Omega-3 acid ethyl esters

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Omega-3 acid ethyl esters
Ethyl eicosapentaenoate.png
Chemical structure of ethyl eicosapentaenoate, an important omega-3-acid ethyl ester
Combination of
Eicosapentaenoic acid Antilipemic agent
Docosahexaenoic acid Antilipemic agent
Clinical data
Trade names Lovaza, Omtryg, others
AHFS/Drugs.com Monograph
License data
Pregnancy
category
Routes of
administration 		By mouth
ATC code
  • None
Legal status
Legal status
  • UK: POM (Prescription only) [2]
  • US: ℞-only
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
DrugBank
UNII
KEGG

Omega-3-acid ethyl esters are a mixture of ethyl eicosapentaenoic acid and ethyl docosahexaenoic acid, which are ethyl esters of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found in fish oil. [3] Together with dietary changes, they are used to treat high blood triglycerides which may reduce the risk of pancreatitis. [3] [4] They are generally less preferred than statins, and use is not recommended by NHS Scotland as the evidence does not support a decreased risk of heart disease. [3] [5] [6] Omega-3-acid ethyl esters are taken by mouth. [3]

Contents

Common side effects include burping, nausea, and an upset abdomen. [3] [5] Serious side effects may include liver problems and anaphylaxis. [3] While use in pregnancy has not been well studied, some omega-3 fatty acids appear beneficial. [1] How it works is not entirely clear. [3]

Omega-3-acid ethyl ester medicines were approved for medical use in the European Union in 2000 and in the United States in 2004. [3] [6] [7] Beyond the branded prescription formulation, it is also available as a generic medication and over the counter. [3] [5] In 2021, it was the 218th most commonly prescribed medication in the United States, with more than 1 million prescriptions. [8] [9]

Medical use

Omega-3 acid ethyl esters are used in addition to changes in diet to reduce triglyceride levels in adults with severe (≥ 500 mg/dL) hypertriglyceridemia. [10] In the European Union and other major markets outside the US, omega-3 acid ethyl esters are indicated for hypertriglyceridemia by itself, or in combination with a statin for people with mixed dyslipidemia. [2] [6]

Intake of large doses (2.0 to 4.0 g/day) of long-chain omega-3 fatty acids as prescription drugs or dietary supplements are generally required to achieve significant (> 15%) lowering of triglycerides, and at those doses, the effects can be significant (from 20% to 35% and even up to 45% in individuals with levels greater than 500 mg/dL). It appears that both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) lower triglycerides, but DHA appears to raise LDL cholesterol more than EPA, while DHA raises HDL cholesterol while EPA does not. [11]

Other fish-oil based drugs

Other omega-3 fish oil-based prescription drugs on the market have similar uses and mechanisms of action. [12]

Dietary supplements

There are many fish oil dietary supplements on the market. [17] There appears to be little difference in effect between dietary supplement and prescription forms of omega-3 fatty acids as to ability to lower triglycerides, but the ethyl ester products work less well when taken on an empty stomach or with a low-fat meal. [11] The ingredients of dietary supplements are not as carefully controlled as prescription products and have not been tested in clinical trials as such drugs have. [18] Prescription omega-3 products are more concentrated, requiring fewer softgels for the same daily dose. [17]

In people with CKD who require hemodialysis, there is a risk that vascular blockage due to clotting, may prevent dialysis therapy from being possible. Omega-3 fatty acids contribute to the production of eicosanoid molecules that reduce clotting. However, a Cochrane review in 2018 did not find clear evidence that omega-3 supplementation has any impact on the prevention of vascular blockage in people with CKD. [19] There was also moderate certainty that supplementation did not prevent hospitalisation or death within a 12-month period. [19]

Side effects

Special caution should be taken with people who have fish and shellfish allergies. [10] In addition, as with other omega-3 fatty acids, taking omega-3 acid ethyl esters puts people who are on anticoagulants at risk for prolonged bleeding time. [10] [11]

Side effects include stomach ache, burping, and a bad taste; some people on very high doses (8g/day) in clinical trials had atrial fibrillation. [10]

Omega-3 acid ethyl esters have not been tested in pregnant women and are rated pregnancy category C; it is excreted in breast milk and the effects on infants are not known. [10]

Pharmacology

After ingestion, omega-3-acid ethyl esters are metabolized mostly in the liver like other dietary fatty acids. [2]

Mechanism of action

Omega-3-acid ethyl esters, like other omega-3 fatty acid-based drugs, appears to reduce production of triglycerides in the liver and to enhance clearance of triglycerides from circulating very low-density lipoprotein (VLDL) particles. The way it does that is not clear, but potential mechanisms include increased breakdown of fatty acids; inhibition of diglyceride acyltransferase, which is involved in biosynthesis of triglycerides in the liver; and increased activity of lipoprotein lipase in blood. [2] [12] The synthesis of triglycerides is reduced in the liver because EPA and DHA are poor substrates for the enzymes responsible for triglyceride synthesis.

Physical and chemical properties

The active ingredient is concentrated omega-3 acid ethyl esters that are made from fish body oils that are purified and esterified. [20] For the Lovaza product, each 1000 mg softgel capsule contains 840 mg omega-3 fatty acids: eicosapentaenoic acid ethyl ester (460 mg) and docosahexaenoic acid ethyl ester (380 mg). [2]

History

Pronova BioPharma ASA had its roots in Norway's codfish liver oil industry. The company was founded in 1991 as a spinout from the JC Martens company, which in turn was founded in 1838 in Bergen, Norway. [21] Pronova developed the concentrated omega-3-acid ethyl esters formulation that is the active pharmaceutical ingredient of Lovaza. [20]

Pronova won approvals to market the drug, called Omacor in Europe (and initially in the US), in several European countries in 2001 after conducting a three and a half year trial in 11,000 subjects; [22] The company partnered with other companies like Pierre Fabre in France. [23] In 2004, Pronova licensed the US and Puerto Rican rights to Reliant Therapeutics, whose business model was in-licensing of cardiovascular drugs. [24] In that same year, Reliant and Pronova won FDA approval for the drug, [25] and it was launched in the US and Europe in 2005. Global sales in 2005 were $144M, and by 2008, they were $778M. [26] In 2007 GlaxoSmithKline acquired Reliant for $1.65 billion in cash. [27]

In 2009, generic companies Teva Pharmaceuticals and Par Pharmaceutical made clear their intentions to file Abbreviated New Drug Applications ("ANDAs") to bring generics to market, and in April 2009, Pronova sued them from infringing the key US patents covering Lovaza, US 5,656,667 (due to expire in April 2017), US 5,502,077 (exp March 2013). Subsequently, in May 2012, a district court ruled in Pronova's favor, saying that the patents were valid. [28] [29] [30] The generic companies appealed, and in September 2013, the Federal Circuit reversed, saying that because more than one year before Pronova's predecessor company applied for a patent, it had sent samples of the fish oil used in Lovaza to a researcher for testing. This event thus constituted "public use" that invalidated the patent in question. [31] [32] Generic versions of Lovaza were introduced in America in April 2014. [33]

Pronovo has continued to manufacture the ingredients in Lovaza, and in 2012, BASF announced it would acquire Pronova for $844 million. [34] The deal closed in 2013. [35]

Brand names

Related Research Articles

<span class="mw-page-title-main">Fat</span> Esters of fatty acid or triglycerides

In nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such compounds, most commonly those that occur in living beings or in food.

Omega−3 fatty acids, also called Omega−3 oils, ω−3 fatty acids or n−3 fatty acids, are polyunsaturated fatty acids (PUFAs) characterized by the presence of a double bond, three atoms away from the terminal methyl group in their chemical structure. They are widely distributed in nature, being important constituents of animal lipid metabolism, and they play an important role in the human diet and in human physiology. The three types of omega−3 fatty acids involved in human physiology are α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). ALA can be found in plants, while DHA and EPA are found in algae and fish. Marine algae and phytoplankton are primary sources of omega−3 fatty acids. DHA and EPA accumulate in fish that eat these algae. Common sources of plant oils containing ALA include walnuts, edible seeds, and flaxseeds as well as hempseed oil, while sources of EPA and DHA include fish and fish oils, and algae oil.

Essential fatty acids, or EFAs, are fatty acids that humans and other animals must ingest because the body requires them for good health, but cannot synthesize them.

<span class="mw-page-title-main">Cod liver oil</span> Dietary supplement derived from liver of cod fish

Cod liver oil is a dietary supplement derived from liver of cod fish (Gadidae). As with most fish oils, it contains the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and also vitamin A and vitamin D. Historically, it was given to children because vitamin D had been shown to prevent rickets, a consequence of vitamin D deficiency.

<span class="mw-page-title-main">Hypertriglyceridemia</span> High triglyceride blood levels

Hypertriglyceridemia is the presence of high amounts of triglycerides in the blood. Triglycerides are the most abundant fatty molecule in most organisms. Hypertriglyceridemia occurs in various physiologic conditions and in various diseases, and high triglyceride levels are associated with atherosclerosis, even in the absence of hypercholesterolemia and predispose to cardiovascular disease.

Krill oil is an extract prepared from a species of Antarctic krill, Euphausia superba. Processed krill oil is commonly sold as a dietary supplement. Two components of krill oil are omega-3 fatty acids similar to those in fish oil, and phospholipid-derived fatty acids (PLFA), mainly phosphatidylcholine.

Fish oil is oil derived from the tissues of oily fish. Fish oils contain the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), precursors of certain eicosanoids that are known to reduce inflammation in the body and improve hypertriglyceridemia. There has been a great deal of controversy in the 21st century about the role of fish oil in cardiovascular disease, with recent meta-analyses reaching different conclusions about its potential impact.

<span class="mw-page-title-main">Eicosapentaenoic acid</span> Chemical compound

Eicosapentaenoic acid is an omega-3 fatty acid. In physiological literature, it is given the name 20:5(n-3). It also has the trivial name timnodonic acid. In chemical structure, EPA is a carboxylic acid with a 20-carbon chain and five cis double bonds; the first double bond is located at the third carbon from the omega end.

<span class="mw-page-title-main">Docosahexaenoic acid</span> Chemical compound

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, and retina. It is given the fatty acid notation 22:6(n-3). It can be synthesized from alpha-linolenic acid or obtained directly from maternal milk, fatty fish, fish oil, or algae oil. The consumption of DHA contributes to numerous physiological benefits, including cognition. As the primary structural component of nerve cells in the brain, the function of DHA is to support neuronal conduction and to allow optimal function of neuronal membrane proteins.

Docosapentaenoic acid (DPA) designates any straight open chain polyunsaturated fatty acid (PUFA) which contains 22 carbons and 5 double bonds. DPA is primarily used to designate two isomers, all-cis-4,7,10,13,16-docosapentaenoic acid and all-cis-7,10,13,16,19-docosapentaenoic acid. They are also commonly termed n-6 DPA and n-3 DPA, respectively; these designations describe the position of the double bond being 6 or 3 carbons closest to the (omega) carbon at the methyl end of the molecule and is based on the biologically important difference that n-6 and n-3 PUFA are separate PUFA classes, i.e. the omega-6 fatty acids and omega-3 fatty acids, respectively. Mammals, including humans, can not interconvert these two classes and therefore must obtain dietary essential PUFA fatty acids from both classes in order to maintain normal health.

A wax ester (WE) is an ester of a fatty acid and a fatty alcohol. Wax esters are the main components of three commercially important waxes: carnauba wax, candelilla wax, and beeswax.

<span class="mw-page-title-main">Linoleoyl-CoA desaturase</span> Class of enzymes

Linoleoyl-CoA desaturase (also Delta 6 desaturase, EC 1.14.19.3) is an enzyme that converts between types of fatty acids, which are essential nutrients in the human body. The enzyme mainly catalyzes the chemical reaction

<span class="mw-page-title-main">Ethyl eicosapentaenoic acid</span> Medication

Ethyl eicosapentaenoic acid, sold under the brand name Vascepa among others, is a medication used to treat dyslipidemia and hypertriglyceridemia. It is used in combination with changes in diet in adults with hypertriglyceridemia ≥ 150 mg/dL. Further, it is often required to be used with a statin.

Amarin Corporation is an Irish-American biopharmaceutical company founded in 1993 and headquartered in Dublin, Ireland and Bridgewater, New Jersey. The company develops and markets medicines for the treatment of cardiovascular disease. It has developed the drug Vascepa (AMR-101), a prescription grade omega-3 fatty acid.

Omega-3 carboxylic acids (Epanova) is a formerly marketed yet still not an Food And Drug Administration (FDA) approved prescription medication–since taken off market by the manufacturer–used alongside a low fat and low cholesterol diet that lowers high triglyceride (fat) levels in adults with very high levels. This was the third class of fish oil-based drug, after omega-3 acid ethyl esters and ethyl eicosapentaenoic acid (Vascepa), to be approved for use as a drug. The first approval by US Food and Drug Administration was granted 05 May 2014. These fish oil drugs are similar to fish oil dietary supplements, but the ingredients are better controlled and have been tested in clinical trials. Specifically, Epanova contained at least 850 mg omega-3-acid ethyl esters per 1 g capsule.

<span class="mw-page-title-main">Epoxydocosapentaenoic acid</span> Group of chemical compounds

Epoxide docosapentaenoic acids are metabolites of the 22-carbon straight-chain omega-3 fatty acid, docosahexaenoic acid (DHA). Cell types that express certain cytochrome P450 (CYP) epoxygenases metabolize polyunsaturated fatty acids (PUFAs) by converting one of their double bonds to an epoxide. In the best known of these metabolic pathways, cellular CYP epoxygenases metabolize the 20-carbon straight-chain omega-6 fatty acid, arachidonic acid, to epoxyeicosatrienoic acids (EETs); another CYP epoxygenase pathway metabolizes the 20-carbon omega-3 fatty acid, eicosapentaenoic acid (EPA), to epoxyeicosatetraenoic acids (EEQs). CYP epoxygenases similarly convert various other PUFAs to epoxides. These epoxide metabolites have a variety of activities. However, essentially all of them are rapidly converted to their corresponding, but in general far less active, vicinal dihydroxy fatty acids by ubiquitous cellular soluble epoxide hydrolase. Consequently, these epoxides, including EDPs, operate as short-lived signaling agents that regulate the function of their parent or nearby cells. The particular feature of EDPs distinguishing them from EETs is that they derive from omega-3 fatty acids and are suggested to be responsible for some of the beneficial effects attributed to omega-3 fatty acids and omega-3-rich foods such as fish oil.

Cytochrome P450 omega hydroxylases, also termed cytochrome P450 ω-hydroxylases, CYP450 omega hydroxylases, CYP450 ω-hydroxylases, CYP omega hydroxylase, CYP ω-hydroxylases, fatty acid omega hydroxylases, cytochrome P450 monooxygenases, and fatty acid monooxygenases, are a set of cytochrome P450-containing enzymes that catalyze the addition of a hydroxyl residue to a fatty acid substrate. The CYP omega hydroxylases are often referred to as monoxygenases; however, the monooxygenases are CYP450 enzymes that add a hydroxyl group to a wide range of xenobiotic and naturally occurring endobiotic substrates, most of which are not fatty acids. The CYP450 omega hydroxylases are accordingly better viewed as a subset of monooxygenases that have the ability to hydroxylate fatty acids. While once regarded as functioning mainly in the catabolism of dietary fatty acids, the omega oxygenases are now considered critical in the production or break-down of fatty acid-derived mediators which are made by cells and act within their cells of origin as autocrine signaling agents or on nearby cells as paracrine signaling agents to regulate various functions such as blood pressure control and inflammation.

<span class="mw-page-title-main">Seaweed oil</span>

Seaweed oil, also called algae oil or algal oil, is used for making food, with the purified product almost colorless and odorless. It is also under development as a possible alternative fuel and manufacturing agent.

Pronova BioPharma is a Norwegian company. In Denmark it is a bulk manufacturer of omega-3 products with a manufacturing plant in Kalundborg. It was acquired by BASF in 2014.

Frederick D. Sancilio is an American pharmaceutical scientist, research professor and serial entrepreneur best known for founding several biotechnology and contract research organizations including, Alcami, Endeavor Pharmaceuticals, Clearway Global, Omega Blu Supplements and Sancilio Pharmaceuticals. Sancilio has participated in the development of more than 40 drug product patents that have been granted by the United States Patent and Trademark Office.

References

  1. 1 2 "Omega-3 polyunsaturated fatty acids Use During Pregnancy". Drugs.com. Retrieved 13 April 2019.
  2. 1 2 3 4 5 "Omacor". Summary of Product Characteristics (SmPC). Electronic Medicines Compendium (EMC). 11 December 2019. Retrieved 15 May 2020.
  3. 1 2 3 4 5 6 7 8 9 "Omega-3-acid Ethyl Esters Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 13 April 2019.
  4. ↑ Karalis DG (February 2017). "A Review of Clinical Practice Guidelines for the Management of Hypertriglyceridemia: A Focus on High Dose Omega-3 Fatty Acids". Advances in Therapy. 34 (2): 300–323. doi:10.1007/s12325-016-0462-y. PMC   5331085 . PMID   27981496.
  5. 1 2 3 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 206–207. ISBN   9780857113382.
  6. 1 2 3 "Omega-3 fatty acid medicines". European Medicines Agency. 17 September 2018. Retrieved 13 April 2019.
  7. ↑ "Drug Approval Package: Omacor (Omega-3-Acid Ethyl Esters) NDA #021654". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 15 May 2020.
  8. ↑ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  9. ↑ "Omega-3-acid Ethyl Esters - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  10. 1 2 3 4 5 "Lovaza Label" (PDF). U.S. Food and Drug Administration. 2016. Updated labels available at "Lovaza approval history". U.S. Food and Drug Administration.
  11. 1 2 3 Jacobson TA, Maki KC, Orringer CE, Jones PH, Kris-Etherton P, Sikand G, et al. (NLA Expert Panel) (2015). "National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2". Journal of Clinical Lipidology. 9 (6 Suppl): S1–122.e1. doi: 10.1016/j.jacl.2015.09.002 . PMID   26699442.
  12. 1 2 Weintraub HS (November 2014). "Overview of prescription omega-3 fatty acid products for hypertriglyceridemia". Postgraduate Medicine. 126 (7): 7–18. doi:10.3810/pgm.2014.11.2828. PMID   25387209. S2CID   12524547.
  13. ↑ "Vascepa (icosapent ethyl)". CenterWatch. Retrieved 31 March 2016.
  14. ↑ "Epanova (omega-3-carboxylic acids)". CenterWatch. Archived from the original on 25 December 2014. Retrieved 15 December 2014.
  15. ↑ Food and Drug Administration, Center for Drug Evaluation and Research (2021). Approved Drug Products with Therapeutic Equivalence Evaluations (41 ed.). Food and Drug Administration. p. 830.
  16. ↑ "AstraZeneca to discontinue Epanova trial, expects $100 million writedown". Reuters. 13 January 2020. Retrieved 15 January 2020.
  17. 1 2 Ito MK (December 2015). "A Comparative Overview of Prescription Omega-3 Fatty Acid Products". Pharmacy and Therapeutics. 40 (12): 826–57. PMC   4671468 . PMID   26681905.
  18. ↑ Sweeney ME (14 April 2015). Khardori R (ed.). "Hypertriglyceridemia Pharmacologic Therapy". Medscape Drugs & Diseases.
  19. 1 2 Tam KW, Wu MY, Siddiqui FJ, Chan ES, Zhu Y, Jafar TH, et al. (Cochrane Kidney and Transplant Group) (November 2018). "Omega-3 fatty acids for dialysis vascular access outcomes in patients with chronic kidney disease". The Cochrane Database of Systematic Reviews. 2018 (11): CD011353. doi:10.1002/14651858.CD011353.pub2. PMC   6517057 . PMID   30480758.
  20. 1 2 "Omega-3 ethylester concentrate". Adis Insight. Springer Nature Switzerland AG.
  21. ↑ "170 Year History". Epax. Archived from the original on 23 January 2016. Retrieved 31 March 2016.
  22. ↑ "Pronova wins Omacor approval". Pharma Times. 22 March 2001. Archived from the original on 14 April 2016.
  23. ↑ "Omacor approved". ICIS Chemical Business. 26 March 2001.
  24. ↑ Ernst A (27 November 2007). "German Court Invalidates Omega-3 Drug Patent". Law360.
  25. ↑ VHA Pharmacy Benefits Management Strategic Healthcare Group; Medical Advisory Panel (October 2005). "Omega-3-acid ethyl esters (Lovaza, formerly Omacor)" (PDF). National PBM Drug Monograph.
  26. ↑ "Pronova Biopharma Pharmaceutical Production Facility, Denmark". Pharmaceutical Technology. Retrieved 31 March 2016.
  27. ↑ "GSK to Acquire Reliant Pharmaceuticals for $1.65B". Genetic Engineering News. 21 November 2007.
  28. ↑ U.S. patent 5,656,667
  29. ↑ U.S. patent 5,502,077
  30. ↑ "US District Court rules in Pronova BioPharma's favour on Lovaza(TM) patents". Press Release. Pronova BioPharma. 29 May 2012.
  31. ↑ Davis R (12 September 2013). "Fed. Circ. Nixes Pronova's Patent Win Against Teva, Par". Law360.
  32. ↑ Pronova Biopharma Norge AS v. Teva Pharmaceuticals, Inc, USA and Par Pharmaceutical, Inc. and Par Pharmaceutical Companies, Inc.(United States Court of Appeals for the Federal Circuit 2012-1498, -149912 September 2013), Text .
  33. ↑ Staton T (9 April 2014). "Teva puts GSK and Amarin on notice with generic Lovaza launch". FiercePharmaMarketing.
  34. ↑ McBride R (21 November 2012). "BASF to snap up fish oil drugmaker Pronova BioPharma in $844M buyout". FierceBiotech.
  35. ↑ Palmer E (22 January 2013). "BASF lands Pronova making it a top omega-3 maker". FierceManufacturing.
  36. ↑ "Omega-3-acid Ethyl Esters Brand Name Changed from Omacor to Lovaza". University of Utah Pharmacy Services. 15 August 2007. Archived from the original on 3 March 2016.
  37. ↑ Ito MK (December 2015). "A Comparative Overview of Prescription Omega-3 Fatty Acid Products". P & T. 40 (12): 826–857. PMC   4671468 . PMID   26681905.
  38. ↑ Omtryg Label Revised April 2014
  39. ↑ "Omega-3 acid ethyl esters products". FDA. Retrieved 31 March 2016.
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