PreTAB

Virtus Pharmaceuticals LLC

PreTAB tablet (PNV-Ca with 1 mg FA)

FULL PRESCRIBING INFORMATION: CONTENTS*

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• KEEP THIS OUT OF REACH OF CHILDREN.
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

FULL PRESCRIBING INFORMATION

NDC: 76439-259-10

R_x

PRENATAL / POSTNATAL

Prescription Folate

DESCRIPTION: PreTAB tablet (PNV-Ca with 29 mg Fe; 1 mg FA) is an orally administered PRENATAL / POSTNATAL prescription folate specifically formulated for the dietary management of patients with unique nutritional needs requiring increased folate levels.

PreTAB tablet (PNV-Ca with 29 mg Fe; 1 mg FA) should be administered under the supervision of a licensed medical practitioner.

Each pink tablet contains the following dietary ingredients:

Other Ingredients: Calcium Carbonate (Min 37% Ca) Granular USP98 Kosher, Microcrystalline Cellulose Kosher, Croscarmellose Sodium Kosher, Magnesium Stearate Kosher, Silicon Dioxide Kosher, FD&C Red # 40 (Lakes), and other ancillary ingredients as needed to ensure product stability.

Caution: Contains FD&C Red # 40 (Lakes).Since additives, preservatives, bioavailability enhancers, colors and/or flavors of natural origin, etc. 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 marketplace and ensure the highest therapeutic target, safety and quality.

ALLERGY STATEMENT: 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.

PHARMACOLOGY: FOLATE - Folates are best known for reducing the incidence of fetal neural tube defects (NTDs).² NTDs are congenital malformations produced by failure of the neural tube to form and close properly during embryonic development.² 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 folate.³ 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 folate.³

^{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.4}

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 childhood.^5,6,7 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].^8” 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]."⁹ 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 (R_x)-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).^10,11 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]."¹² 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.

ADVERSE REACTIONS: Allergic reactions have been reported following the use of oral and parenteral folate. Call your medical practitioner about side effects.

Mild transient diarrhea, polycythemia vera, itching, transitory exanthema and the feeling of swelling of the entire body has been associated with cobalamin.

Paresthesia, somnolence, nausea, and headaches have been reported with pyridoxine.

PATIENT INFORMATION: This product is a dietary management / prescription (R_x) folate supplement to be used only under licensed medical supervision. Your licensed medical practitioner may choose to prescribe this product along with other medications.

Uses

INDICATIONS AND USAGE: This product is indicated for the distinct nutritional requirements of individuals who have suboptimal folates levels in the cerebrospinal fluid, plasma and/or red blood cells, and require a maintenance level. Folate is effective in the treatment of hyperhomocysteinemia and/or megaloblastic anemias,¹³ (as may be seen in tropical or nontropical sprue) and in anemias of nutritional origin,¹⁴ pregnancy, infancy, childhood or other related folate-malabsorption complications of an inborn or environmental origin.

KEEP THIS PRODUCT OUT OF THE REACH OF CHILDREN.

INTERACTIONS: Always 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.

DRUG INTERACTIONS: Drugs which may interact with folate include but are not limited to:

• First generation anticonvulsants: High dose folate may result in decreased serum levels for first generation anticonvulsants (carbamazepine, fosphenytoin, phenytoin, phenobarbital, primidone, valproic acid, valproate). This may possibly reduce the effectiveness of first generation anticonvulsants and/or increase the frequency of seizures in susceptible patients. Caution should be used when prescribing folates among patients who are receiving treatment with first generation anticonvulsants.
• Second-generation anticonvulsants: Information on the effect of second-generation anticonvulsants (including, but not limited to, lamotrigine) on folate levels is limited and interactions cannot be ruled out.
• Capecitabine: Folinic acid (5-formyltetrahydrofolate) may increase the toxicity of capecitabine.
• Cholestyramine: Reduces folic acid absorption and reduces serum folate levels.
• Colestipol: Reduces folic acid absorption and reduces serum folate levels.
• Colchicine: Colchicine may decrease folate plasma levels.
• Levodopa: Levodopa may decrease folate plasma levels.
• Cycloserine: Reduces folic acid absorption and reduces serum folate levels.
• Dihydrofolate Reductase Inhibitors (DHFRI): DHFRIs block the conversion of folic acid to its active forms, and lower plasma and red blood cell folate levels. DHFRIs include aminopterin, methotrexate, pyrimethamine, triamterene, and trimethoprim. Caution should be exercised when using folate with folate antagonists. Patients, typically, should not be given folate simultaneously with a folate antagonist, for the purpose of reducing or preventing clinical toxicity, as the therapeutic effect of the antagonist may be nullified.
• 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.
• 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, including, but not limited to pancreatin and pancrelipase: Reduced folate levels have occurred in some patients taking pancreatic extracts.
• Pentamidine: Reduced folate levels have been seen with prolonged intravenous pentamidine.
• 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.
• Folate may enhance the toxicity of fluorouracil.
• Concurrent administration of chloramphenicol and folate in folate-deficient patients may result in antagonism of the haematopoietic response to folate.
• Caution should be exercised with the concomitant use of folate 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 B₆ include but are not limited to:

• Vitamin B₆ should not be given to patients receiving the drug levodopa because the action of levodopa may be antagonized by vitamin B₆. Vitamin B₆ may or may not interfere with levodopa even when used concurrently with carbidopa.

Drugs which may interact with vitamin B₁₂ include but are not limited to:

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

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 as mood elevation is possible following coadministration of folate with antidepressant therapy.

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.¹

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.

REFERENCES:

• 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.
• 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.
• Letter Regarding Dietary Supplement Health Claim for Folic Acid With Respect to Neural Tube Defects (Docket No. 91N-100H). October 10, 2000.
• Hendler SS, Rorvik D. PDR for Nutritional Supplements. 2nd ed. Montvale, NJ. Physicians’ Desk Reference Inc; 2008.
• The Federal Register Notice of April 9, 1971 (36 FR 6843).
• The Federal Register Notice of August 2, 1973 (38 FR 20750).
• The Federal Register Notice of October 17, 1980 (45 FR 69044).
• The Federal Register Notice of March 5, 1996 (61 FR 8760).
• The Federal Register Notice of August 2, 1973 (38 FR 20750).
• Code of Federal Regulations Title 21 Section 172.345.
• Code of Federal Regulations Title 21 Section 101.9(j)(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.
• Hallert C, Tobiasson P, Walan A. Serum folate determinations in tracing adult coeliacs. Scand J Gastroenterol. 1981;16:263-67.
• Wu A, Chanarin I, Levi AJ. Macrocytosis of chronic alcoholism. The Lancet. 1974;1:829-31.

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.

PATIENT INFORMATION: PreTAB tablet (PNV-Ca with 29 mg Fe; 1 mg FA) is a PRENATAL / POSTNATAL prescription folate to be used only under licensed medical supervision.

PREGNANCY and NURSING MOTHERS: PreTAB tablet (PNV-Ca with 29 mg Fe; 1 mg FA) is intended for use as a prescription PRENATAL folate before, during, and after pregnancy regardless of lactation status.

DOSAGE AND ADMINISTRATION: One tablet daily or as directed by 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.

HOW SUPPLIED: PreTAB tablet (PNV-Ca with 29 mg Fe; 1 mg FA) is supplied as pink, tablet debossed on one side with "V259", dispensed in bottles of 100 tablets.

NDC: 76439-259-10

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 R_x 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.

KEEP THIS OUT OF REACH OF CHILDREN.

Call your medical practitioner about side effects. You may report side effects by calling (813) 283-1344.

R_x

Manufactured for:
Virtus Pharmaceuticals, LLC
Tampa, Florida 33619
MADE IN USA

Virtus
PHARMACEUTICALS

Rev. 02/2014

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Virtus
PHARMACEUTICALS

Product Code: 76439-259-10

PreTAB tablet
(PNV-Ca with 29 mg Fe; 1 mg FA)

PRENATAL / POSTNATAL

Prescription Folate

R_x

100 Tablets      Made in USA