Omega-3-Acid Ethyl Esters

Description

11 DESCRIPTION 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

What Is Omega-3-Acid Ethyl Esters Used For?

1 INDICATIONS AND USAGE 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.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION 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 )

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS 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.

Drug Interactions

7 DRUG INTERACTIONS 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.

Contraindications

4 CONTRAINDICATIONS 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 )

Pregnancy and Breastfeeding

8.1 Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. It is unknown whether omega-3-acid ethyl esters can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.Omega-3-acid ethyl esters should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus. Animal Data Omega-3-acid ethyl esters have been shown to have an embryocidal effect in pregnant rats when given in doses resulting in exposures 7 times the recommended human dose of 4 grams per day based on a body surface area comparison. In female rats given oral gavage doses of 100, 600, and 2,000 mg per kg per day beginning 2 weeks prior to mating and continuing through gestation and lactation, no adverse effects were observed in the high-dose group (5 times human systemic exposure following an oral dose of 4 grams per day based on body surface area comparison). In pregnant rats given oral gavage doses of 1,000, 3,000, and 6,000 mg per kg per day from gestation Day 6 through 15, no adverse effects were observed (14 times human systemic exposure following an oral dose of 4 grams per day based on a body surface area comparison). In pregnant rats given oral gavage doses of 100, 600, and 2,000 mg per kg per day from gestation Day 14 through lactation Day 21, no adverse effects were seen at 2,000 mg per kg per day (5 times the human systemic exposure following an oral dose of 4 grams per day based on a body surface area comparison). However, decreased live births (20% reduction) and decreased survival to postnatal Day 4 (40% reduction) were observed in a dose-ranging study using higher doses of 3,000 mg per kg per day (7 times the human systemic exposure following an oral dose of 4 grams per day based on a body surface area comparison). In pregnant rabbits given oral gavage doses of 375, 750, and 1,500 mg per kg per day from gestation Day 7 through 19, no findings were observed in...

8.3 Nursing Mothers Studies with omega-3-acid ethyl esters have demonstrated excretion in human milk. The effect of this excretion on the infant of a nursing mother is unknown; caution should be exercised when omega-3-acid ethyl esters are administered to a nursing mother. An animal study in lactating rats given oral gavage 14C-ethyl EPA demonstrated that drug levels were 6 to 14 times higher in milk than in plasma.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Omega-3-acid ethyl esters, USP are supplied as 1-gram oblong, transparent soft gelatin capsules filled with light yellowish oil printed with "O3" in white ink across one side. Bottles of 120: NDC 72998-850-12 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.