Prescription Drug Information: OMEGA-3-ACID ETHYL ESTERS (Page 2 of 3)

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-acids ethyl esters and any potential adverse effects on the breastfed child from omega-3-acids 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.

11 DESCRIPTION

Omega-3-acid ethyl esters, USP, a lipid-regulating agent, is supplied as a liquid-filled gel capsule for oral administration. Each 1-gram capsule of omega-3-acid ethyl esters 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 C22 H34 O2 , and the molecular weight of EPA ethyl ester is 330.51. The structural formula of EPA ethyl ester is:

//rxdruglabels.com/lib/images-rx/omega-3-acid-ethyl-esters/epa-300x71.jpg
(click image for full-size original)

The empirical formula of DHA ethyl ester is C24 H36 O2 , and the molecular weight of DHA ethyl ester is 356.55. The structural formula of DHA ethyl ester is:

//rxdruglabels.com/lib/images-rx/omega-3-acid-ethyl-esters/dha-300x55.jpg
(click image for full-size original)

Omega-3-acid ethyl esters capsules USP also contain the following inactive ingredients: gelatin, glycerin and purified water. The imprinting ink contains the following: propylene glycol, shellac glaze and titanium dioxide.

12 CLINICAL PHARMACOLOGY

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 -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 (Cmax ) 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 Cmax of 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 Cmax of exposure to rosuvastatin at steady state.

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

13 NONCLINICAL TOXICOLOGY

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 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 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 a body surface area [mg/m2 ]).

14 CLINICAL STUDIES

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.

Table 2. Median Baseline and Percent Change from Baseline in Lipid Parameters in Subjects with Severe Hypertriglyceridemia (≥500 mg/dL)

Parameter

Omega-3-Acid Ethyl Esters

n = 42

Placebo

n = 42

Difference

BL

% Change

BL

% Change

TG

816

-44.9

788

+6.7

-51.6

Non-HDL-C

271

-13.8

292

-3.6

-10.2

TC

296

-9.7

314

-1.7

-8/0

WLDL-C

175

-41.7

175

-0.9

-40.8

HDL-C

22

+9.1

24

0.0

+9.1

LDL-C

89

+44.5

108

-4.8

+49.3

BL = Baseline (mg per 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.

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