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CLINICAL PHARMACOLOGY Mechanism Of Action Omega-3 long-chain polyunsaturated fatty acids (LC-PUFA) have an important role in brain and central nervous system development and functioning1-4. Decreased omega-3 fatty acids levels, mainly DHA and EPA, are associated with the occurrence of psychiatric, neurodegenerative, and other neurodevelopmental disorders such as dyspraxia, dyslexia, autism³, peroxisomal disorders5, Alzheimer's disease6, and ADHD3, Administration of phosphatidylserine {PS} enriched with omega-3 fatty acids was found to significantly increase DHA level in rat brains7. While the exact mechanism by which Vayarin® exerts its effects is not fully understood, PS present in the mammalian nervous system, which is charactenzed by its substantial levels of omega-3 fatty acids, has been implicated in numerous membrane related functions, such as maintaining the integrity of cell membranes, cell excitability, cell-to-cell recognition and communication8. PS has been found to regulate key proteins in neuronal membranes, including sodium/calcium ATPase9 and protein kinase C10 which undertake crucial functions in diverse signal transduction pathways. Similarly, PS interacts with Raf-1 protein kinase to promote a cascade of reactions that are believed to be involved in cell survival11. Additionally, PS has been found to influence neurotransmitter activity, such as the release of acetylcholine, dopamine and noradrenaline12,13 and to increase brain glucose levels. Absorption and Metabolism Fallowing dietary ingestion of phospholipids, pancreatic digestive enzymes cleave specific fatty acids, leading to the formation of lysophosphclipids that are absorbed by the mucosal cells of the intest ne and could be reacylated into phospholipids14. The fatty acids released can be furtJier used for triglyceride synthesis. Because of the high activity of decarboxylases in the mucosal cells, the majority of the PS is converted into other phospholipids, primarily to phosphatidylethanolamine15. The reacylated PS, phosphatidylethanolamine and other phospholipids enter the lympn and circulation, and are redistributed. Drug Interactions PS can potentially interact with some anticholinergic and cholinergic medications. It is recommended to consult with a physician about Vayarin® interactions that may apply to specific medical conditions. Toxicity Vayarin®, similar to phosphatidylserine extracted from bovine cortex (BC-PS), contains saturated and monounsaturated fatty acids as well as ornega-3 LC-PUFA. The safety profile of BC-PS was determined in several non-clinical studies. Repeat-dose safety studies in rats and dogs show that oral administration of BC-PS at doses up to 1000 mg/kg/day for up to 6 months was without any significant adverse effects of toxicological concern16. The results of teratogenicity studies in rats at doses up to  200 mg/kg/day and in rabbits at doses up to 450 mg/kg/day showed that oral administration of PS did not affect embryonic and fetal development16. In a micronucleus test, BC-PS was administered to mice at total dosages of 30,150 and 300 mg/kg in two equal doses separated by 24-hours. The results of the study diu not reveal any evidence of mutagenic potential or bone marrow toxicity16. Clinical Experience17,18 Double-blind Study Method A 15-weeK, double-blind, placebo-controlled clinical trial was conducted with 200 ADHD children randomized to receive either Vayarin® or placebo (4 capsules/day). The effect of Vayarin® was assessed by rating scales and questionnaires, including the Conners' parent (CRS-P) and teacher (CRS-T) rating scales and the child health questionnaire (CHQ). Results 162 participants completed the study, of whom 147 were included in the efficacy analysis. Significant reduction in ADHD scores was detected in the CRS-P assessment. In addition, a significant beneficial effect was observed in the quality of life questionnaire {CHQ). Subgroup analysis of children with a hyperactive/impulsive behavior, as well as mood and benavior-dysregulation, revealed a more pronounced reduction in ADHD scores. Open-label Extension Method A 15-week, open-label extension was conducted in 150 children with ADHD who completed the previously reported double-blind study. Vayarin® (2 capsules) was administered daily. The effect of Vayarin® was assessed by CRS-P,T and by the CHQ. Results Of 140 participants that completed the study, 127 were included in the efficacy analysis. Children switching to Vayarin® (2 capsules/day) from placebo treatment during the double-blind phase showed a significant reduction in ADHD scores compared to baseline scores in the CRS-T and CRS-P. Safety Evaluation The treatment was generally well tolerated. There were no clinically meaningful differences between treatment groups on the tested blood parameters in the double-blind study and within the treatment group in the open-label extension. In addition, no clinically significant findings were observed during physical examination, vital signs or weight measurements m both study phases (additional safety information is detailed in the Adverse Events section). REFERENCES 1. Richardson, A.J., 0meqa-3 fatty acids in ADHD and related neu rod eve I op mental disorders. Irrt Rev Psychiatry, 2006. 13(2): p. 15W2. 2. SanGiovanni, J.P., et al., Meta-analysis of dietary essential fatly acids and long-chain polyunsaturated fatty acids as they relate to visual resolution acuity in healthy preterm infants. Pediatrics, 2000.105(6): p. 1292-8. 3. Schuchardt, J.P., et al., Significance of long-chain polyunsaturated fatty acids (PUFAs) for the development and behaviour of children. Eur J Pediatr, 2010.169(2): p. 149-64. 4. Kawashima, A., et al., Effects of eicosapentaenoic acid on synaptic plasticity. fatty acid profile and phosphoiinositide 3-kinase signaling in rat hippocampus and differentiated PC12 cells. J Nutr Biochern, 2010.21(4): p. 268-77. 5. Martinez, M.„ Severe deficiency of docosahexaenoic acid in Beroxisomal disorders: a defect of delta 4 desaturation? eurology, 1990. 40(8): p. 1292-8. 6. Soderberg, M., et al., Fatty acid composition of brain phospholipids in aqinq and in Alzheimer's disease. Lipids, 1991.26(6): p. 421-5. 7. Vaisman, N., Pelled, D., n-3 phosphatidyl serine attenuated scopolamine-induced amnesia in middle-aged rats. Prog Neuropsychopharmacol Biol Psychiatry, 2009.33(6): p. 952-9.. 8. Mozzi, R., Buratta, S., Goracci, G., Metabolism and functions of phosphatidylserine in mammalian brain. Neurochem Res, 2003. 28(2): p. 195-214. 9. Wheeler, R.P.W., R., ATPase activity of the sodium pump needs of phosphatidylserine. Nature, 1970. 225(5231): p. 449-450. 10. Bittova, L., Stahelin, R.V., Cho, W., Roles of ionic residues of the C1 domain in protein kinase C-alpha activation and the origin of phosphatidylserine specificity. J Biol Ghem. 2001. 276(6): p. 4218-26. 11. Vance, J.E., Phosphatidylserine and Phosphatidylethanolamine in Mammalian Cells: Two Metabolically-related Aminophospholipids. ASBMB, 2008: p. 1-48. 12. Pepeu, G., Pepeu, I.M.,Amaducci, L., A review of phosphatidylserine pharmacological and clinical effects. Is phosphatidylserine a drug for the ageing brain? Pharmacol Res, 1996.33(2): p. 73-80. 13. Mazzari, S. and A. Battistella, Phosphatidylserine effects on dopamine release from striatum synaptosomes. In: Multidisciplinary Approach to Brain Development. Elsevier North Holland Amsterdam, 1980: p. 569-570. 14. Tso, P., Intestinal lipid absorption. Physiology of the gastrointestinal tract, ed. L.R. Johnson. Vol. 56.1994, New York: Raven Press. 15. Wise, E.M., Elwyn, D., Rates of reactions involved in phosphatide synthesis in liver and small intestine of intact rats. Journal of Biological Chemistry, 1965. 240: p. 1537-1548. 16. Heywood, R., Cozens, D., Richold, M., Toxicology of a phosphatidylserine preparation from bovine brain. C. Trials Journal, 1987.24(1): p. 25-32. 17. Manor, I. et al., The effect of phosphatidylserine containing omega-3 fatty-acids on attentiion-deficit hyperactivity disorder symptoms in children: a double-blind placebo-controlled trial, followed by an open-label extension. Eur Psychiatry, 2012.27(5): p.335-42. 18. Manor, I. et al., Safety of phosphatidylserine containing omega-3 fatty acids in ADHD children: A double-blind placebo-controlled trial followed by an open-label extension. Eur Psychiatry, 2013. Eur Psychiatry, 2013. 28(6):p. 386-91.

Find Lowest Prices on Vayarin® (lipirinen) Capsule DESCRIPTION Vayarin® is an orally administered prescription medical food for the clinical dietary management of complex lipid imbalances associated with ADHD. Vayarin® is a specially formulated and processed composition designed to address the distinct, medically determined lipid nutritional requirements of children with ADHD, the dietary management of which cannot be achieved by modification of the normal diet or use of dietary supplements. Each Vayarin® capsule provides: Lipirinen®......75 mg Lipirinen® is a proprietary composition containing phosphatidylserine (PS) conjugated to omega-3 fatty acids enriched with Eicosapentaenoic acid (EPA). Lipids Imbalances In ADHD There is a growing body of scientific evidence demonstrating that low levels of certain lipids are associated with Attention Deficit Hyperactivity Disorder (ADHD). While ADHD is a complex disorder, the etiology of which is multi-factorial, ADHD has been shown to be associated with metabolic disturbances such as lipid and glucose metabolism [1, 2]. The abnormalities in lipid metabolism that may occur in ADHD are associated with increased oxidative stress, higher rates of lipid degradation and decreased synthesis of phospholipids containing omega-3 fatty acids. Reduced levels of phosphatidylserine containing omega-3 fatty acids (PS-Omega-3) have implications in membrane structure and function, where they are believed to play an important role in signal transduction pathways, secretory vesicle release, and cell growth regulation [3, 4]. Compared to healthy children of the same age, children with ADHD have lower blood levels of omega-3 LC-PUFA [5-13]. These lipids, found also in the brain, play an essential role in brain development and function. In turn, it has been reported that omega-3 fatty acid deficiency is correlated to decreased brain phosphatidylserine, which is mainly in the form of PS-Omega-3 [14, 15]. PS-Omega-3 play an important role in the functioning of neuronal membranes, such as signal transduction, secretory vesicle release, cell-tocell communication, and cell growth regulation [4]. Thus, reduced levels of PS-Omega-3 and omega-3 may represent a complex lipid imbalance playing a role in the etiology/pathogenesis of ADHD and other neuronal disorders. Vayarin® is a proprietary lipid composition of Phosphatidylserine-Omega-3 (PS-Omega-3), enriched with EPA. This form has been specially designed to deliver these essential lipids to the brain in order to support and maintain proper brain function. Moreover, the enrichment of EPA in the Vayarin® product allows for better regulation of lipids and targets the specific imbalances that appear to be associated with ADHD [16]. Figure 1: Schematic structure of phosphatidylserine conjugated to EPA. Chemical Structure Ingredients Phosphatidylserine (PS), Hydroxypropyl methylcellulose, Silicon dioxide, Contains less than 1% of Mixed tocopherols (D-alpha-tocopherol, D-betatocopherol, D-gamma-tocopherol, D-delta-tocopherol), Sunflower oil, Ascorbyl palmitate, Rosemary extract (Rosemary leaf, Propylene glycol, Distilled monoglycerides) (preservative), Caramel (color), Titanium dioxide (color). Vayarin® capsules contain shellfish (Krill). May contain soy and fish. Vayarin® capsules do not contain sugar, lactose, yeast or gluten. REFERENCES 3. Mozzi, R., S. Buratta, and G. Goracci, Metabolism and functions of phosphatidylserine in mammalian brain. Neurochem Res, 2003. 28(2): p. 195-214. 4. Vance, J.E. and R. Steenbergen, Metabolism and functions of phosphatidylserine. Prog Lipid Res, 2005. 44(4): p. 207-34. 14. Hamilton, L., et al., n-3 fatty acid deficiency decreases phosphatidylserine accumulation selectively in neuronal tissues. LIPIDS, 2000. 35(8): p. 863-9. 15. Murthy, M., et al., Differential effects of n-3 fatty acid deficiency on phospholipid molecular species composition in the rat hippocampus. J Lipid Res, 2002. 43(4): p. 611-7.

INDICATIONS Physician Supervision Vayarin® is a medical food product dispensed by prescription and must be used under physician supervision. DOSAGE AND ADMINISTRATION Usual dose is 2 capsules daily or as directed by a physician. HOW SUPPLIED Available as hard she capsules.  Commercial product is supplied in bottles of 60 capsules. Commercial Product (60 capsules) 75959-233-60* Use under medical/ physician supervision. Sample Product (4 capsules) 75959-233-04* Professional Samples -Not for sale. * VAYA Pharma™ does not represent these product codes to be actual National Drug Codes (NDCs). NDC format codes are product codes adjusted according to standard industry practice to meet the formatting requirements of pharmacy and health insurance computer systems. Storage Dispense and keep in original bottle. Store at up to 77°F (25°C). Protect from light and moisture. Warning Keep this product out of the reach of children. Vayarin® is composed of Lipiinen™, a proprietary composition containing phospliatidyIseme-omega-3, EPA enriched. Distributed by: VAYA Pharma™ Inc. Revised: Jan 2014

PATIENT INFORMATION No information provided. Please refer to the WARNINGS AND PRECAUTIONS section.

OVERDOSE No information provided. CONTRAINDICATIONS Vayarin® is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to Vayarin® or any of its components.

SIDE EFFECTS Adverse Events The adverse events of Vayarin® were evaluated in a randomized, double blind, placebo-controlled study of 15 weeks followed by an open label extension of an additional 15 weeks [38]. Adverse events reported during the course of the double-blind phase (table 2): 12 participants from the Vayarin® group and 5 participants from the placebo group were classified by the study physicians as suffering from treatment related, or probably related, adverse events (13 and 5 adverse events, respectively). There were no significant differences between the study groups in either the incidence or number of adverse events recorded (P = 0.848 and P = 0.982, respectively). Adverse events reported during the course of the open-label extension (table 2): 5 participants reported 7 adverse events that were classified by the study physicians as related or probably related to the study treatment. Table 2 Study design Double-blind study (4 capsules/day) Open-label extension (2 capsules/day) Treatment Group Adverse event* Vayarin® (n=137) Placebo (n=63) Vayarin® (n=150) Gastrointestinal discomfort 6 4 4 Atopic dermatitis 1 0 0 SGOT value 1 0 0 Headache 0 1 1 Insomnia 0 0 1 Tics 1 0 0 High triglycerides 0 1 1 Nausea 1 0 0 Hyperactivity 1 0 0 Tantrnm 2 0 0 Table 2. Adverse events reported during the course of the double-blind and the open label phase. *Judged by the study physicians as related or probably related to the study treatment Drug Abuse Vayarin® does not have any known drug abuse or withdrawal effects. DRUG INTERACTIONS No information provided. REFERENCES 38. Manor, I., et al., Safety of phosphatidylserine containing omega3 fatty acids in ADHD children: a double-blind placebo-controlled trial followed by an open-label extension. Eur Psychiatry, 2013. 28(6): p. 386-91.