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Ethyl-EPA

Common Name(s): Eicosapentaenoic acid ethyl ester, Ethyl icosapentate, Ethyl-eicosapentaenoate, Ethyl-eicosapentaenoic acid, Ethyl-EPA, Ethyl-ester EPA

Medically reviewed by Drugs.com. Last updated on Jul 1, 2019.

Clinical Overview

Use

Limited data from clinical trials evaluating adjunctive use of the dietary supplement ethyl-EPA have shown potential benefit in treating symptoms of depression. Use of ethyl-EPA has also been evaluated in cerebral focal ischemia and dyslexia.

Dosing

Depression: 1 g/day of ethyl-EPA dietary supplement plus fluoxetine (20 mg/day) for 8 weeks.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. No adequate or well-controlled studies in pregnant women have been published for either the prescription or dietary supplement of ethyl-EPA. Omega-3 fatty acid ethyl esters are excreted in human milk; the effect on breastfeeding infants is unknown. Use caution.

Interactions

None well documented.

Adverse Reactions

Major adverse events associated with ethyl-EPA are characteristic of omega-3 triglycerides and are GI related (eg, reflux, eructation, nausea, vomiting, distension, diarrhea, constipation); the most common adverse effects are diarrhea or loose stools.

Toxicology

No data are available for the ethyl-EPA dietary supplement.

Source

Ethyl-EPA is a synthetic ethyl ester of the naturally occurring omega-3 fatty acid EPA. EPA occurs naturally in the triglyceride form, whereas the ethyl ester is synthesized by substituting ethanol in place of glycerol in the triglyceride. Ethyl-EPA dietary supplements contain less than 95% ethyl-EPA.NIH 2016, Vascepa 2017 A highly purified form (95% or more ethyl-EPA), known generically as ethyl icosapent or icosapent ethyl, is available as a prescription pharmaceutical in the United States (Vascepa) and in Japan (Epadel).EMA 2010, Vascepa 2017

History

As a dietary supplement, ethyl-EPA has been commercially available in the United States and Europe since the 1980s. As a prescription product, ethyl-EPA has been on the market since 1991 in Japan (Epadel), where it is licensed for the treatment of peripheral vascular disease and hyperlipidemia. In December 2000, the European Medicines Agency designated ethyl-EPA as an Orphan Medicinal Product for the treatment of Huntington disease; however, the new drug application for Huntington disease was not approved based on a lack of efficacy data.EMA 2010 In 2012, the US Food and Drug Administration approved ethyl-EPA (Vascepa) as an adjunct to a lipid-lowering diet and exercise program to reduce triglyceride levels in adults with severe hypertriglyceridemia (500 mg/dL or higher).Vascepa 2017

Pharmacokinetic and toxicology data provided in this monograph are from animal studies conducted to support the orphan drug application for Huntington disease in Europe that used ethyl-EPA at a concentration of at least 90.5%; pharmacology studies used a product containing approximately 95% ethyl-EPA. The clinical relevance of the variations in purity is unknown.EMA 2010

Chemistry

Ethyl-EPA ([5Z,8Z,11Z,14Z,17Z]-eicosa-5,8,11,14,17-pentaenoic acid ethyl ester) is the ethyl ester of EPA, a long-chain polyunsaturated fatty acid with a molecular weight of 330.51. EPA consists of a 20-carbon chain with 5 double bonds (20:5). As represented by the omega-3 nomenclature, the first double bond is located at the third carbon from the methyl group (omega) end of the chain.Wardlaw 1999, Whitney 1999 Ethyl-EPA is a prodrug of EPA. After oral administration, ethyl-EPA is de-esterified and releases EPA as the active metabolite, which is subsequently absorbed in the small intestine. After entering the endoplasmic reticulum of the enterocytes, it is incorporated into chylomicrons and enters systemic circulation predominantly through the thoracic duct lymphatic system.Mahayni 2017, Scarsi 2015 EPA is bound to plasma proteins and is incorporated into cell membrane phospholipids (especially in the CNS, retina, and myocardium), triglycerides, and cholesteryl esters. The overall metabolism of EPA is complex and the endogenous fraction far exceeds that taken in exogenously from food, dietary supplements, or pharmaceuticals.Scarsi 2015, Vascepa 2017

Uses and Pharmacology

The absorption and overall metabolism of polyunsaturated fatty acids is a complex process that involves not only a steady state between free fractions and those bound to phospholipids and triglycerides, but also the metabolism of very–low-density lipoprotein and chylomicrons in skeletal muscle and adipose tissue, a process that is also subject to considerable inter- and intrapatient variability. Baseline levels of EPA, comprised of total and unesterified plasma EPA plus red blood cell EPA, have high interpatient variability and are a reflection of dietary intake. Baseline levels significantly affect the interpretation of EPA pharmacokinetic parameters.Mahayni 2011, Scarsi 2015

Compared to the natural triglyceride form, EPA in the ethyl ester form is absorbed better when taken with fat (either as a high-fat meal or as olive oil) or with a regular meal, but is poorly absorbed if taken with low-fat food or no food.EMA 2010 However, EPA in the ethyl ester form has been shown to have lower bioavailability than the natural triglyceride, re-esterified triglyceride, or the free fatty acid forms.NIH 2016

After oral administration, de-esterification of ethyl-EPA releases EPA as the active metabolite, which is then absorbed in the small intestine. Dietary fat, which stimulates pancreatic enzymes, increases absorption of omega-3 fatty acids, whereas calcium ions affect absorption by binding to free fatty acids and reducing their bioavailability. Unlike dietary lipids, which are mostly dependent on pancreatic lipase, absorption of polyunsaturated fatty acid ethyl esters also requires carboxyl ester lipase (bile salt–dependent lipase) to cleave the free fatty acid from the ester bond. Once absorbed, peak plasma levels of EPA are reached in about 5 hours and exhibit a mean steady-state volume of distribution of approximately 88 L.Scarsi 2015 Following oral administration of ethyl-EPA (at least 90.5% ethyl-EPA) to rats, the distribution of EPA within the body was similar to that following the administration of either the free acid or the triglyceride forms of EPA.EMA 2010 Less than 1% of EPA circulating in plasma is free unesterified fatty acid; more than 99% of unesterified EPA is bound to plasma proteins and is incorporated into phospholipids, triglycerides, and cholesteryl esters. Both the free and bound fractions are taken as the index of bioavailability. EPA is metabolized primarily via beta-oxidation in the liver and has a total plasma clearance of 684 mL/hour, with an elimination half-life of about 89 hours. Cytochrome P450 metabolism is a minor elimination pathway, and EPA does not undergo renal excretion. The total and free EPA in plasma, plus that incorporated into cell membranes (ie, CNS, retina, myocardium) constitute the endogenous fraction, which far exceeds that taken in exogenously from food, dietary supplements, or pharmaceuticals.Scarsi 2015

Depression

Clinical data

A systematic review and meta-analysis of the adjunctive use of nutraceuticals for treatment of depression identified 8 double-blind, randomized controlled trials involving omega-3 fatty acids, 4 of which were specific for ethyl-EPA and published between 2002 and 2010. Of the 4 ethyl-EPA studies, 2 clearly sourced the dietary supplement; however, the provider of ethyl-EPA was not stated for the other 2 studies, both of which conferred with Laxdale Ltd., who is a provider of prescription-strength ethyl-EPA. The results were primarily positive for omega-3 fatty acids, specifically EPA or ethyl-EPA, with 6 of the 11 data sets revealing a statistically significant benefit (P=0.007). However, heterogeneity among studies was significant. Study populations of the 4 ethyl-EPA trials ranged from 20 to 70 subjects, with dosages of 1 to 4 g/day given over 4 to 12 weeks; a range of antidepressant medications were also used by participants, with fluoxetine being used solely in 3 studies. Primary outcomes were measured by the Hamilton Depression Rating Scale-17 and -24 in 3 studies, while the Montgomery-Asberg Depression Rating Scale was used in the fourth. Compared to placebo, a statistically significant reduction in depression rating scores between baseline and end point were observed with the 2 prescription-strength ethyl-EPA studies and for dietary supplement ethyl-EPA plus fluoxetine; no significant difference was observed with dietary supplement ethyl-EPA in patients with diabetes. The dose-response study (N=70) demonstrated improvement with 1 g/day but not 2 or 4 g/day of prescription ethyl-EPA, and the fluoxetine comparator study (N=60) demonstrated reduction in depression symptoms with dietary supplement ethyl-EPA plus fluoxetine compared to either agent alone.Sarris 2016 The effects of adjunctive use of ethyl-EPA on the biological risk factors of adults with diabetes mellitus with comorbid major depressive disorder were investigated in a small double-blind, randomized controlled trial (N=25). Compared to placebo, the administration of ethyl-ester EPA 1 g/day (more than 90% ethyl-ester EPA plus tocopherols as stabilizers) for 12 weeks significantly improved 6 of 11 oxidative stress markers (P=0.039), cortisol area under the curve (AUC) over time (P=0.045), fatty acids in the phospholipid fraction (including increases in both EPA and docosapentaenoic acid with a decrease in arachidonic acid) (P=0.005), and increases in high-density lipoprotein and total cholesterol (P=0.03). One patient experienced an allergic reaction while using EPA and discontinued use; no other severe adverse events were observed. No effects were observed on inflammatory markers, total cortisol AUC, one-carbon-cycle factors, or low-density lipoprotein cholesterol.Mocking 2012

Dyslexia

Clinical data

In a double-blind, randomized controlled trial (N=62), administration of ethyl-EPA 500 mg/day plus carnosine 400 mg/day as a dietary supplement for 90 days to Finnish children with reading difficulties but no specific language impairment failed to produce any benefit compared with placebo. Measures included reading accuracy and speed, spelling, decoding fluency, arithmetic skills, and subjective assessments provided by teachers, parents, and the children. Higher plasma levels of EPA were confirmed in the children taking the EPA and carnosine dietary supplement.Kairaluoma 2009

Focal cerebral ischemia

Animal data

In a focal cerebral ischemia rat model, prophylactic administration of ethyl-EPA 100 mg/kg/day was administered for 3, 5, or 7 days prior to induced ischemia. Different withdrawal intervals of 3, 5, and 7 days prior to ischemia following 7-day pretreatment with ethyl-EPA were also examined. Pretreatment with ethyl-EPA for 5 and 7 days (but not 3 days) significantly improved infarct volumes and neurological scores. Withdrawal of ethyl-EPA administration for 3 days prior to ischemia, but not 5 and 7 days, also demonstrated significant infarct volume reduction and neurological improvement. However, despite marked increases in plasma EPA, postischemic administration was not neuroprotective even at high doses of 600 mg/kg/day. Mechanisms included suppressed oxidative stress, DNA damage, and lipid peroxidation during ischemia reperfusion. Pretreatment inhibited endothelial damage and subsequent Rho-kinase activation following transient ischemia. The strength of ethyl-EPA as a dietary supplement or prescription was not stated; the product was provided by Mochida Pharmaceuticals, who produces both a prescription and nonprescription ethyl-EPA product.Ueda 2013

Dosing

Dietary fat stimulates pancreatic enzymes and increases absorption of omega-3 fatty acids, whereas calcium ions bind to free fatty acids and reduce bioavailability.Scarsi 2015 Prescribing information for icosapent ethyl advises administering with or immediately following a meal.Vascepa 2017

Depression

1 g/day of ethyl-EPA dietary supplement plus fluoxetine (20 mg/day) for 8 weeks reduced depression scores in a comparator study, and was more effective when used adjunctively with an antidepressant compared to either agent alone.Sarris 2016 Biological risk factors (ie, oxidative stress markers, cortisol AUC) were also improved with 1 g/day (unknown strength) in patients with diabetes mellitus and comorbid major depressive disorder.Mocking 2012

Pregnancy / Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. No adequate or well-controlled studies in pregnant women have been published for either the prescription-strength or dietary supplement product.Vascepa 2017 According to the prescribing information for Vascepa, it is unknown if ethyl-EPA can cause harm when administered to a pregnant woman. Use only if potential benefit outweighs potential risk to the fetus.

Omega-3 fatty acid ethyl esters are excreted in human milk; the effect on breastfeeding infants is unknown. In an animal study of lactating rats, ethyl-EPA levels were 6 to 14 times higher in milk than plasma.Vascepa 2017

Interactions

No drug interaction data are available for the ethyl-EPA dietary supplement.

In vitro, EPA was found to be a weak inhibitor of cytochrome P450 (CYP-450) 2C19, 2C9, and 2C8, and even weaker for 2B6 and 3A. In vitro studies suggest that EPA has low potential to induce CYP3A, 2C9, and 1A2. Ethyl-EPA is not a substrate or inhibitor of P-glycoprotein transporter processes.Whitney 1999 Coadministration of prescription-strength ethyl-EPA with atorvastatin, omeprazole, rosiglitazone, or warfarin (racemic) did not result in pharmacokinetic changes.Vascepa 2017

Prolonged bleeding time has been reported in some studies with omega-3 fatty acids; however, the prolongation did not exceed normal limits and did not produce clinically significant bleeding events. Monitoring is recommended in patients receiving icosapent ethyl and other drugs affecting coagulation.Vascepa 2017

Adverse Reactions

Major adverse events associated with ethyl-EPA are characteristic of omega-3 triglycerides and are GI related (eg, reflux, eructation, nausea, vomiting, distension, diarrhea, constipation); the most common adverse effect is diarrhea or loose stools, which could increase the risk of dehydration or reduce uptake of fat-soluble vitamins.EMA 2010 In the prescribing information for Vascepa, arthralgia was reported in 2.3% of patients receiving icosapent ethyl, compared to 1% with placebo.Vascepa 2017

Toxicology

No data are available for the dietary supplement ethyl-EPA.

No clinically relevant neoplasms were observed with the prescription product, icosapent ethyl, in animal carcinogenic and mutagenic studies. An in vitro chromosomal aberration study was positive for clastogenicity. Fertility studies in rats led to increased anogenital distance in female pups and increased cervical ribs with 3 g/kg/day of icosapent ethyl (human equivalent of 4 g/day or 7 times the human systemic exposure).Vascepa 2017 In a 2-year carcinogenicity study conducted in Wistar rats, ethyl-EPA (90.5% or more) significantly increased mortality rates in female rats in the high-dose group (1 mL/kg/day) compared with controls (P<0.001). Additionally, females experienced significant reductions in food consumption and body weight, higher incidences of gastric ulceration, and reduced platelet counts.EMA 2010

References

European Medicines Agency. Withdrawal assessment report for ethyl eicosapent soft gelatin capsules. http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_report/2010/03/WC500075024.pdf. Published March 4, 2010. Accessed May 31, 2017.
Kairaluoma L, Närhi V, Ahonen T, Westerholm J, Aro M. Do fatty acids help in overcoming reading difficulties? A double-blind, placebo-controlled study of the effects of eicosapentaenoic acid and carnosine supplementation on children with dyslexia. Child Care Health Dev. 2009;35(1):112-119.18991979
Mahayni H. Clinical Pharmacology and Biopharmaceutics review(s) for application number: 202057Orig1s000 (Vascepa). Center for Drug Evaluation and Research. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202057Orig1s000ClinPharmR.pdf. Published November 10, 2011. Accessed May 31, 2017.
Mocking RJ, Assies J, Bot M, Jansen EH, Schene AH, Pouwer F. Biological effects of add-on eicosapentaenoic acid supplementation in diabetes mellitus and co-morbid depression: a randomized controlled trial. PLoS One. 2012;7(11):e49431.23209576
National Institutes of Health Office of Dietary Supplements. Omega-3 Fatty Acids Fact Sheet for Health Professionals. https://ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional/. Updated November 2, 2016. Accessed May 19, 2017.
Sarris J, Murphy J, Mischoulon D, et al. Adjunctive nutraceuticals for depression: A systematic review and meta-analyses. Am J Psychiatry. 2016;173(6):575-587.27113121
Scarsi C, Levesque A, Lisi L, Navarra P. The free fractions of circulating docosahexaenoic acid and eicosapentenoic acid as optimal end-point of measure in bioavailability studies on n-3 fatty acids. Prostaglandins Leukot Essent Fatty Acids. 2015;96:11-16.25559240
Ueda M, Inaba T, Nito C, Kamiya N, Katayama Y. Therapeutic impact of eicosapentaenoic acid on ischemic brain damage following transient focal cerebral ischemia in rats. Brain Res. 2013;1519:95-104.23643859
Vascepa (icosapent ethyl) [prescribing information]. Bedminster, NJ: Amarin Pharma; February 2017.
Wardlaw GM. Perspectives in Nutrition. 4th ed. Boston, MA: WBC/McGraw-Hill; 1999.
Whitney EN, Rolfes SR. Understanding Nutrition. 8th ed. Belmont, CA: West/Wadsworth; 1999.

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This information relates to an herbal, vitamin, mineral or other dietary supplement. This product has not been reviewed by the FDA to determine whether it is safe or effective and is not subject to the quality standards and safety information collection standards that are applicable to most prescription drugs. This information should not be used to decide whether or not to take this product. This information does not endorse this product as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this product. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this product. This information is not specific medical advice and does not replace information you receive from your health care provider. You should talk with your health care provider for complete information about the risks and benefits of using this product.

This product may adversely interact with certain health and medical conditions, other prescription and over-the-counter drugs, foods, or other dietary supplements. This product may be unsafe when used before surgery or other medical procedures. It is important to fully inform your doctor about the herbal, vitamins, mineral or any other supplements you are taking before any kind of surgery or medical procedure. With the exception of certain products that are generally recognized as safe in normal quantities, including use of folic acid and prenatal vitamins during pregnancy, this product has not been sufficiently studied to determine whether it is safe to use during pregnancy or nursing or by persons younger than 2 years of age.

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