Levomefolate Calcium / Acetylcysteine / Mecobalamin / Algal Powder Caplets

(6 mg-600 mg-2 mg-90.314 mg)

DIETARY MANAGEMENT / PRESCRIPTION (Rx) FOLATE

58657-202-90 (90 Caplets)

Certified Gluten Free

Rx

DESCRIPTION:

Levomefolate Calcium/ Acetylcysteine/ Mecobalamin/ Algal Powder Caplets (6 mg-600 mg-2 mg-90.314 mg) is an orally administered prescription folate-containing product specifically formulated for the dietary management of patients with unique nutritional needs requiring increased folate levels. This product should be administered under the supervision of a licensed medical practitioner.

Each caplet contains: 6 mg of L-Methylfolate Calcium*, 90.314 mg of Algal Powder (Schizochytrium), 600 mg of N-Acetyl-L-Cysteine, and 2 mg of Methylcobalamin. *CAS#151533-22-1

INGREDIENTS:

Each caplet contains the following ingredients:

L-Methylfolate Calcium*                 6 mg

N-Acetyl-L-Cysteine                        600 mg

Methylcobalamin                              2 mg

Algal Powder (Schizochytrium)       90.314 mg

* CAS#151533-22-1

Other Ingredients May Contain: Dibasic Calcium Phosphate Dihydrate, Microcrystalline Cellulose, Hypromellose, Polyvinyl Alcohol, Ascorbic Acid, Vegetable Magnesium Stearate, Vegetable Stearic Acid, Silica, Titanium Dioxide (color), Ubidecarenone, Croscarmellose Sodium, Caramel, Modified Starch, Sugar, Maltodextrin, Tocopherol, Corn Oil, Polyethylene Glycol, Talc, and Carnauba Wax.

CAUTION: Contains wheat and soy.

If you are pregnant or nursing, please consult a licensed medical practitioner.

INDICATIONS AND USAGE:

Levomefolate Calcium / Acetylcysteine / Mecobalamin / Algal Powder Caplets (6 mg-600 mg-2 mg-90.314 mg) is an orally administered prescription folate-containing product specifically formulated for the dietary management of patients with unique nutritional needs requiring increased folate levels, as determined by a licensed medical practitioner.

DOSAGE AND ADMINISTRATION:

The usual adult dose may be taken as one caplet daily, or as directed by a licensed medical practitioner.

FOLATE is essential for the production of certain coenzymes in many metabolic systems such as purine and pyrimidine synthesis. About 70% of food folate and cellular folate is comprised of L-methylfolate. It is the primary form of folate in circulation, and is also the form transported across membranes – particularly across the blood brain barrier – into peripheral tissues. In the cell, L-methylfolate is used in the remethylation of homocysteine to form methionine and tetrahydrofolate (THF). L-methylfolate is converted into functional, metabolically active coenzyme forms for use in the body, and supplies the active folate substrate, THF for use in transformylation and methylation biochemistry.1

Folates are best known for reducing the incidence of fetal neural tube defects (NTDs).2,3,4 NTDs are congenital malformations produced by failure of the neural tube to form and close properly during embryonic development.4,5 During the first four weeks of pregnancy – when many women do not even realize that they have conceived, adequate maternal folate intake is essential to reduce the risk of NTDs. Folate is also essential in the synthesis and maintenance of nucleoprotein in erythropoiesis. It also promotes white blood cell (WBC) and platelet production in folate-deficiency anemia. Folate is associated with methylation and transformylation biochemistry. Folate is involved in transformylation and methylation metabolism as well as, indirectly, succinylation metabolism (through the “methyl trap” hypothesis). Folate plays a central role in the formation of nucleic acid precursors, such as thymidylic acid and purine nucleotides, which are essential for nucleic acid synthesis and cell division. IOM/NAS (1998) noted that the evidence for a protective effect from folate supplements is much stronger than that for food folate.4 Other ingredients are added to folate as cofactors, coenzymes and co-metabolites; in studies by Czeizel and Dudas (1992) and Berry et al. (1999), factors other than folate intake may affect the magnitude of risk reduction or participate in a co-protective effect with folate.4,5

L-methylfolate supplementation increases the formation of endothelial nitric oxide synthase resulting in increase nitric oxide. This causes vasodilation to the nerves, increasing blood supply to the nerves, and reducing vascular oxidative stress.6 L-methylfolate supplementation also increases nitric oxide levels by increasing the amount of tetrahydrobiopterin (BH4). BH4 is required for nitric oxide synthesis.7

FOLATE COENZYMES, COFACTORS, AND COMETABOLITES - The following ingredients are added to enhance the bioavailable potential of folate, and include:

METHYLCOBALAMIN - Methylcobalamin is required for two important reactions: the conversion of methylmalonyl CoA to succinyl CoA, a Krebs cycle intermediate, and the conversion of homocysteine to methionine, a reaction in which the methyl group of L-methylfolate is donated to remethylate homocysteine. Homocysteine has been found to stimulate or alter transcription factors involved in inflammation, with an important ancillary consequence of BH4 depletion. For example, it has been reported that homocysteine-mediated activation of sterol regulatory element binding protein (SREBP) upregulates expression of 3-hydroxy-3-methyl-glutaryl-coenzyme (HMG-CoA reductase) with increased biosynthesis and cellular uptake of cholesterol, the depletion of BH4 being a secondary effect.

FOLATE REGULATION: The Federal Register Notices from 1971 to 1973 establish that increased folate is proper supplement in megaloblastic anemias of tropical and nontropical sprue, nutritional origin, pregnancy, infancy, and childhood.8,9 Folate metabolism may be affected by malabsorption issues that differ widely among population groups. The March 5, 1996 Federal Register Notice (61 FR 8760) states “The agency concluded that the scientific literature did not support the superiority of any one source of folate over others, and that the data were insufficient to provide a basis for stating that a specific amount of folate is more effective than another amount [emphasis added].1 The actual amount and source of folate require the supervision of a licensed medical practitioner to achieve a satisfactory maintenance level, and may exceed the 0.8 mg UL. The Federal Register Notice of August 2, 1973 (38 FR 20750) specifically states that “dietary supplement preparations are available without a prescription (21 CFR 121.1134). Levels higher than dietary supplement amounts are available only with a prescription. Oral preparations supplying more than 0.8 mg of folate per dosage unit would be restricted to prescription dispensing and that a dietary supplement furnishing 0.8 mg could be prescribed when a maintenance level of 0.8 mg per day was indicated.9”  When clinical symptoms have subsided and the blood picture and/or CSF folate levels have become normal, a maintenance level should be used. "Patients should be kept under supervision of a licensed practitioner and adjustment of the maintenance level made if relapse appears imminent. In the presence of alcoholism, hemolytic anemia, anticonvulsant therapy, or chronic infection, the maintenance level may need to be increased [emphasis added].9” In the Letter Regarding Dietary Supplement Health Claim for Folic Acid, Vitamin B6, and Vitamin B12 and Vascular Disease (Docket No. 99P-3029) dated November 28, 2000, FDA wrote “... high intakes of folate may partially and temporarily correct pernicious anemia while the neurological damage of vitamin B12 deficiency progresses. IOM/NAS (1998) set the UL for all adults of 1 mg per day because of devastating and irreversible neurological consequences of vitamin B12 deficiency, the data suggesting that pernicious anemia may develop at a younger age in some racial or ethnic groups, and the uncertainty about the extent of the occurrence of vitamin B12 deficiency in younger age groups (IOM/NAS, 1998) [emphasis added].10”

Summary: This product is a dietary management / prescription folate that, due to advanced folate levels, requires administration under the care of a licensed medical practitioner. The "Rx" on the label is to ensure prescription dispensing and that the product is administered under the supervision of a licensed medical practitioner due to the increased risk associated with masking of B12 deficiency (pernicious anemia). The "Rx" status and a National Drug Code (NDC), or similar Product Code, facilitate pedigree reporting requirements and supply-chain control as well as, in some cases, insurance-reimbursement applications.

These statements have not been evaluate by the Food and Drug Administration (FDA). This product is not intended to diagnose, treat, cure, or prevent any disease.

CONTRAINDICATIONS:

This product is contraindicated in patients with a known hypersensitivity to any of the articles contained in this product. This product is contraindicated for individuals with conditions for which any of the ingredients are contraindicated.

WARNINGS:

Caution is recommended in patients with a family history of bipolar illness. Mood elevation is possible in this population.

Caution is also recommended in patients taking anticonvulsant medications as folate may interfere with anticonvulsant medication, and may lower seizure threshold. Furthermore, it has been reported that anticonvulsant medications interfere with folate metabolism, but the exact action is unclear; therefore caution is recommended with patients in this therapeutic group.

Patients undergoing cancer treatment should consult their licensed medical practitioner for advice.

PRECAUTIONS:

Folate alone is improper therapy in the treatment of pernicious anemia and other megaloblastic anemias where vitamin B12 is deficient. Folate in doses above 0.1 mg daily may obscure pernicious anemia in that hematologic remission may occur while neurological manifestations progress. Daily ingestion of more than 3 grams per day of omega-3 fatty acids (DHA, ALA, and EPA) may have potential antithrombotic activities, or effects, and may increase bleeding times. Administration of omega-3 fatty acids, including DHA, should be avoided in patients with inherited or acquired bleeding diathesis, including those taking anticoagulants. Exercise caution to ensure that the prescribed dosage of DHA does not exceed 1 gram (1000 mg) per day.

ADVERSE REACTIONS:

Allergic reactions have been reported following the use of oral and parenteral folate.11 Mild transient diarrhea, polycythemia vera, itching, transitory exanthema, and the feeling of swelling of the entire body have been associated with methylcobalamin.12 Allergic reactions, acne, skin reactions, photosensitivity, nausea, vomiting, abdominal pain, loss of appetite, paresthesia, somnolence, nausea, and headaches have been associated with pyridoxal-5’-phosphate.13

Call your licensed medical practitioner about side effects.

DRUG INTERACTIONS:

Talk to your licensed medical practitioner, healthcare practitioner, personal physician, and/or pharmacist before taking or using any prescription, over-the-counter medicines, or herbal/health supplements alongside this product. Drugs which may interact with folate include:

• Antiepileptic drugs (AED): The AED class including, but not limited to, phenytoin, carbamazepine, primidone, valproic acid, fosphenytoin, valproate, phenobarbital and lamotrigine have been shown to impair folate absorption and increase the metabolism of circulating folate.
  
• Additionally, concurrent use of folic acid has been associated with enhanced phenytoin metabolism, lowering the level of the AED in the blood and allowing breakthrough seizures to occur. Caution should be used when prescribing this product among patients who are receiving treatment with phenytoin and other anticonvulsants.
  
• Cholestyramine: Reduces folic acid absorption and reduces serum folate levels.
  
• Colestipol: Reduces folic acid absorption and reduces serum folate levels.
  Cycloserine: Reduces folic acid absorption and reduces serum folate levels.
  
• Fluoxetine: Fluoxetine exerts a noncompetitive inhibition of the 5-methyltetrahydrofolate active transport in the intestine.
  
• Isotretinoin: Reduced folate levels have occurred in some patients taking isotretinoin.
  
• L-dopa, triamterene, colchicine, and trimethoprim may decrease plasma folate levels.
  
• Nonsteroidal Anti-inflammatory Drugs (NSAIDs): NSAIDs have been shown to inhibit some folate dependent enzymes in laboratory experiments.
  
• NSAIDs include ibuprofen, naproxen, indomethacin and sulindac.
  
• Oral Contraceptives: Serum folate levels may be depressed by oral contraceptive therapy.
  
• Methylprednisolone: Reduced serum folate levels have been noted after treatment with methylprednisolone.
  
• Pancreatic Enzymes: Reduced serum folate levels have occurred in some patients taking pancreatic extracts, such as pancreatin and pancrelipase.
  
• Pentamidine: Reduced folate levels have been seen with prolonged intravenous pentamidine.
  
• Pyrimethamine: High levels of folic acid may result in decreased serum levels of pyrimethamine.
  
• Smoking and Alcohol: Reduced serum folate levels have been noted.
  
• Sulfasalazine: Inhibits the absorption and metabolism of folic acid. Metformin treatment in patients with type 2 diabetes decreases serum folate.
  
• Warfarin can produce significant impairment in folate status after a 6-month therapy.
  
• Caution should be exercised with the concomitant use of folinic acid and trimethoprim- sulfamethoxazole for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection as it is associated with increased rates of treatment failure and mortality in a placebo controlled study.

Drugs which may interact with vitamin B12 (Methylcobalamin):

• Antibiotics, cholestyramine, colchicines, colestipol, metformin, para-aminosalicylic, and potassium chloride may decrease the absorption of vitamin B12.
  
• Nitrous oxide can produce a functional vitamin B12 deficiency.

HOW SUPPLIED:

Levomefolate Calcium / Acetylcysteine / Mecobalamin /Algal Powder Caplets (6 mg-600 mg-2 mg-90.314mg) is supplied as a coated caplet with the imprint "M202", and are supplied in bottles of 90 caplets and are dispensed under the supervision of a licensed medical practitioner.

Bottle of 90†        58657-202-90 (90 ct. bottle / 90 caplets)

†This product is a prescription folate with or without other dietary ingredients, due to increased folate levels (AUG 2 1973 FR 20750). The "Rx" on the label is to ensure prescription dispensing and that the product is administered under the supervision of a licensed medical practitioner due to the increased risk associated with masking of B12 deficiency (pernicious anemia).

Based on the risk of obscuring pernicious anemia, this product requires supervision of a licensed medical practitioner. The "Rx" status and a National Drug Code (NDC), or similar Product Code, facilitate pedigree reporting requirements and supply-chain control as well as, in some cases, insurance-reimbursement applications.

FOR THE PHARMACIST

This product is not an Orange Book (OB) rated product, therefore all prescriptions using this product shall be pursuant to state statutes as applicable. There are no claims of bioequivalence or therapeutic equivalence.

This product may, under certain circumstances, be dispensed through a certified mail-order program as long as there is record of prescription AND confirmation that the patient is under the supervision of a licensed medical practitioner.

STORAGE: 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.

Call your medical practitioner about side effects. You may report side effects by calling 877-250-3427.

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

KEEP THIS OUT OF THE REACH OF CHILDREN.

Rx

DIETARY MANAGEMENT / PRESCRIPTION (Rx) FOLATE

REFERENCES:

1. Federal Register Notice of March 5, 1996 (61 FR 8759-60).
   
2. Hendler SS, Rorvik D, eds. PDR for Nutritional Supplements. Montvale, NJ: Thomson Healthcare; 2001. 10.
   
3. Hendler SS, Rorvik D. PDR for Nutritional Supplements. 2nd ed. Montvale, NJ. Physicians’ Desk Reference Inc; 2008. 11.
   
4. Bendich A, Deckelbaum R. Preventive Nutrition: The Comprehensive Guide for Health Professionals. 2009. Dietary Supplement Facts Regulations at http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/DietarySupplements/ucm2006823.htm. 
   
5. Letter Regarding Dietary Supplement Health Claim for Folic Acid With Respect to Neural Tube Defects. October 10, 2000.
   
6. Veves A. et al. Diabetes 1998. 47:457-463.
   
7. Verhaar, MC. Atherosclerosis, Thrombosis, Vascular Biology, 2001.
   
8. Federal Register Notice of April 9, 1971 (36 FR 6843).
   
9. Federal Register Notice of August 2, 1973 (38 FR 20750).
   
10. Letter Regarding Dietary Supplement Health Claim for Folic Acid, Vitamin B6, and Vitamin B12 and Vascular Disease. November 28, 2000.
    
11. Natural Standard Research Collaboration (NIH). Folate (folic acid) Monograph 2009.
    
12. Natural Standard Research Collaboration (NIH). Vitamin B12 Monograph 2009.
    
13. Alternative Medicine Review Vitamin B6 Monograph Volume 6, Number 1, 2001.

Manufactured for:
Method Pharmaceuticals, LLC
Arlington, TX 76006
www.methodpharm.com
MADE IN USA

Method Pharmaceuticals, LLC
Rev. 03/15

PRINCIPAL DISPLAY PANEL

58657-202-90
Levomefolate Calcium /
Acetylcysteine / Mecobalamin/
Algal Powder Capsules
(6 mg-600 mg-2 mg-90.314mg)
DIETARY MANAGEMENT /
PRESCRIPTION (Rx ) FOLATE
Certified Gluten Free
Rx
90 Caplets             MADE IN THE USA