Omega-3 acid ethyl esters are the omega-3 fatty acidseicosapentaenoic acid and docosahexaenoic acid found in fish oil. Together with dietary changes, they are used to treat high blood triglycerides which may reduce the risk of pancreatitis. 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. Omega-3 acid ethyl esters are taken by mouth. Common side effects include burping, nausea, and an upset abdomen. Serious side effects may include liver problems and anaphylaxis. While use in pregnancy has not been well studied, some omega-3 fatty acids appear beneficial. How it works is not entirely clear. Omega-3 acid ethyl ester medicines were approved for medical use in the European Union in 2000, and in the United States in 2004. It is available as a generic medication and over the counter. A one-month supply in the United Kingdom costs the NHS about £6 as of 2019. In the United States the wholesale cost of this amount is about 7.50 USD. In 2017, it was the 158th most commonly prescribed medication in the United States, with more than three million prescriptions.
Medical use
Omega-3 acid ethyl esters are used in addition to changes in diet to reduce triglyceride levels in adults with severe hypertriglyceridemia. 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. Intake of large doses of long-chain omega-3 fatty acids as prescription drugs or dietary supplements are generally required to achieve significant lowering of triglycerides, and at those doses the effects can be significant. It appears that both eicosapentaenoic acid and docosahexaenoic acid lower triglycerides, but DHA appears to raise LDL-C more than EPA, while DHA raises HDL-C while EPA does not.
Other fish-oil based drugs
There are other omega-3 fish oil based prescription drugs on the market that have similar uses and mechanisms of action.
There are many fish oil dietary supplements on the market. 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. 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. Prescription omega-3 products are more concentrated, requiring fewer softgels for the same daily dose.
Side effects
Special caution should be taken with people who have fish and shellfish allergies. 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. Side effects include stomach ache, burping, and a bad taste; some people on very high doses in clinical trials had atrial fibrillation. 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.
Pharmacology
After ingestion, omega-3 acid ethyl esters are metabolized mostly in the liver like other dietary fatty acids.
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 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. The synthesis of triglycerides is reduced in the liver as EPA and DHA are poor substrates for the enzymes responsible for triglyceride synthesis.
Pronova BioPharma ASA had its roots in Norway's codfish liver oil industry; it was founded in 1991 as a spinout from the JC Martens company, which in turn was founded in 1838 in Bergen, Norway. Pronova developed the concentrated omega-3 acid ethyl esters formulation that is the active pharmaceutical ingredient of Lovaza. It won approvals to market the drug, called Omacor in Europe in several European countries in 2001 after conducting a three and a half year trial in 11,000 subjects; it partnered with other companies like Pierre Fabre in France. In 2004 Pronova licensed the US and Puerto Rican rights to Reliant Therapeutics, the business model of which was in-licensing cardiovascular drugs. In that same year, Reliant and Pronova won FDA approval for the drug and it was launched in the US and Europe in 2005; global sales in 2005 were $144M and by 2008 they were $778M. In 2007 GlaxoSmithKline acquired Reliant for $1.65 billion in cash. In 2009 generic companies Teva Pharmaceuticals and Par Pharmaceutical made clear their intentions to file Abbreviated New Drug Applications to bring generics to market, and in April 2009 Pronova sued them from infringing the key US patents covering Lovaza, US 5,656,667 US 5,502,077 and in May 2012 a district court ruled in Pronova's favor, saying that the patents were valid. 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, and this constituted "public use" that made the patent invalid. Generic versions of Lovaza were introduced in America in April 2014. Pronovo has continued to manufacture the ingredients in Lovaza, and in 2012 BASF announced it would acquire Pronova for $844 million, and the deal closed in 2013.
Brand names
Lovaza, sold by GlaxoSmithKline in the US; created and manufactured by Pronova It was approved in the United States in 2004.
Omtryg is another brand of omega-3 acid ethyl esters developed by Trygg Pharma, Inc. and approved by the FDA in 2004.
As of March 2016 there were four additional generic versions.
