OMEGA-3-ACID ETHYL ESTERS

Omega-3-acid ethyl esters, USP, lipid-regulating agents, are supplied as a liquid-filled gel capsule for oral administration. Each 1-gram capsule of omega-3-acid ethyl esters, USP contains at least 900 mg of the ethyl esters of omega-3 fatty acids sourced from fish oils. These are predominantly a combination of ethyl esters of eicosapentaenoic acid (EPA — approximately 465 mg) and docosahexaenoic acid (DHA — approximately 375 mg). The empirical formula of EPA ethyl ester is C 22 H 34 O 2 , and the molecular weight of EPA ethyl ester is 330.51. The structural formula of EPA ethyl ester is: The empirical formula of DHA ethyl ester is C 24 H 36 O 2 , and the molecular weight of DHA ethyl ester is 356.55. The structural formula of DHA ethyl ester is: Omega-3-acid ethyl esters, USP also contain the following inactive ingredients: gelatin, glycerol, and purified water. Chemical Structure Chemical Structure

Omega-3-acid ethyl esters is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (greater than or equal to 500 mg per dL) hypertriglyceridemia (HTG). Omega-3-acid ethyl esters are a combination of ethyl esters of omega 3 fatty acids, principally EPA and DHA, indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia (HTG). ( 1 ) Limitations of Use: The effect of omega-3-acid ethyl esters on the risk for pancreatitis has not been determined. ( 1 ) The effect of omega-3-acid ethyl esters on cardiovascular mortality and morbidity has not been determined. ( 1 ) Usage Considerations: Patients should be placed on an appropriate lipid-lowering diet before receiving omega-3-acid ethyl esters and should continue this diet during treatment with omega-3-acid ethyl esters. Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal before instituting therapy with omega-3-acid ethyl esters. Every attempt should be made to control serum lipids with appropriate diet, exercise, weight loss in obese patients, and control of any medical problems such as diabetes mellitus and hypothyroidism that are contributing to the lipid abnormalities. Medications known to exacerbate hypertriglyceridemia (such as beta blockers, thiazides, estrogens) should be discontinued or changed if possible prior to consideration of triglyceride-lowering drug therapy. Limitations of Use: The effect of omega-3-acid ethyl esters on the risk for pancreatitis has not been determined. The effect of omega-3-acid ethyl esters on cardiovascular mortality and morbidity has not been determined.

Assess triglyceride levels carefully before initiating therapy. Identify other causes (e.g., diabetes mellitus, hypothyroidism, medications) of high triglyceride levels and manage as appropriate [see Indications and Usage (1) ]. Patients should be placed on an appropriate lipid-lowering diet before receiving omega-3-acid ethyl esters, and should continue this diet during treatment with omega-3-acid ethyl esters. In clinical studies, omega-3-acid ethyl esters was administered with meals. The daily dose of omega-3-acid ethyl esters is 4 grams per day. The daily dose may be taken as a single 4-gram dose (4 capsules) or as two 2-gram doses (2 capsules given twice daily). Patients should be advised to swallow omega-3-acid ethyl esters whole. Do not break open, crush, dissolve, or chew omega-3-acid ethyl esters. The daily dose of omega-3-acid ethyl esters is 4 grams per day taken as a single 4-gram dose (4 capsules) or as two 2-gram doses (2 capsules given twice daily). ( 2 ) Patients should be advised to swallow omega-3-acid ethyl esters whole. Do not break open, crush, dissolve, or chew omega-3-acid ethyl esters. ( 2 )

Omega-3-acid ethyl esters are contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to omega-3-acid ethyl esters or any of its components. Omega-3-acid ethyl esters are contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to omega-3-acid ethyl esters or any of its components. ( 4 )

The most common adverse reactions (incidence >3% and greater than placebo) were eructation, dyspepsia, and taste perversion. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact KD Pharma USA at 1-877-241-7978 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions reported in at least 3% and at a greater rate than placebo for subjects treated with omega-3-acid ethyl esters based on pooled data across 23 clinical trials are listed in Table 1. Adverse Reaction Trials included subjects with HTG and severe HTG. Omega-3-acid ethyl esters (n = 655) Placebo (n = 370) n % n % Eructation 29 4 5 1 Dyspepsia 22 3 6 2 Taste perversion 27 4 1 <1 Additional adverse reactions from clinical trials are listed below: Digestive System Constipation, gastrointestinal disorder and vomiting. Metabolic and Nutritional Disorders Increased ALT and increased AST. Skin Pruritus and rash. 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the events described below have been identified during post-approval use of omega-3-acid ethyl esters. Because these events are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or to always establish a causal relationship to drug exposure. The following events have been reported: anaphylactic reaction, hemorrhagic diathesis, urticaria.

Omega-3-acids may prolong bleeding time. Patients taking omega-3-acid ethyl esters and an anticoagulant or other drug affecting coagulation (e.g., anti-platelet agents) should be monitored periodically. ( 7.1 ) 7.1 Anticoagulants or Other Drugs Affecting Coagulation Some trials with omega-3-acids demonstrated prolongation of bleeding time. The prolongation of bleeding time reported in these trials has not exceeded normal limits and did not produce clinically significant bleeding episodes. Clinical trials have not been done to thoroughly examine the effect of omega-3-acid ethyl esters and concomitant anticoagulants. Patients receiving treatment with omega-3-acid ethyl esters and an anticoagulant or other drug affecting coagulation (e.g., anti-platelet agents) should be monitored periodically.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Do not freeze. Keep out of reach of children.