5.563" Vayarol
Transcription
5.563" Vayarol
5.563" Vayarol® rats were administered phytosterol ester doses of 0, 1,000, 3,000, or 9,000 mg/kg body weight/day [26]), no toxicological effects were observed following the administration of these doses. Neither developmental nor reproductive performance toxicity following DHA supplementation was observed in either rats or rabbits [27, 28]. In general, the scientific literature indicates that doses of up to 1.3 g/kg body weight/day of EPA or DHA are well Each capsule contains Lipirolen™ 1000 mg, providing: tolerated and produce no serious adverse effects in laboratory Phytosterol esters .......................................................... 630 mg animals [29, 30]. Docosahexaenoic acid (DHA) ....................................... 232.5 mg EXPERIENCE Eicosapentaenoic acid (EPA) ......................................... 92.5 mg CLINICAL Vayarol® was evaluated in a randomized, double blind, placebo-controlled study of 12 weeks [31]. CHEMICAL STRUCTURE* DESCRIPTION Vayarol® is an orally administered prescription medical food for the dietary management of hypertriglyceridemia. H H H H O O Ninety one men and women (aged 18–65 years) with mixed hyperlipidemia were randomly assigned to receive Vayarol® or placebo. Fasting blood samples were obtained at baseline and endpoint for assessing lipids and lipoprotein profiles, as well as other cardiovascular disease (CVD) risk factors. Of the 91 randomized subjects, 84 subjects completed the study, of them, 67 subjects were included in the per-protocol (PP) analysis (17 subjects were excluded from the PP analysis since they failed to maintain their lifestyle habits, or failed to meet the compliance criteria). The two study groups were comparable with regard to age, gender, weight, Body Mass Index (BMI), and lipid profile. Triglyceride Levels Following Vayarol® Administration * Betasitosterol ester of DHA *The chemical structure of one of the most abundant phytosterol ester molecule present in Vayarol®. INGREDIENTS Phytosterol Esters, Fish Oil, Gelatin, Glycerin, Water, Rosemary Extract (preservative), Mixed Tocopherols (E306-E309), Ascorbyl Palmitate (E304), Carmine (color), Titanium Dioxide (color). Rx Only Capsules Vayarol® Sample Vayarol® capsules contain: Soy and fish (e.g. anchovy, sardine, mackerel, herring). May contain shellfish. Vayarol® capsules do not contain sugar, lactose, yeast or gluten. Capsules Rx Only 8.938" PHARMACOLOGY Vayarol® is a prescription medical food used under medical supervision. • Metabolism and absorption Phytosterol esters are usually hydrolyzed in the gastrointestinal tract into their phytosterol and fatty acid components [6]. Phytosterols have been reported to be poorly absorbed from the gastrointestinal tract, and as a result, low levels of phytosterols are present in the blood [7]. Of the phytosterols that are absorbed, the majority are quickly secreted back into the bile, where they are re-circulated back to the gastrointestinal tract [8]. Sanders [9] reported that the predominant route of excretion is via the feces, in which 75% to 96% of the administered amount is recovered within 24 hours of dosing. In contrast to phytosterols, DHA and EPA are absorbed from the gastrointestinal tract efficiently. Sixty to ninety percent of an administered dose of EPA or DHA is absorbed and incorporated into plasma phospholipids primarily in the liver, and then circulate in the blood stream [10]. From plasma phospholipids, DHA and EPA can be distributed to cellular membranes in a variety of tissues including the brain, eye, liver, kidney, red blood cells and adipose tissue [11-14]. Further metabolism of DHA and EPA results from their removal from the membrane phospholipids, for use as fatty acid precursors in the synthesis of eicosanoids, which are endogenous compounds involved in blood clotting and immune responses. • Drug interactions Cholestyramine administration should be separated from phytosterol use by two to four hours to avoid binding of the latter in the gut. There are no formal studies with Vayarol® and concomitant anticoagulants. Several clinical trials have examined the effect of DHA and EPA consumption on bleeding time and other parameters related to blood clotting and fibrinolysis. Out of these studies, some studies reported decrease in platelet aggregation and clotting factor levels, while others reported that these parameters did not change significantly [15-23]. Patients receiving treatment with Vayarol® and an anticoagulant or other drug affecting coagulation (e.g., aspirin, NSAIDS, warfarin, coumarin) should be monitored periodically. No significant pharmacokinetic interactions have been noted between statins and phytosterols to date. • Toxicity In vitro and in vivo studies have indicated that phytosterols are not mutagenic or genotoxic [24]. In an acute toxicity study (in which a single dose of 3.2 g sitosterol/kg body weight was administered to mice [25]) and in a 13-week subchronic toxicity studies (in which Rev. 7 Vayarol® Placebo • Mechanism of Action The values are presented as mean ± standard error (SE). * The exact mechanism by which Vayarol® exerts its effects is not p = 0.025 based on two-tailed student’s t-test comparison of the fully understood. Potential mechanisms of action include inhibition mean difference from baseline for independent samples. of triglyceride (TG) synthesis and very-low density lipoprotein (VLDL) secretion (by inhibition of diacyl-glycerol acyltransferase Low Density Lipoprotein - Cholesterol (LDL-C) Levels and phosphatidic acid phosphohydrolase), stimulation of fatty Following Vayarol® Administration acid-oxidation (by activation of peroxisomal proliferator-activated 165 receptors (PPARs)), and increase of TG clearance rates (by increasing plasma lipolytic activity) [1]. Furthermore, inflammation 160 and vasodilation might be influenced through modification of eicosanoid profiles [2, 3]. In addition, Vayarol® may reduce the absorption of both dietary and biliary cholesterol from the 155 intestinal tract, by displacing cholesterol from micelles [4, 5]. Front LDL-C levels (mg/dL) Vayarol® Sample 150 145 140 135 Week 0 Week 12 The values are presented as mean ± SE. The typical increase in LDL-C levels, frequently seen with omega-3 fatty acids, was not observed. Diastolic Blood Pressure and CRP Levels Following Vayarol® Administration Placebo Week 0 Week 12 Vayarol® Week 0 p* Week 12 Diastolic BP (mmHg) 82.03 ± 1.6 83.15 ± 2.65 83.00 ± 1.68 77.32 ±1.77 0.036 CRP (mg/L) 3.25 ± 0.45 4.51 ± 0.72 3.08 ± 0.59 2.46 ± 0.42 0.018 The values are presented as mean ± SE. *p value based on comparison of the mean difference from baseline for independent samples (student’s t-test and Mann Whitey test for BP and CRP, respectively). BP-blood pressure; CRP-C reactive protein. PHYSICIAN SUPERVISION Vayarol® is a medical food product dispensed by prescription and must be used under physician supervision. Vayarol® is an orally administered prescription medical food for the dietary management of hypertriglyceridemia. Vayarol® is particularly indicated for individuals at risk for elevated LDL-C levels after omega-3 fatty acid consumption. CONTRAINDICATIONS Vayarol® is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to Vayarol® or any of its components. 5.563" Of notice, Vayarol® is not indicated for individuals with a condition known as phytosterolemia, also referred to as sitosterolemia [32, 33]. PRECAUTIONS • Safety and effectiveness of Vayarol® in pediatric patients or pregnant or lactating patients have not been established. Therefore, Vayarol® is not recommended for these populations. • Vayarol® should be used with caution in patients with known hypersensitivity to soy and/or fish. DRUG ABUSE Vayarol® does not have any known drug abuse or withdrawal effects. ADVERSE EVENTS In a randomized, double blind, placebo-controlled study of 12 weeks, the consumption of Vayarol® was reported to be well tolerated, most subjects maintained good health throughout the study and no serious adverse events (SAE) related to the study treatment were reported. Five adverse events were classified by the study physicians as possibly related to the study treatment: three in the Vayarol® group (complaints of itching rash, fatigue and abdominal discomfort) and two in the placebo group (complaints of mild abdominal discomfort and urticaria). All five subjects completed the study. Other complaints such as low back pain, fever, etc. were classified as unlikely to be associated with treatment, and no pattern or trend emerged suggesting any difference in the distribution of complaints between the treatment groups. DOSAGE AND ADMINISTRATION Usual dose is 2 capsules daily or as directed by a physician. HOW SUPPLIED Available as soft gel capsules. Commercial product is supplied in bottles of 60 capsules. Commercial Product Use under medical/ (60 capsules) 75959-122-60* physician supervision. Sample Product (Packet of 2 capsules) 75959-122-02* 8.938" Rev. 7 Professional Samples -Not for sale. 11. Vidgren, H.M., et al., Incorporation of n-3 fatty acids into plasma lipid fractions, and erythrocyte membranes and platelets during dietary supplementation with fish, fish oil, and docosahexaenoic acid-rich oil among healthy young men. LIPIDS, 1997. 32(7): p. 697-705. 12. Fenton, W.S., et al., A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. Am J Psychiatry, 2001. 158(12): p. 2071-4. 13. Yasui, T., et al., Effects of eicosapentaenoic acid on urinary calcium excretion in calcium stone formers. Eur Urol, 2001. 39(5): p. 580-5. 14. Berson, E.L., et al., Clinical trial of docosahexaenoic acid in patients with retinitis pigmentosa receiving vitamin A treatment. Arch Ophthalmol, 2004. 122(9): p. 1297-305. 15. Turini, M.E., et al., Effects of a fish-oil and vegetable-oil formula on aggregation and ethanolamine-containing lysophospholipid generation in activated human platelets and on leukotriene production in stimulated neutrophils. Am J Clin Nutr, 1994. 60(5): p. 717-24. 16. Prisco, D., et al., Effect of n-3 fatty acid ethyl ester supplementation on fatty acid composition of the single platelet phospholipids and on platelet functions. Metabolism, 1995. 44(5): p. 562-9. 17. Mori, T.A., et al., Interactions between dietary fat, fish, and fish oils and their effects on platelet function in men at risk of cardiovascular disease. Arterioscler Thromb Vasc Biol, 1997. 17(2): p. 279-86. 18. Nilsen, D.W., et al., Lipopolysaccharide induced monocyte thromboplastin synthesis and coagulation responses in patients undergoing coronary bypass surgery after preoperative supplementation with n-3 fatty acids. Thromb Haemost, 1993. 70(6): p. 900-2. 19. Scheurlen, M., et al., Fish oil preparations rich in docosahexaenoic acid modify platelet responsiveness to prostaglandin-endoperoxide/thromboxane A2 receptor agonists. Biochem Pharmacol, 1993. 46(2): p. 245-9. 20. Eritsland, J., et al., Long-term effects of n-3 polyunsaturated * VAYA Pharma™ does not represent these product codes to be fatty acids on haemostatic variables and bleeding episodes in actual National Drug Codes (NDCs). NDC format codes are product patients with coronary artery disease. Blood Coagul codes adjusted according to standard industry practice to meet Fibrinolysis, 1995. 6(1): p. 17-22. the formatting requirements of pharmacy and health insurance computer systems. 21. Eritsland, J., et al., Effect of dietary supplementation with n-3 fatty acids on coronary artery bypass graft patency. Am J STORAGE Cardiol, 1996. 77(1): p. 31-6. Store between 41°F to 77°F (5°C - 25°C). Protect from light and moisture. 22. Eritsland, J., et al., Long-term metabolic effects of n-3 polyunsaturated fatty acids in patients with coronary artery WARNING disease. Am J Clin Nutr, 1995. 61(4): p. 831-6. Keep this product out of the reach of children. 23. Freese, R. and M. Mutanen, Alpha-linolenic acid and marine long-chain n-3 fatty acids differ only slightly in their effects on Lipirolen™ is a proprietary composition containing Phytosterol hemostatic factors in healthy subjects. Am J Clin Nutr, 1997. Esters of omega 3. ® 66(3): p. 591-8. Vayarol and Lipirolen™ are trademarks of Enzymotec Ltd. 24. Wolfreys, A.M. and P.A. Hepburn, Safety evaluation of Distributed by: VAYA Pharma™, Inc. phytosterol esters. Part 7. Assessment of mutagenic activity of phytosterols, phytosterol esters and the cholesterol derivative, 4-cholesten-3-one. Food Chem Toxicol, 2002. REFERENCES 40(4): p. 461-70. 1. Jacobson, T.A., Role of n-3 fatty acid in the treatment of 25. 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Faecal concentrations of bile acids and neutral sterols in healthy normolipidaemic volunteers consuming a controlled 31. Bitzur, R., et al., The Metabolic Effects of Omega-3 Plant diet either with or without a phytosterol ester-enriched Sterol Esters in Mixed Hyperlipidemic Subjects. Cardiovasc margarine. Food Chem Toxicol, 1999. 37(11): p. 1063-71. Drugs Ther. 2010. 24(5_6): p. 429_37. 8. Salen, G., E.H. Ahrens, Jr., and S.M. Grundy, Metabolism of 32. Heinemann, T., G. Axtmann, and K. von Bergmann, beta-sitosterol in man. J Clin Invest, 1970. 49(5): p. 952-67. Comparison of intestinal absorption of cholesterol with different plant sterols in man. Eur J Clin Invest, 1993. 23(12): 9. Sanders, D.J., et al., The safety evaluation of phytosterol p. 827-31. esters. Part 6. The comparative absorption and tissue distribution of phytosterols in the rat. Food Chem Toxicol, 33. Miettinen, T.A., R.S. Tilvis, and Y.A. Kesaniemi, Serum plant 2000. 38(6): p. 485-91. sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected 10. Hansen, J.B., et al., Comparative effects of prolonged intake male population. Am J Epidemiol, 1990. 131(1): p. 20-31. of highly purified fish oils as ethyl ester or triglyceride on lipids, haemostasis and platelet function in normolipaemic Rev. 8/12 men. Eur J Clin Nutr, 1993. 47(7): p. 497-507. Back