Omega-3 acid ethyl esters are the omega-3 fatty acids eicosapentaenoic
acid (EPA) and docosahexaenoic acid (DHA), i.e., the ester part,
attached at one end to an ethanol molecule - the ethyl part. These
FDA-approved prescription products are used in combination with
changes in diet to lower blood triglyceride levels in adults with
severe (≥ 500 mg/dL) hypertriglyceridemia. This was the first
fish oil-derived product to be approved for use as a drug. The first
approvals came in Europe in 2001. The first approval in the US came in
2004. These prescription products have been tested in clinical trials.
In the US, omega-3 ethyl esters are also manufactured and sold as
1 Medical use
1.1 Other fish-oil based drugs
1.2 Dietary supplements
2 Side effects
4 Mechanism of action
5 Physical and chemical properties
7 Brand names
9 External links
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. In the European markets and other major
markets outside the US, omega-3 acid ethyl esters are indicated for
hypertriglyceridemia as a monotherapy, or in combination with a statin
for patients with mixed dyslipidemia and as secondary prevention after
heart attack in addition to other standard therapy (e.g. statins,
anticoagulants, beta-blockers, and ACE-I).
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 that
500 mg/dL). It appears that both eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA) lower triglycerides, but DHA appears to
LDL-C ("bad cholesterol") more than EPA, while DHA raises HDL-C
("good cholesterol") 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.
Ethyl eicosapentaenoic acid
Ethyl eicosapentaenoic acid (Vascepa). EPA-only ethyl esters.
Omega-3 carboxylic acids (Epanova). This product contains free fatty
acids, not ethyl esters.
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.
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 (8g/day) in clinical trials had atrial
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.
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 (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. They may interfere with lipid
production due to being poor substrates for the enzymes that create
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, 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).
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 (and
initially in the US) 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 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 (due to
expire in April 2017) US 5,502,077 (exp March 2013) 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
BASF announced it would acquire Pronova for $844 million, and
the deal closed in 2013.
Lovaza (US)/Omacor Europe), sold by
GlaxoSmithKline in the US; created
and manufactured by Pronova
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.
^ a b c d e Lovaza Label Revised: March 2016. Updated labels available
at FDA website here
^ a b c d UK electronic Medicines Compendium (eMC) Omacor. Last
Updated on eMC 20-Apr-2015
^ a b c Jacobson TA, et al, NLA Expert Panel. National Lipid
Association Recommendations for Patient-Centered Management of
Dyslipidemia: Part 2. J Clin Lipidol. 2015 Nov-Dec;9(6
Suppl):S1-S122.e1. PMID 26699442 Free full text
^ a b Weintraub, HS (2014). "Overview of prescription omega-3 fatty
acid products for hypertriglyceridemia". Postgrad Med. 126: 7–18.
doi:10.3810/pgm.2014.11.2828. PMID 25387209. Archived from the
original on 20 April 2015. Retrieved 20 April 2015.
^ CenterWatch Vascepa (icosapent ethyl) Page accessed March 31, 2016
^ "Epanova (omega-3-carboxylic acids)". CenterWatch. Retrieved 15
^ a b Ito MK. A Comparative Overview of Prescription Omega-3 Fatty
Acid Products. P T. 2015 Dec;40(12):826-57. PMID 26681905 Free
PMC Article PMC 4671468
^ Sweeney MET.
Hypertriglyceridemia Pharmacologic Therapy for Medscape
Drugs & Diseases, Ed. Khardori R. Updated: Apr 14, 2015, page
accessed April 1, 2016
^ a b Adis Insight Omega-3 ethylester concentrate Page accessed March
^ Epax History Page accessed March 31, 2016
^ Pharma Times. March 22, 2001. Pronova wins Omacor approval
^ Staff, ICIS Chemical Business. 26 March 2001 Omacor approved
^ Amanda Ernst for Law360 November 27, 2007 German Court Invalidates
Omega-3 Drug Patent
^ VHA Pharmacy Benefits Management Strategic Healthcare Group and the
Medical Advisory Panel. October 2005 National PBM Drug Monograph
Omega-3-acid ethyl esters (Lovaza, formerly Omacor)
^ Staff, Pharmaceutical Technology. Pronova Biopharma Pharmaceutical
Production Facility, Denmark. Page accessed March 31, 2016
^ Staff, Genetic Engineering News. Nov 21, 2007. GSK to Acquire
Reliant Pharmaceuticals for $1.65B
^ U.S. Patent 5,656,667
^ U.S. Patent 5,502,077
^ Pronova BioPharma May 29, 2012 Press Release: US District Court
rules in Pronova BioPharma's favour on Lovaza(TM) patents
^ Ryan Davis for Law360 September 12, 2013 Fed. Circ. Nixes Pronova's
Patent Win Against Teva, Par
^ United States Court of Appeals for the Federal Circuit. Pronova
Biopharma Norge AS vs Teva Pharmaceuticals, Inc and Par
Pharmaceutical. 2012-1498, -1499. Decided September 12, 2013 Federal
^ Tracy Staton for FiercePharmaMarketing April 9, 2014 Teva puts GSK
and Amarin on notice with generic Lovaza launch
^ Ryan McBride for FierceBiotech. November 21, 2012
BASF to snap up
fish oil drugmaker Pronova BioPharma in $844M buyout
^ Eric Palmer for FierceManufacturing. January 22, 2013
Pronova making it a top omega-3 maker
^ University of Utah Pharmacy Services (August 15, 2007) "Omega-3-acid
Ethyl Esters Brand Name Changed from Omacor to Lovaza" Archived March
3, 2016, at the Wayback Machine.
^ Omtryg Label Revised April 2014
Omega-3 acid ethyl esters products Page accessed March 31, 2016
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