Omega-3-Acid Ethyl Esters

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.

In patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored periodically during therapy with omega-3-acid ethyl esters. In some patients, increases in ALT levels without a concurrent increase in AST levels were observed.

In some patients, omega-3-acid ethyl esters increases LDL-C levels. LDL-C levels should be monitored periodically during therapy with omega-3-acid ethyl esters.

Laboratory studies should be performed periodically to measure the patient's TG levels during therapy with omega-3-acid ethyl esters.

Omega-3-acid ethyl esters contain ethyl esters of omega-3 fatty acids (EPA and DHA) obtained from the oil of several fish sources. It is not known whether patients with allergies to fish and/or shellfish, are at increased risk of an allergic reaction to omega-3-acid ethyl esters. Omega-3-acid ethyl esters should be used with caution in patients with known hypersensitivity to fish and/or shellfish.

In a double-blind, placebo-controlled trial of 663 subjects with symptomatic paroxysmal AF (n = 542) or persistent AF (n = 121), recurrent AF or flutter was observed in subjects randomized to omega-3-acid ethyl esters who received 8 grams per day for 7 days and 4 grams per day thereafter for 23 weeks at a higher rate relative to placebo. Subjects in this trial had median baseline triglycerides of 127 mg per dL, had no substantial structural heart disease, were taking no anti-arrhythmic therapy (rate control permitted), and were in normal sinus rhythm at baseline.

At 24 weeks, in the paroxysmal AF stratum, there were 129 (47%) first recurrent symptomatic AF or flutter events on placebo and 141 (53%) on omega-3-acid ethyl esters [primary endpoint, HR 1.19; 95% CI: 0.93, 1.35]. In the persistent AF stratum, there were 19 (35%) events on placebo and 34 (52%) events on omega-3-acid ethyl esters [HR 1.63; 95% CI: 0.91, 2.18]. For both strata combined, the HR was 1.25; 95% CI: 1.00, 1.40. Although the clinical significance of these results is uncertain, there is a possible association between omega-3-acid ethyl esters and more frequent recurrences of symptomatic atrial fibrillation or flutter in patients with paroxysmal or persistent atrial fibrillation, particularly within the first 2 or 3 months of initiating therapy.

Omega-3-acid ethyl esters are not indicated for the treatment of AF or flutter.

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% of subjects treated with Omega-3-acid ethyl esters and at with omega-3-acid ethyl esters based on pooled data across 23 clinical trials are listed in Table 1.

Additional adverse reactions from clinical trials are listed below:

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.

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.

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.

Safety and effectiveness in pediatric patients have not been established.

A limited number of subjects older than 65 years were enrolled in the clinical trials of omega-3-acid ethyl esters. Safety and efficacy findings in subjects older than 60 years did not appear to differ from those of subjects younger than 60 years.

The mechanism of action of omega-3-acid ethyl esters is not completely understood. Potential mechanisms of action include inhibition of acyl-CoA:1,2-diacylglycerol acyltransferase, increased mitochondrial and peroxisomal β-oxidation in the liver, decreased lipogenesis in the liver, and increased plasma lipoprotein lipase activity. Omega-3-acid ethyl esters may reduce the synthesis of triglycerides in the liver because EPA and DHA are poor substrates for the enzymes responsible for TG synthesis, and EPA and DHA inhibit esterification of other fatty acids.

In a rat carcinogenicity study with oral gavage doses of 100, 600, and 2,000 mg per kg per day, males were treated with omega-3-acid ethyl esters for 101 weeks and females for 89 weeks without an increased incidence of tumors (up to 5 times human systemic exposures following an oral dose of 4 grams per day based on a body surface area comparison). Standard lifetime carcinogenicity bioassays were not conducted in mice.

Omega-3-acid ethyl esters were not mutagenic or clastogenic with or without metabolic activation in the bacterial mutagenesis (Ames) test with Salmonella typhimurium and Escherichia coli or in the chromosomal aberration assay in Chinese hamster V79 lung cells or human lymphocytes. Omega-3-acid ethyl esters were negative in the in vivo mouse micronucleus assay.

In a rat fertility study with oral gavage doses of 100, 600, and 2,000 mg per kg per day, males were treated for 10 weeks prior to mating and females were treated for 2 weeks prior to and throughout mating, gestation, and lactation. No adverse effect on fertility was observed at 2,000 mg per kg per day (5 times human systemic exposure following an oral dose of 4 grams per day based on a body surface area comparison).

The effects of omega-3-acid ethyl esters 4 grams per day were assessed in 2 randomized, placebo-controlled, doubleblind, parallel-group trials of 84 adult subjects (42 on omega-3-acid ethyl esters, 42 on placebo) with very high triglyceride levels. Subjects whose baseline triglyceride levels were between 500 and 2,000 mg per dL were enrolled in these 2 trials of 6 and 16 weeks' duration. The median triglyceride and LDL-C levels in these subjects were 792 mg per dL and 100 mg per dL, respectively. Median high-density lipoprotein cholesterol (HDL-C) level was 23.0 mg per dL.

The changes in the major lipoprotein lipid parameters for the groups receiving omega-3-acid ethyl esters or placebo are shown in Table 2.

Omega-3-acid ethyl esters 4 grams per day reduced median TG, VLDL-C, and non-HDL-C levels and increased median HDL-C from baseline relative to placebo. Treatment with omega-3-acid ethyl esters to reduce very high TG levels may result in elevations in LDL-C and non-HDL-C in some individuals. Patients should be monitored to ensure that the LDL-C level does not increase excessively.

The effect of omega-3-acid ethyl esters on the risk of pancreatitis has not been determined.

The effect of omega-3-acid ethyl esters on cardiovascular mortality and morbidity has not been determined.

Store at 20°-25°C (68°-77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Do not freeze. Protect from light. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Information for Patients:

• Omega-3-acid ethyl esters should be used with caution in patients with known sensitivity or allergy to fish and/or shellfish [see Warnings and Precautions (5.2)].
• Advise patients that use of lipid-regulating agents does not reduce the importance of adhering to diet [see Dosage and Administration (2)].
• Advise patients not to alter omega-3-acid ethyl esters in any way and to ingest intact capsules only [see Dosage and Administration (2)].
• Instruct patients to take omega-3-acid ethyl esters as prescribed. If a dose is missed, advise patients to take it as soon as they remember. However, if they miss one day of omega-3-acid ethyl esters, they should not double the dose when they take it.