Omega-3 carboxylic acids
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Omega-3 carboxylic acids (Epanova) is a formerly-marketed yet still
FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
approved prescription medication–since taken off market by the manufacturer–used alongside a
low fat Diet food (or dietetic food) refers to any food or beverage whose recipe is altered to reduce fat, carbohydrates, and/or sugar in order to make it part of a weight loss program or diet. Such foods are usually intended to assist in weight loss or ...
and low cholesterol diet that lowers high
triglyceride A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''wikt:tri-#Prefix, tri-'' and ''glyceride''). Triglycerides are the main constituents of body fat in humans and other ...
(fat) levels in adults with very high levels. This was the third class of
fish oil 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 b ...
-based drug, after omega-3 acid ethyl esters (Lovaza and Omtryg) and
ethyl eicosapentaenoic acid Ethyl eicosapentaenoic acid (E-EPA, icosapent ethyl), 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 hypertrigly ...
(Vascepa), to be approved for use as a drug. The first approval by US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
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. Following phase III clinical trial in mixed dyslipidaemia,
AstraZeneca AstraZeneca plc () is a British-Swedish multinational pharmaceutical and biotechnology company with its headquarters at the Cambridge Biomedical Campus in Cambridge, England. It has a portfolio of products for major diseases in areas includi ...
announced on 13 January 2019 that their clinical trials were terminated for futility because no medical benefit of the medication could be found.


Medical uses

Omega-3 carboxylic acids are used in addition to changes in diet to reduce
triglyceride A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''wikt:tri-#Prefix, tri-'' and ''glyceride''). Triglycerides are the main constituents of body fat in humans and other ...
levels in adults with severe (≥ 500 mg/dL)
hypertriglyceridemia 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 ...
.Epanova label
Revised: May, 2014. Updates can be found at FDA label pag
here
/ref> 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. However, DHA appears to raise
LDL cholesterol Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall dens ...
more than EPA, and further, DHA raises
HDL cholesterol High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are t ...
while EPA does not.


Other fish-oil based drugs

There are other omega-3 fish oil based drugs on the market that have similar uses and mechanisms of action. * Omega-3 acid ethyl esters (brand names Omarcor or Lovaza, Omtryg, and as of March 2016, four generic versions).FDA Omega-3 acid ethyl esters products
Page accessed March 31, 2016
*
Ethyl eicosapentaenoic acid Ethyl eicosapentaenoic acid (E-EPA, icosapent ethyl), 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 hypertrigly ...
(Vascepa, and 1 generic as ethyl icosapent)


Dietary supplements

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. Importantly, EPA and DHA ethyl esters (prescription forms) work better when taken with a mildly-fattening meal of about 350 calories. The ingredients of dietary supplements are not as carefully controlled as prescription products and have not been fixed and tested in clinical trials, as prescription drugs have.Sweeney MET
Hypertriglyceridemia Pharmacologic Therapy
for Medscape Drugs & Diseases, Ed. Khardori R. Updated: Apr 14, 2015, page accessed April 1, 2016
Furthermore, the prescription forms are more concentrated, requiring fewer capsules to be taken and increasing the likelihood of compliance.


Side effects

Special caution should be taken with people who have with fish and shellfish allergies. In addition, as with other omega-3 fatty acids, taking omega-3 carboxylic acids puts people who are on
anticoagulants Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where they ...
at risk for prolonged
bleeding time Bleeding time is a medical test done on someone to assess their platelets function. It involves making a patient bleed, then timing how long it takes for them to stop bleeding using a stopwatch or other suitable devices. The term template bleedin ...
. Side effects include
diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...
,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
,
abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a m ...
, and burping. Omega-3 carboxylic acids have not been tested in pregnant women and are rated pregnancy category C because it is excreted in breast milk and the effects on infants are not known.


Pharmacology

Omega-3 carboxylic acids are directly absorbed in the small intestine. Maximum plasma concentrations are achieved between 5–8 hours after dosing for total EPA and between 5–9 hours after dosing for total DHA. Both DHA and EPA are metabolized primarily in the liver, just like other fatty acids derived from food. The half-life of EPA from Omega-3 carboxylic acids is about 37 hours. For DHA, the half-life is about 46 hours.


Mechanism of action

Omega-3 carboxylic acids, 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 Very-low-density lipoprotein (VLDL), density relative to extracellular water, is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins ( chylomicrons, VLDL, intermediate-density lipoprotein, low-density l ...
(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 Lipoprotein lipase (LPL) (EC 3.1.1.34, systematic name triacylglycerol acylhydrolase (lipoprotein-dependent)) is a member of the lipase gene family, which includes pancreatic lipase, hepatic lipase, and endothelial lipase. It is a water-solubl ...
in blood.


Physical and chemical properties

Omega-3 carboxylic acids are derived from
fish oil 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 b ...
and are a purified mixture of the polyunsaturated free fatty acids
docosahexaenoic acid Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, and retina. In physiological literature, it is given the name 22:6(n-3). It can be synthesized from alpha-lin ...
(DHA) and
eicosapentaenoic acid Eicosapentaenoic acid (EPA; also icosapentaenoic 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-c ...
(EPA). The drug contains a concentration of DHA at 15–25% and a concentration of EPA at 50–60%.


History

Omega-3 carboxylic acids was approved by the US FDA in May 2014, and such formulation(s) was the third prescription form of an
omega-3 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 chem ...
product approved in the
United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territori ...
. A notable difference is that the carboxylic acid treatment was the first approved in free fatty acid form. Development was completed and regulatory approval was obtained by
AstraZeneca AstraZeneca plc () is a British-Swedish multinational pharmaceutical and biotechnology company with its headquarters at the Cambridge Biomedical Campus in Cambridge, England. It has a portfolio of products for major diseases in areas includi ...
, but omega-3 carboxylic acids were first created at Chrysalis Pharma in Switzerland. Later, Princeton-based Omthera obtained rights from Chysalis, and Astrazeneca acquired Omthera in 2013 for $323 million in cash along with up to $120 million in milestones.John Carroll for FierceBiotech.May 6, 2014.
AstraZeneca wins FDA OK for another fish-oil heart pill, enters crowded market
/ref> At the time Epanova was approved, AstraZeneca's plan was to develop a combination product with
rosuvastatin Rosuvastatin, sold under the brand name Crestor among others, is a statin medication, used to prevent cardiovascular disease in those at high risk and treat abnormal lipids. It is recommended to be used together with dietary changes, exercise, ...
, the patent on which was set to expire in 2016. Clinical trials of Epanova for severe hypertriglyceridemia showed good results. However, a clinical trial on mixed dyslipidaemia (hypertriglyceridemia with hypocholesterolemia) was started on 30 October 2014, which was terminated after Phase III clinical trials, on 13 January 2019, due to lack of medical benefit in the results.


References

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External links


AstraZeneca-US Official website
Fatty acids Dietary supplements Fish products AstraZeneca brands Drugs acting on the cardiovascular system Hypolipidemic agents Discontinued products