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 Oct 1, 2022.
The dietary supplement ethyl-EPA has been studied in combination with antidepressants in a small number of patients for the treatment of depression.
A systematic review and meta-analysis documented use of ethyl-EPA 1 g/day dietary supplement plus fluoxetine 20 mg/day for 8 weeks for reduction in depressive symptoms.
Contraindications have not been identified.
Information regarding safety and efficacy in pregnancy and lactation is lacking. No adequate or well-controlled studies of use during pregnancy have been published. Effects on breastfeeding infants are unknown. Use with caution.
None well documented.
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.
EPA occurs naturally in the triglyceride form. EPA is an essential n-3 fatty acid and natural metabolite of alpha-linolenic acid; the majority of the body's EPA is derived from consumption, mostly commonly marine fish. Ethyl-EPA is the ethyl ester of EPA, acting as a prodrug for EPA.(Bays 2015, Boston 2004, NIH 2016) Quality and quantity of ingredients in ethyl-EPA dietary supplements may vary. Icosapent ethyl is a highly purified prescription form (approximately 95% purity) of EPA ethyl ester.(EMA 2010, FDA 2011, Ito 2015, NIH 2016)
As a dietary supplement, ethyl-EPA has been commercially available in the United States and Europe since the 1980s.
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.(FDA 2011, 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 and dietary supplements.(Scarsi 2015)
Uses and Pharmacology
The absorption and overall metabolism of polyunsaturated fatty acids is a complex process.(Scarsi 2015)
Compared with 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 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) 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. CYP-450 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)
A systematic review and meta-analysis of the adjunctive use of nutraceuticals for the 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 with 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 the dietary supplement ethyl-EPA in patients with diabetes. The dose-response study (N=70) demonstrated improvement with 1 g/day but not 2 g/day or 4 g/day of prescription ethyl-EPA, and the fluoxetine comparator study (N=60) demonstrated reductions in depression symptoms with dietary supplement ethyl-EPA plus fluoxetine compared with 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 with 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 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)
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
In a focal cerebral ischemia rat model, prophylactic 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 for 5 and 7 days prior) 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 ethyl-EPA product was provided by Mochida Pharmaceuticals, who produces both a prescription and nonprescription ethyl-EPA product.(Ueda 2013)
A systematic review and meta-analysis indicated that ethyl-eicosapentaenoic acid has no significant effect on any scale of Huntington disease at 6 months. At 12 months, 2 studies suggested significant improvements in the Total Motor Score and Total Motor Score-4 in both fixed- and quality-effect models.(Morsy 2019)
A systematic review and meta-analysis documented use of ethyl-EPA 1 g/day dietary supplement plus fluoxetine 20 mg/day for 8 weeks for reduction in depressive symptoms.(Sarris 2016)
Pregnancy / Lactation
Information regarding safety and efficacy in pregnancy and lactation is lacking. No adequate or well-controlled studies on use during pregnancy have been published. Use caution.
Omega-3 fatty acid ethyl esters are excreted in human milk; the effect of ethyl-EPA on breastfeeding infants is unknown. In an animal study of lactating rats, ethyl-EPA levels were 6 to 14 times higher in milk than in plasma.(Vascepa 2021)
No drug interaction data are available regarding use of ethyl-EPA as a dietary supplement.
In vitro, EPA was a weak inhibitor of CYP2C19, 2C9, and 2C8, and an even weaker inhibitor 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-gp transporter processes.(Whitney 1999)
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)
Data are limited regarding toxicity with ethyl-EPA dietary supplement.
In a 2-year carcinogenicity study conducted in Wistar rats, ethyl-EPA (at least 90.5% pure) 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)
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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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