Download 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
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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
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1. Jacobson, T.A., Role of n-3 fatty acid in the treatment of
25. Gupta, M.B., et al., Anti-inflammatory and antipyretic activities
hypertriglyceridemia and cardiovascular disease. Am J CLin
of beta-sitosterol. Planta Med, 1980. 39(2): p. 157-63.
Nutr, 2008. 87: p. 1981-90.
26. Kim, J.C., et al., Subchronic toxicity of plant sterol esters
2. Calder, P.C., Omega-3 Fatty Acids and Inflammatory
administered by gavage to Sprague Dawley rats. Food Chem
Processes. Nutrients, 2010. 2: p. 355-374.
Toxicol, 2002. 40(11): p. 1569-80.
3. Norris, P.G., J. C.J., and M.J. Weston, Effect of dietary
27. Hammond, B.G., et al., Safety assessment of DHA-rich
supplementation with fish oil on systolic blood pressure in
microalgae from Schizochytrium sp. Regul Toxicol Pharmacol,
mild essential HT. Br. Med. J. 1986. 293: p. 104-105.
2001. 33(3): p. 356-62.
4. Ikeda, I., Y. Tanabe, and M. Sugano, Effects of sitosterol and
28. Hammond, B.G., et al., Safety assessment of DHA-rich
sitostanol on micellar solubility of cholesterol. J Nutr Sci
microalgae from Schizochytrium sp. Regul Toxicol Pharmacol,
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2001. 33(2): p. 205-17.
5. Ling, W.H. and P.J. Jones, Dietary phytosterols: a review of
29. Minami, A., et al., Effect of eicosapentaenoic acid ethyl ester
metabolism, benefits and side effects. Life Sci, 1995. 57(3):
v. oleic acid-rich safflower oil on insulin resistance in type 2
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diabetic model rats with hypertriacylglycerolaemia. Br J Nutr,
2002. 87(2): p. 157-62.
6. Mattson, F.H., R.A. Volpenhein, and B.A. Erickson, Effect of
plant sterol esters on the absorption of dietary cholesterol.
30. Poulsen, R.C.K., M.C., Detrimental effect of high dose
J Nutr, 1977. 107(7): p. 1139-46.
eicosapentaenoic acid supplementation on bone density in
ovariectomised Sprague Dawley rats. Asia Pac J Clin Nutr,
7. Weststrate, J.A., et al., Safety evaluation of phytosterol esters.
2004. 13(Suppl.)(S49).
Part 4. 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
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men. Eur J Clin Nutr, 1993. 47(7): p. 497-507.
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