5.1 Monitoring: Laboratory Tests

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 low-density lipoprotein cholesterol (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.

5.2 Fish Allergy

Omega-3-acid ethyl esters contains 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.

5.3 Recurrent Atrial Fibrillation (AF) or Flutter

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/day for 7 days and 4 grams/day thereafter for 23 weeks at a higher rate relative to placebo. Subjects in this trial had median baseline TG levels of 127 mg/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 AF or flutter in patients with paroxysmal or persistent AF, particularly within the first 2 to 3 months of initiating therapy.

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

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% of subjects treated with omega-3-acid ethyl esters and at a greater rate than placebo based on pooled data across 23 clinical trials are listed in Table 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.

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.

8.1 Pregnancy

Risk Summary

The available data from published case reports and the pharmacovigilance database on the use of omega-3-acid ethyl esters in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, omega-3-acid ethyl esters given orally to female rats prior to mating through lactation did not have adverse effects on reproduction or development when given at doses 5 times the maximum recommended human dose (MRHD) of 4 grams/day, based on a body surface area comparison. Omega-3-acid ethyl esters given orally to rats and rabbits during organogenesis was not teratogenic at clinically relevant exposures, based on body surface area comparison (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data:In female rats given oral doses of omega-3-acid ethyl esters (100, 600, or 2,000 mg/kg/day) beginning 2 weeks prior to mating through lactation, no adverse effects were observed at 2,000 mg/kg/day (5 times the MRHD based on body surface area [mg/m 2]). In a dose-ranging study, female rats given oral doses of omega-3-acid ethyl esters (1,000, 3,000, or 6,000 mg/kg/day) beginning 2 weeks prior to mating through Postpartum Day 7 had decreased live births (20% reduction) and pup survival to Postnatal Day 4 (40% reduction) at or greater than 3,000 mg/kg/day in the absence of maternal toxicity at 3,000 mg/kg/day (7 times the MRHD based on body surface area [mg/m 2]).

In pregnant rats given oral doses of omega-3-acid ethyl esters (1,000, 3,000, or 6,000 mg/kg/day) during organogenesis, no adverse effects were observed in fetuses at a maternally toxic dose (increased food consumption) of 6,000 mg/kg/day (14 times the MRHD based on body surface area [mg/m 2]). In pregnant rats given oral doses of omega-3-acid ethyl esters (100, 600, or 2,000 mg/kg/day) from Gestation Day 14 through Lactation Day 21, no adverse effects were observed at 2,000 mg/kg/day (5 times the MRHD based on body surface area [mg/m 2]).

In pregnant rabbits given oral doses of omega-3-acid ethyl esters (375, 750, or 1,500 mg/kg/day) during organogenesis, no adverse effects were observed in fetuses given 375 mg/kg/day (2 times the MRHD based on body surface area [mg/m 2]). However, at higher doses, increases in fetal skeletal variations and reduced fetal growth were evident at maternally toxic doses (reduced food consumption and body weight gain) greater than or equal to 750 mg/kg/day (4 times the MRHD), and embryolethality was evident at 1,500 mg/kg/day (7 times the MRHD).

8.2 Lactation

Risk Summary

Published studies have detected omega-3 fatty acids, including EPA and DHA, in human milk. Lactating women receiving oral omega-3 fatty acids for supplementation have resulted in higher levels of omega-3 fatty acids in human milk. There are no data available on the effects of omega-3 fatty acid ethyl esters on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for omega-3-acid ethyl esters and any potential adverse effects on the breastfed child from omega-3-acid ethyl esters or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

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.

12.1 Mechanism of Action

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 TG 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.

12.3 Pharmacokinetics

Absorption

In healthy volunteers and in subjects with hypertriglyceridemia, EPA and DHA were absorbed when administered as ethyl esters orally. Omega-3-acids administered as ethyl esters induced significant dose-dependent increases in serum phospholipid EPA content, though increases in DHA content were less marked and not dose-dependent when administered as ethyl esters.

Specific Populations

Age:Uptake of EPA and DHA into serum phospholipids in subjects treated with omega-3-acid ethyl esters was independent of age (younger than 49 years versus 49 years and older).

Male and Female Patients:Females tended to have more uptake of EPA into serum phospholipids than males. The clinical significance of this is unknown.

Pediatric Patients:Pharmacokinetics of omega-3-acid ethyl esters have not been studied.

Patients with Renal or Hepatic Impairment:Omega-3-acid ethyl esters has not been studied in patients with renal or hepatic impairment.

Drug Interaction Studies

Simvastatin:In a 14-day trial of 24 healthy adult subjects, daily coadministration of simvastatin 80 mg with omega-3-acid ethyl esters 4 grams did not affect the extent (AUC) or rate (C max) of exposure to simvastatin or the major active metabolite, beta-hydroxy simvastatin, at steady state.

Atorvastatin:In a 14-day trial of 50 healthy adult subjects, daily coadministration of atorvastatin 80 mg with omega-3-acid ethyl esters 4 grams did not affect AUC or C maxof exposure to atorvastatin, 2-hydroxyatorvastatin, or 4-hydroxyatorvastatin at steady state.

Rosuvastatin:In a 14-day trial of 48 healthy adult subjects, daily coadministration of rosuvastatin 40 mg with omega-3-acid ethyl esters 4 grams did not affect AUC or C maxof exposure to rosuvastatin at steady state.

In vitrostudies using human liver microsomes indicated that clinically significant cytochrome P450-mediated inhibition by EPA/DHA combinations are not expected in humans.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a rat carcinogenicity study with oral gavage doses of 100, 600, and 2,000 mg/kg/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/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 typhimuriumand Escherichia colior in the chromosomal aberration assay in Chinese hamster V79 lung cells or human lymphocytes. Omega-3-acid ethyl esters were negative in the in vivomouse micronucleus assay.

In a rat fertility study with oral doses of 100, 600, and 2,000 mg/kg/day, males were treated for 10 weeks prior to mating and females were treated for 2 weeks prior to mating and through lactation. No adverse effect on fertility was observed at 2,000 mg/kg/day (5 times the MRHD of 4 grams/day based on body surface area [mg/m 2]).

14.1 Severe Hypertriglyceridemia

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

BL = Baseline (mg/dL); % Change = Median Percent Change from Baseline;

Difference = Omega-3-acid ethyl esters Median % Change – Placebo Median % Change. TC = Total cholesterol. VLDL-C = Very-low-density lipoprotein (VLDL) cholesterol.

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.