OMEGA-3-ACID ETHYL ESTERS (Page 3 of 4)

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Omega-3-acid ethyl esters capsules USP are supplied as 1 gram oblong, clear, soft gel capsules filled with slightly yellow to yellow liquid and imprinted with “PC25” in white ink. They are supplied in bottles of 120 (NDC 42806-552-12)

Store at 20° C to 25° C (68° to 77° F) [See USP Controlled Room Temperature]. Do not freeze. Keep out of reach of children.

Protect from light.

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