Omega-3-Acid Ethyl Esters (Page 2 of 4)

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.

7 DRUG INTERACTIONS

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 USE IN SPECIFIC POPULATIONS

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.

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/day based on a body surface area comparison. Animal Data:

In female rats given oral gavage doses of 100, 600, and 2,000 mg/kg/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/day based on body surface area comparison).

In pregnant rats given oral gavage doses of 1,000, 3,000, and 6,000 mg/kg/day from gestation day 6 through 15, no adverse effects were observed (14 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).

In pregnant rats given oral gavage doses of 100, 600, and 2,000 mg/kg/day from gestation day 14 through lactation day 21, no adverse effects were seen at 2,000 mg/kg/day (5 times the human systemic exposure following an oral dose of 4 grams/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/kg/day (7 times the human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).

In pregnant rabbits given oral gavage doses of 375, 750, and 1,500 mg/kg/day from gestation day 7 through 19, no findings were observed in the fetuses in groups given 375 mg/kg/day (2 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison). However, at higher doses, evidence of maternal toxicity was observed (4 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).

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 C-ethyl EPA demonstrated that drug levels were 6 to 14 times higher in milk than in plasma. 14

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.

9 DRUG ABUSE AND DEPENDENCE

Omega-3-acid ethyl esters do not have any known drug abuse or withdrawal effects.

11 DESCRIPTION

Omega-3-acid ethyl esters, USP, a lipid-regulating agent, 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 H O , and the molecular weight of EPA ethyl ester is 330.51. The structural formula of EPA ethyl ester is: 22 34 2

400f230c-figure-01
(click image for full-size original)

The empirical formula of DHA ethyl ester is C H O , and the molecular weight of DHA ethyl ester is 356.55. The structural formula of DHA ethyl ester is: 24 36 2

400f230c-figure-02
(click image for full-size original)

Omega-3-acid ethyl esters capsules, USP also contain the following inactive ingredients: alpha-tocopherol, gelatin, glycerin and purified water (components of the capsule shell).

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 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.

12.3 Pharmacokinetics

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 (omega-3-acid ethyl esters capsules) 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.

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

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

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

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

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

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

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

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

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