Omega-3-Acid Ethyl Esters Capsules

Overview of Omega-3-Acid Ethyl Esters Capsules

Dosage Strengths of Omega-3-Acid Ethyl Esters Capsules

Omega-3-Acid Ethyl Esters Capsules: 1,000 mg †

General Information

Fish oil, omega-3 fatty acids are mixtures of ethyl esters or free fatty acids derived from fish oil primarily composed of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These products are FDA approved as an adjunct to diet to reduce triglyceride levels in adult patients with severe (500 mg/dl or greater) hypertriglyceridemia. The effect of fish oil, omega-3 fatty acids on the risk for pancreatitis or on cardiovascular morbidity and mortality has not been established. Results from a multicenter, randomized, double-blind, placebo-controlled, parallel-group study of 254 adults with hypertriglyceridemia indicate simvastatin combined with the fish oil product Lovaza provides greater benefit to the lipid profile than simvastatin alone.1 The prescription-only formulation of fish oil, omega-3 fatty acids was FDA-approved in November 2004.

Mechanism of Action

The mechanism of action of fish oil, omega-3 fatty acids for the treatment of hypertriglyceridemia is not completely understood. Omega-3 fatty acids reduce the hepatic production of triglyceride (TG)-rich very-low-density lipoproteins and may increase the removal rate of TG-rich lipoproteins by increasing lipoprotein lipase activity. Inhibition of acyl-CoA:1,2-diacylglycerol acyltransferase, increased mitochondrial and hepatic peroxisomal beta-oxidation, decreased hepatic lipogenesis, and increased plasma lipoprotein lipase activity are potential mechanisms of action.234

Pharmacokinetics

Fish oil, omega-3 fatty acids is administered orally. When administered as ethyl esters, omega-3 fatty acids induce significant, dose-dependent increases in serum phospholipid eicosapentaenoic acid (EPA) content. Increases in docosahexaenoic acid (DHA) content were less marked and not dose-dependent when administered as ethyl esters.25 Following repeat dosing of omega-3 carboxylic acids under low-fat meal conditions for approximately 2 weeks, maximum plasma concentrations are achieved 5 to 8 hours after dosing for total EPA and between 5 to 9 hours after dosing for total DHA. Steady-state concentrations of EPA and DHA in plasma are achieved within 2 weeks of repeat daily dosing with omega-3 carboxylic acids. EPA and DHA from omega-3 carboxylic acids are mainly oxidized in the liver similar to fatty acids derived from dietary sources.3

Affected cytochrome P450 isoenzymes: none

While omega-3-fatty acid containing products have shown increased hepatic concentrations of CYP450 and activities of certain CYP450 isoenzymes in rats, the potential to induce CYP450 activities in humans has not been studied. However, the free forms of the EPA and DHA are typically undetectable in human circulation. Clinically significant interactions of fish oil, omega-3 fatty acids with other drugs due to inhibition or induction of CYP450 mediated metabolism are not expected.253

Route-Specific Pharmacokinetics

Oral Route

Lovaza: Lovaza was administered with meals in clinical trials.2

Omtryg: Administration of Omtryg under fasted condition in clinical trials resulted in decreases in the peak (Cmax) and total (AUC_0-72h) exposure by up to 20 to 80-fold, respectively, for total plasma EPA and by up to 2 to 4-fold, respectively, for total plasma DHA, in comparison to those observed under fed condition (high-fat high-calorie meal).5

Epanova: Epanova was administered without regard to meals in clinical trials. Administration of a single dose of Epanova with a high-fat meal increased the overall exposure of total and free baseline-adjusted EPA by approximately 140% and 80%, respectively, compared to fasting conditions. There was no change in overall exposure of baseline-adjusted total DHA; however, there was a 40% increase in AUC for baseline-adjusted free DHA. Overall exposures of unadjusted total and free EPA increased by 80% and 50%, respectively, although there was no change in overall exposure for unadjusted total and free DHA.3

Contraindications/Precautions

Fish oil, omega-3-fatty acids are contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to fish oil, omega-3-fatty acids or any of its components. Use with caution in patients with known fish hypersensitivity. These products are derived from fish oils. It is not known whether patients with allergies to fish and/or shellfish are at increased risk of an allergic reaction.253

Because fish oil, omega-3 fatty acids may increase LDL or total serum cholesterol, they should be used cautiously in patients with hypercholesterolemia or mixed dyslipidemias. As with any lipid-regulating product, LDL-C levels should be monitored periodically.253

Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulant therapy, thrombolytic therapy, or anti-platelet therapy. Theoretically, the risk of bleeding may be increased, but some studies have not shown clinically significant bleeding events with concurrent use. Periodically monitor patients receiving concurrent therapy with fish oils and drugs affecting coagulation for bleeding.253

A possible association exists between omega-3-acid ethyl esters and more frequent recurrences of symptomatic atrial fibrillation (AF) or atrial flutter in patients with paroxysmal or persistent AF, particularly within the first 2—3 months of initiating therapy. The clinical significance is uncertain.25

Use fish oil, omega-3 fatty acids during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is unknown whether fish oil, omega-3 fatty acids can cause fetal harm or affect reproductive capacity. A 20% reduction in live births and 40% reduction in pup survival to postnatal day 4 were observed following oral administration of fish oil, omega-3 fatty acid to pregnant rats at doses 7-times the maximum recommended human dose (MRHD).2

Use fish oil, omega-3 fatty acids with caution in breastfeeding mothers. Studies demonstrate excretion in human milk; however, the effect of this excretion on the infant is unknown. An animal study in lactating rates demonstrated drug concentrations were 6- to 14-times higher in milk than in plasma.2

Pregnancy

Use fish oil, omega-3 fatty acids during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is unknown whether fish oil, omega-3 fatty acids can cause fetal harm or affect reproductive capacity. A 20% reduction in live births and 40% reduction in pup survival to postnatal day 4 were observed following oral administration of fish oil, omega-3 fatty acid to pregnant rats at doses 7-times the maximum recommended human dose (MRHD).2

Breastfeeding

Use fish oil, omega-3 fatty acids with caution in breast-feeding mothers. Studies demonstrate excretion in human milk; however, the effect of this excretion on the infant is unknown. An animal study in lactating rates demonstrated drug concentrations were 6- to 14-times higher in milk than in plasma.2

Adverse Reactions/Side Effects

Gastrointestinal-related adverse reactions reported during clinical trials of fish oil, omega-3 fatty acids compared to placebo include: eructation (3% to 4% vs. <= 1%), dyspepsia (3% vs. 2%), dysgeusia (4% vs. < 1%), diarrhea (7% to 15% vs. 2%), nausea (4% to 6% vs. 1%), and abdominal pain or discomfort (3% to 5% vs. 2%). Other gastrointestinal-related adverse reactions reported in clinical trials included constipation, gastrointestinal disorder, vomiting, and abdominal distension.253

Prolonged bleeding time has been reported in some clinical trials of fish oil, omega-3 fatty acids.6 The prolongation of bleeding time reported in selected studies has not exceeded normal limits and did not produce clinically significant bleeding episodes; however, patients should report minor bleeding such as nosebleeds (epistaxis) or bruising (ecchymosis) to their health care professional for evaluation. Theoretically, the risk of such bleeding may be increased with the concurrent use of other drugs (e.g., anticoagulants or platelet inhibitors) known to increase bleeding risk; however, some studies have not reported clinically significant bleeding events with the concurrent administration of fish oils. Although bleeding or prolongation of bleeding time were not reported in clinical trials of omega-3-acid ethyl esters, post-marketing reports of hemorrhagic diathesis (i.e., coagulopathy) have been reported.253

Fish oil, omega-3 fatty acids may increase total cholesterol levels or LDL and aggravate hypercholesterolemia in those patients with a combined hyperlipidemia. As with any lipid-regulating product, LDL-C levels should be monitored periodically. In some patients, elevated hepatic enzymes (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)) have been observed. ALT and AST concentrations should be monitored periodically during therapy.7253

Allergic reactions appear rare, but pruritus and skin rash (unspecified) have been observed in some patients; skin rash occurred in roughly 1.8% of patients in clinical trials. In addition, anaphylactoid reactions and urticaria have been reported in post-marketing surveillance reports.82

Among patients with paroxysmal atrial fibrillation (AF) without substantial structural heart disease and who were in normal sinus rhythm without antiarrhythmic therapy except potential rate control, first recurrence of symptomatic AF or flutter events was reported more frequently in omega-3-acid ethyl esters recipients (53%) compared with placebo recipients (47%) (HR 1.19; 95% CI 0.93 to 1.35). Similar findings were noted among patients with persistent AF (52% with omega-3-acid ethyl esters vs. 35% with placebo) (HR 1.63; 95% CI 0.91 to 2.18). Although the clinical significance of these findings is uncertain, a possible association exists between omega-3-acid ethyl esters and more frequent recurrences of symptomatic AF or atrial flutter in patients with paroxysmal or persistent AF, particularly within the first 2 to 3 months of initiating therapy.2

Other adverse reactions reported more frequently with fish oil, omega-3 fatty acids than placebo in clinical trials include naso-pharyngitis, fatigue, and arthralgia.3

Storage

Store this medication in its original container at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

• 1. Davidson MH, Stein AA, Bays HE, et al. Efficacy and tolerability of adding prescription Omega-3 Fatty Acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study.  The NDA for the prescription-only formulation was submitted in 2000 after the use of this proprietary product in the GISSI-Prevention trial, which found significant reductions in the risk of total death (14%) and cardiovascular death (17%) in patients receiving n-3 polyunsaturated fatty acids (PUFA).Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999;354:447-455.
• 2. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. Lovaza (omega-3 acid ethyl esters, also known as fish oil, omega-3 fatty acids) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2020 Sep.
• 3. a. b. c. d. e. f. g. h. i. j. k. Epanova (omega-3-carboxylic acids) package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017 Mar.
• 4. Bays HE, Tighe AP, Sadovsky R, et al. Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications. Expert Rev Cardiovasc Ther. 2008;6:391-409.
• 5. a. b. c. d. e. f. g. h. i. j. Omtryg (omega-3-acid ethyl esters A) package insert. Arlington, VA: Trygg Pharma Inc.; 2016 Mar.
• 6. Schoene NW. Vitamin E and omega-3 fatty acids: effectors of platelet responsiveness. Nutrition 2001;17:793-6.
• 7. Kris-Etherton PM, Harris WS, Appel LJ for the American Heart Association Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002;106:2747-57. Erratum published: Circulation 2003;107:512.
• 8. Lovaza (omega-3 acid ethyl esters, also known as fish oil, omega-3 fatty acids) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2008 Jun.