Prenatal/Postnatal Multivitamin/Multimineral/DHA softgel Prescription Folate

Rx

DESCRIPTION: PNV - Iron Polysaccharides/Folic Acid/DHA (29 mg-1 mg-200 mg) is a prescription prenatal/postnatal multivitamin/ multimineral nutritional supplement with Omega-3 fatty acid. PNV - Iron Polysaccharides/Folic Acid/DHA (29 mg-1 mg-200 mg) is an oblong shaped, dark blue colored softgel, imprinted with 230.

Inactive Ingredients

Gelatin (Bovine), Yellow Bees Wax, Glycerin, Soybean Oil, Soy Lecithin, Purified Water, Natural Creamy Orange Flavour, FD&C Blue #1, Sodium Citrate, Titanium Dioxide, Ethyl Vanillin, FD&C Yellow #6 and other ancillary excipients as needed to ensure product stability.

Since additives, preservatives, bioavailability enhances, colors and flavors of natural origin are preferred over synthetics, it may be the case that product color, appearance and/or taste may vary slightly over time; and it may be necessary to substitute excipients during the manufacturing process as needed to preserve product appearance and continuity in order to avoid confusion in the market place and ensure the highest therapeutic target, safety and quality.

Warning: This product contains FD&C Blue #1 and FD&C Yellow #6. It also contains Soy, Fish and Bovine.

FOLATE MECHANISM OF ACTION
FOLATE is essential for the production of certain coenzymes in many metabolic systems such as purine and pyrimidine synthesis. It 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 REGULATION
The Federal Register Notices from 1971 to 1973 established that increased folate was proper therapy in megaloblastic anemias of tropical and nontropical sprue, nutritional origin, pregnancy, infancy and childhood4,5,6. Folate metabolism can be affected by malabsorption issues which differ widely among population groups. The March 5, 1996 Federal Register Notice (61 FR 8760) states that "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]9,10 The actual amount and source of folate require a licensed medical practitioner's supervision 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. 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 close supervision 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]7". However, once the level of active folate exceeds 0.8 mg as prescribed dosages, then the product is no longer a medical food but a dietary management / prescription (Rx) folate regardless of pregnancy/lactation status in spite of the fact that folic acid including reduced forms, may be added to medical foods as defined in section 5(b)(3) of the Orphan Drug Act (21 USC 360ee(b)(3)), or to food (21 CFR 172.345)11. In the Letter Regarding Dietary Supplement Health Claim for Folic Acid, Vitamin B6, and Vitamin B12 and Vascular Disease (Docket No. 99P3029) 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]8." Summary: This product is a dietary management product that due to advanced folate levels, requires administration under the care of a licensed medical practitioner, and the most appropriate way to do that is to provide the product as prescription for pedigree reporting and safety monitoring. The ingredients, indication or claims of this product are not to be construed to be drug claims.

INDICATIONS AND USAGE

PNV - Iron Polysaccharides/Folic Acid/DHA (29 mg-1 mg-200 mg) is a prescription multivitamin/ multimineral nutritional supplement with Omega-3 fatty acid indicated for use in improving the nutritional status of women throughout pregnancy and in the postnatal period for both lactating and non-lactating mothers. PNV - Iron Polysaccharides/Folic Acid/DHA (29 mg-1 mg-200 mg) is also beneficial in improving the nutritional status of women prior to conception.

Pedigree statement: This product is a prescription-folate with or without other dietary ingredients that - due to increased folate levels (AUG 2 1973 FR 20750), requires an Rx on the label because of increased risk associated with masking of B12 deficiency (pernicious anemia). As such, this product requires licensed medical supervision, an Rx status, and a National Drug Code (NDC) as required by pedigree reporting requirements and insurance-reimbursement applications.

INTERACTIONS: Talk to your healthcare practitioner and/or pharmacist before taking or using any prescription or over-the-counter medicines or herbal/health supplements alongside this product.

CONTRAINDICATIONS: This product is contraindicated in patients with a known hypersensitivity to any of the components 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 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.

Folinic acid may enhance the toxicity of fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly formyl-THF and fluorouracil. Concomitant granulocytopenia and fever were present in some but not all of the patients. The concomitant use of formyl-THF with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis carinii pneumonia in patients with HIV infection was associated with increased rates of treatment failure and mortality in a placebo controlled study.35 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 (ALA, EPA, and DHA) 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. Mild transient diarrhea, polycythemia vera, itching, transitory exanthema and the feeling of swelling of the entire body has been associated with cobalamin. Nausea, vomiting, diarrhea, transient skin rash, flushing, epigastric pain, and constipation have been associated with acetylcysteine.

Call your medical practitioner about side effects.

PHARMACOLOGY: FOLATE - Folates are best known for reducing the incidence of fetal neural tube defects (NTDs). NTDs are congenital malformations produced by failure of the neural tube to form and close properly during embryonic development.3 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. As the postnatal period approaches there is increased demand again for folate regardless of lactation status. 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 folate10. Other dietary 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 intakes may affect the magnitude of risk reduction or participate in a co-protective effect with folate10.

KEEP THIS PRODUCT OUT OF THE REACH OF CHILDREN.

This product may - under certain circumstances, be dispensed through a certified mail-order program so long as there is record of prescription AND confirmation that the patient is under licensed medical supervision. This product is not an Orange Book (OB) rated product, therefore all prescriptions using this product shall be pursuant to state statutes as applicable.

++This product is a prescription-folate with or without other dietary ingredients that - due to increased folate levels (AUG 2 1973 FR 20750), requires an Rx on the label because of increased risk associated with masking of B12 deficiency (pernicious anemia). Based on our assessment of the risk of obscuring pernicious anemia, this product requires licensed medical supervision, an Rx status, and a National Drug Code (NDC) - or similar product code, as required by pedigree reporting requirements and supply-chain control as well as - in some cases, for insurance-reimbursement applications.

REFERENCES:

1. Wu A, Chanarin I, Levi AJ. Macrocytosis of chronic alcoholism. The Lancet. 1974;1:829-31.
2. Hallert C, Tobiasson P, Walan A. Serum folate determinations in tracing adult coeliacs. Scand J Gastroenterol. 1981; 16:263-67.
3. De-Regil LM, Fernández-Gaxiola AC, Dowswell T, et al. Effects and safety of periconceptional folate supplementation for preventing birth defects. Cochrane Database Syst Rev. 2010 Oct 6;(10):CD007950. doi: 10.1002/14651858.CD007950.pub2.
4. Federal Register Notice of April 9, 1971 (36 FR 6843).
5. The Federal Register Notice of August 2, 1973 (38 FR 20750).
6. The Federal Register Notice of October 17, 1980 (45 FR 69044).
7. The Federal Register Notice of August 2, 1973 (38 FR 20750).
8. Letter Regarding Dietary Supplement Health Claim for Folic Acid, Vitamin B6, and Vitamin B12 and Vascular Disease (Docket No. 99P-3029). November 28, 2000.
9. The Federal Register Notice of March 5, 1996 (61 FR 8760).
10. Letter Regarding Dietary Supplement Health Claim for Folic Acid With Respect to Neural Tube Defects (Docket No. 91N-100H). October 10, 2000.
11. Code of Federal Regulations Title 21 Section 172.345.
12. Code of Federal Regulations Title 21 Section 101.9(j)(8).
13. Hoag SW, Ramachandruni H, Shangraw RF. Failure of prescription prenatal vitamin products to meet USP standards for folic acid dissolution. J Am Pharm Assoc (Wash). 1997 Jul-Aug;NS37(4):397-400.
14. Younis IR, Stamatakis MK, Callery PS, et al. Influence of pH on the dissolution of folic acid supplements. Int J Pharm. 2009 Feb 9;367(1-2):97-102.
15. Ramos MI, Allen LH, Mungas DM, et al. Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging. Am J Clin Nutr. 2005 Dec;82(6):1346-52.
16. Kamath A, Chauhan A, Kisucka J. et al. Elevated levels of homocysteine compromise blood-brain barrier integrity in mice. Blood. 2006 Jan 15;107(2):591-593.
17. Baik HW, Russell RM. Vitamin B12 deficiency in the elderly. Annu Rev Nutr. 1999;19:357-377.
18. Goebels N, Soyka M. Dementia Associated With Vitamin B12 Deficiency: Presentation of Two Cases and Review of the Literature. The Journal of Neuropsychiatry and Clinical Neurosciences. 2000;12:389-394.
19. Guosong Liu. Prevention of cognitive deficits in Alzheimer's mouse model by elevating brain magnesium. Molecular Neurodegeneration. 2012;7(Suppl 1):L24.
20. Mauskop A, Altura BM. Role of magnesium in the pathogenesis and treatment of migraines. Clin Neurosci. 1998;5(1):24-7.
21. Hendler SS, Rorvik D. PDR for Nutritional Supplements. 2nd ed. Montvale, NJ. Physicians' Desk Reference Inc; 2008:408.
22. Stevens LJ, Zentall SS, Deck JL, Abate ML, Watkins BA, Lipp SR, Burgess JR. Essential fatty acid metabolism in boys with attention-deficit hyperactivity disorder. Am J Clin Nutr. 1995 Oct;62(4):761-8.
23. Heude B, Ducimetiere P, Berr C. Cognitive decline and fatty acid composition of erythrocyte membranes-The EVA study. Am J Clin Nutr. 2003;77:803-8.
24. Soni M, Kos K, Lang IA, et al. Vitamin D and cognitive function. Scand J Clin Lab Invest Suppl. 2012 Apr;243:79-82.
25. Mosekilde L. Vitamin D and the elderly. Clin Endocrinol (Oxf). 2005;Mar;62(3):265-81.
26. Bendich A, Deckelbaum R. Preventive Nutrition: The Comprehensive Guide for Health Professionals. 2009.
27. Paleologos M, Cumming R and Lazarus R. Cohort Study of Vitamin C Intake and Cognitive Impairment. Am. J. Epidemiol. 1998;148(1):45-50.
28. Slutsky I, Abumaria N, Wu LJ, et al. Enhancement of Learning and Memory by Elevating Brain Magnesium. Neuron. 2010 Jan 28;65(2):165-77.
29. Dröge W, Schipper HM. Oxidative stress and aberrant signaling in aging and cognitive decline. Aging Cell. 2007 Jun;6(3):361-70.
30. Berr C, Balansard B, Arnaud J, et al. Cognitive decline is associated with systemic oxidative stress: the EVA study. Etude du Vieillissement Artériel. J Am Geriatr Soc. 2000 Oct;48(10):1285-91.
31. Srinivasan K. Black pepper and its pungent principle-piperine: a review of diverse physiological effects. Crit Rev Food Sci Nutr. 2007;47(8):735-48.
32. Hutto BR. Folate and cobalamin in psychiatric illness. Compr Psychiatry. 1997;38:305-14.
33. Shorvon SD, Carney MWP, Chanarin I, et al. The neuropsychiatry of megaloblastic anemia. Br Med J. 1980;281: 1036-38.
34. Hertert V. Experimental nutritional folate deficiency in man. Trans Assoc Am Physicians. 1962;75: 307-20.
35. Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis. 1994 Oct;170(4):912-7.
36. Carbamazepine interaction. Reactions Weekly. 1998 Apr;696(1):6.
37. Hendler SS, Rorvik D, eds. PDR for Nutritional Supplements. Montvale, NJ: Thomson Healthcare; 2001.
38. Bonanomi L, Gazzaniga A. Toxicological, pharmacokinetic and metabolic studies on acetylcysteine. Eur J Respir Dis Suppl. 1980;111:45-51.
39. Salehpour S, Sene AA, Saharkhiz N, Sohrabi MR, et al. N-Acetylcysteine as an adjuvant to clomiphene citrate for successful induction of ovulation in infertile patients with polycystic ovary syndrome. J Obstet Gynaecol Res. 2012 Sep;38(9):1182-6.
40. Miyazaki I., et al. Dopaminergic Neuron-Specific Oxidative Stress Caused by Dopamine Itself. Acta Medica Okayama. 2008. Vol. 62, No. 3, pp. 141-150.
41. Nguyen L., et al. Environmental Factors in Alzheimer's and Parkinson's Diseases. Vietnamese American Medical Research Foundation. 2013, 3:2.
42. Nikolova G. Oxidative Stress and Parkinson's Disease. Trakia Journal of Sciences. Vol. 10, No. 1, pp 92-100, 2012.

This product has been manufactured in a facility that also manufactures products containing tree nuts, peanuts, fish, egg, wheat, milk, soy and shellfish. Individuals with allergic tendencies to these substances should use discretion.

DOSAGE AND ADMINISTRATION

One softgel daily with or without food, or as prescribed by a licensed health care provider with prescribing authority.

HOW SUPPLIED

PNV - Iron Polysaccharides/Folic Acid/DHA (29 mg-1 mg-200 mg) is supplied in child-resistant blister packs of 30 softgels (NDC 76439-230-30).

STORAGE

Store at controlled room temperature 20°-25°C (68°-77°F). Excursions permitted to 15°-30°C (59°-86°F). [See current USP].

To protect from light, dispense in carton provided. Once open, blisters should be stored in carton.

To report suspected adverse reactions, contact Virtus Pharmaceuticals at 813-283-1344 or FDA at 1-800-FDA-1088 or www.FDA.gov/safety/medwatch

Manufactured for:
Virtus Pharmaceuticals
Tampa, FL. 33619

Rev. 10/13

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

VIRTUS
PHARMACEUTICALS

NDC 76439-230-30

PNV - Iron Polysaccharides/
Folic Acid/DHA

(29 mg-1 mg-200 mg)

PRENATAL / POSTNATAL

Pre/Post-Natal Nutritional Supplement with DHA
Prescription Folate

30 Softgels
Rx