Vayarol

Vayarol® (lipirolen™) Orally Administered Prescription Medical Food

DESCRIPTION

Vayarol® is an orally administered prescription medical food for the dietary management of hypertriglyceridemia.

Each capsule contains Lipirolen™ 1000 mg, providing:

Phytosterol esters......................................... 630 mg
Docosahexaenoic acid (DHA)...................... 232.5 mg
Eicosapentaenoic acid (EPA)........................ 92.5 mg

Chemical Structure*

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).

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.

INDICATIONS

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.

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 (60 capsules)	75959-122-60*	Use under medical/ physician supervision.
Sample Product (Packet of 2 capsules)	75959-122-02*	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

Store between 41°F to 77°F (5°C - 25°C). Protect from light and moisture.

Warning

Keep this product out of the reach of children.

Lipirolen™ is a proprietary composition containing Phytosterol Esters of omega 3.

Distributed by: VAYA Pharma™, Inc. Revised: Aug 2012

SIDE 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 hysicians 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.

DRUG INTERACTIONS

No information provided.

WARNINGS

No information provided.

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.

OVERDOSE

No information provided.

CONTRAINDICATIONS

Vayarol® is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to Vayarol® or any of its components. Of notice, Vayarol® is not indicated for individuals with a condition known as phytosterolemia, also referred to as sitosterolemia^{32, 33}.

REFERENCES

32. Heinemann, T., G. Axtmann, and K. von Bergmann, Comparison of intestinal absorption of cholesterol with different plant sterols in man. Eur J Clin Invest, 1993. 23(12): p. 827-31.

33. Miettinen, T.A., R.S. Tilvis, and Y.A. Kesaniemi, Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population. Am J Epidemiol, 1990. 131(1): p. 20-31.

CLINICAL PHARMACOLOGY

Pharmacology

Vayarol® is a prescription medical food used under medical supervision.

Mechanism Of Action

The exact mechanism by which Vayarol® exerts its effects is not fully understood. Potential mechanisms of action include inhibition of triglyceride (TG) synthesis and very-low density lipoprotein (VLDL) secretion (by inhibition of diacyl-glycerol acyltransferase and phosphatidic acid phosphohydrolase), stimulation of fatty acid-oxidation (by activation of peroxisomal proliferator-activated receptors (PPARs)), and increase of TG clearance rates (by increasing plasma lipolytic activity)¹. Furthermore, inflammation 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 intestinal tract, by displacing cholesterol from micelles ^{4, 5}.

Metabolism And Absorption

Phytosterol esters are usually hydrolyzed in the gastrointestinal tract into their phytosterol and fatty acid components⁶. Phytosterols have been reported to be poorly absorbed from the gastrointestinal tract, and as a result, low levels of phytosterols are present in the blood⁷. Of the phytosterols that are absorbed, the majority are quickly secreted back into the bile, where they are re-circulated back to the gastrointestinal tract⁸. Sanders⁹ 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 stream¹⁰. 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 genotoxic²⁴. In an acute toxicity study (in which a single dose of 3.2 g sitosterol/kg body weight was administered to mice²⁵) and in a 13-week subchronic toxicity studies (in which rats were administered phytosterol ester doses of 0, 1,000, 3,000, or 9,000 mg/kg body weight/day²⁶), 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 tolerated and produce no serious adverse effects in laboratory animals^{29, 30}.

Clinical Experience

Vayarol® was evaluated in a randomized, double blind, placebo-controlled study of 12 weeks³¹.

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

The values are presented as mean ± standard error (SE). * p = 0.025 based on two-tailed student's t-test comparison of the mean difference from baseline for independent samples.

Low Density Lipoprotein - Cholesterol (LDL-C) Levels Following Vayarol® Administration

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		Vayarol®		p*
	Week 0	Week 12	Week 0	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.

REFERENCES

1. Jacobson, T.A., Role of n-3 fatty acid in the treatment of hypertriglyceridemia and cardiovascular disease. Am J CLin Nutr, 2008. 87: p. 1981-90.

2. Calder, P.C., Omega-3 Fatty Acids and Inflammatory Processes. Nutrients, 2010. 2: p. 355-374.

3. Norris, P.G., J. C.J., and M.J. Weston, Effect of dietary supplementation with fish oil on systolic blood pressure in mild essential HT. Br. Med. J. 1986. 293: p. 104-105.

4. Ikeda, I., Y. Tanabe, and M. Sugano, Effects of sitosterol and sitostanol on micellar solubility of cholesterol. J Nutr Sci Vitaminol (Tokyo), 1989. 35(4): p. 361-9.

5. Ling, W.H. and P.J. Jones, Dietary phytosterols: a review of metabolism, benefits and side effects. Life Sci, 1995. 57(3): p. 195-206.

6. Mattson, F.H., R.A. Volpenhein, and B.A. Erickson, Effect of plant sterol esters on the absorption of dietary cholesterol. J Nutr, 1977. 107(7): p. 1139-46.

7. Weststrate, J.A., et al., Safety evaluation of phytosterol esters. Part 4. Faecal concentrations of bile acids and neutral sterols in healthy normolipidaemic volunteers consuming a controlled diet either with or without a phytosterol ester-enriched margarine. Food Chem Toxicol, 1999. 37(11): p. 1063-71.

8. Salen, G., E.H. Ahrens, Jr., and S.M. Grundy, Metabolism of beta-sitosterol in man. J Clin Invest, 1970. 49(5): p. 952-67.

9. Sanders, D.J., et al., The safety evaluation of phytosterol esters. Part 6. The comparative absorption and tissue distribution of phytosterols in the rat. Food Chem Toxicol, 2000. 38(6): p. 485-91.

10. Hansen, J.B., et al., Comparative effects of prolonged intake of highly purified fish oils as ethyl ester or triglyceride on lipids, haemostasis and platelet function in normolipaemic men. Eur J Clin Nutr, 1993. 47(7): p. 497-507.

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 fatty acids on haemostatic variables and bleeding episodes in patients with coronary artery disease. Blood Coagul Fibrinolysis, 1995. 6(1): p. 17-22.

21. Eritsland, J., et al., Effect of dietary supplementation with n-3 fatty acids on coronary artery bypass graft patency. Am J Cardiol, 1996. 77(1): p. 31-6.

22. Eritsland, J., et al., Long-term metabolic effects of n-3 polyunsaturated fatty acids in patients with coronary artery disease. Am J Clin Nutr, 1995. 61(4): p. 831-6.

23. Freese, R. and M. Mutanen, Alpha-linolenic acid and marine long-chain n-3 fatty acids differ only slightly in their effects on hemostatic factors in healthy subjects. Am J Clin Nutr, 1997. 66(3): p. 591-8.

24. Wolfreys, A.M. and P.A. Hepburn, Safety evaluation of phytosterol esters. Part 7. Assessment of mutagenic activity of phytosterols, phytosterol esters and the cholesterol derivative, 4-cholesten-3-one. Food Chem Toxicol, 2002. 40(4): p. 461-70.

25. Gupta, M.B., et al., Anti-inflammatory and antipyretic activities of beta-sitosterol. Planta Med, 1980. 39(2): p. 157-63.

26. Kim, J.C., et al., Subchronic toxicity of plant sterol esters administered by gavage to Sprague Dawley rats. Food Chem Toxicol, 2002. 40(11): p. 1569-80.

27. Hammond, B.G., et al., Safety assessment of DHA-rich microalgae from Schizochytrium sp. Regul Toxicol Pharmacol, 2001. 33(3): p. 356-62.

28. Hammond, B.G., et al., Safety assessment of DHA-rich microalgae from Schizochytrium sp. Regul Toxicol Pharmacol, 2001. 33(2): p. 205-17.

29. Minami, A., et al., Effect of eicosapentaenoic acid ethyl ester v. oleic acid-rich safflower oil on insulin resistance in type 2 diabetic model rats with hypertriacylglycerolaemia. Br J Nutr, 2002. 87(2): p. 157-62.

30. Poulsen, R.C.K., M.C., Detrimental effect of high dose eicosapentaenoic acid supplementation on bone density in ovariectomised Sprague Dawley rats. Asia Pac J Clin Nutr, 2004. 13(Suppl.)(S49).

31. Bitzur, R., et al., The Metabolic Effects of Omega-3 Plant Sterol Esters in Mixed Hyperlipidemic Subjects. Cardiovasc Drugs Ther. 2010. 24(5_6): p. 429_37.

PATIENT INFORMATION

No information provided. Please refer to the PRECAUTIONS section.