acid) For Injection Prescribing Information:December 2003; Mayne Pharma (USA) Inc.
  36. Depakote® (divalproex sodium) Prescribing Information:January 2006; Abbott Laboratories.
  37. Topamax® (topiramate) Prescribing Information:June 2005; ORTHO-McNEIL NEUROLOGICS, INC.
  38. Neurontin®(gabapentin) Prescribing Information:December 2005; Parke-Davis.
  39. YAZ® (drospirenone & ethinyl estradiol) Prescribing Information:February 2007; Bayer Healthcare Pharmaceuticals, Inc.
  40. Lyrica® (pregabalin) Prescribing Information:March 2006; Parke-Davis.
  41. Keppra® (levetiracetam) Prescribing Information: March 2007; UCB, Inc.
  42. Gabitril (tiagabine) Prescribing Information: March 2005: Cephalon, Inc.
  43. Zonegran® (zonisamide) Prescribing Information: December 2004: Elan Pharma International Ltd.; licensed to Eisai Inc.

Metafolin® is a registered trademark of Merck KGaA, Germany.

PDR® is a registered trademark of Thomson Healthcare.

Depakote® is a registered trademark of Abbott Laboratories.

Topamax® is a registered trademark of Ortho-McNeil Neurologics, Inc.

Neurontin® and Lyrica® are registered trademarks of Parke-Davis.

YAZ® is a registered trademark of Bayer Healthcare.

Keppra® is a registered trademark of UCB, Inc.

Gabtril® is a registered trademark of Cephalon, Inc.

Zonegran® is a registered trademark of Elan Pharma International Ltd.; licensed to Eisai Inc.

MANUFACTURED FOR
PAMLAB, L.L.C. Covington, LA 70433

Revised 2/08

Zervalx™ is an orally administered prescription medical food for the dietary management of the following patient conditions:
preconception hyperhomocysteinemia; and/or, intermediate- to higher- risk pregnancies which require an increased dietary folate intake; and/or, hemolytic, megaloblastic, and/or sickle cell anemia complicated by folate deficiency; and/or experiencing methotrexate induced plasma hyperhomocysteinemia. Zervalx™ should always be used under the supervision of a physician.

© 2008, Pamlab, LLC, Covington, LA. (985) 893-4097 Zervalx is a registered trademark of Pamlab, L.L.C. All rights reserved.

Home Site Map