OMACOR®
(omega-3-acid ethyl esters) Capsules
DESCRIPTION
Omacor, a lipid-regulating agent, is supplied as a liquid-filled gel capsule for oral administration. Each one gram capsule of Omacor (omega-3 acid ethyl esters) contains at least 900 mg of the ethyl esters of omega-3 fatty acids. These are predominantly a combination of ethyl esters of eicosapentaenoic acid (EPA - approximately 465 mg) and docosahexaenoic acid (DHA - approximately 375 mg).
The structural formula of EPA ethyl ester is: 
The empirical formula of EPA ethyl ester is C22H34O2, and the molecular weight of EPA ethyl ester is 330.51.
The structural formula of DHA ethyl ester is: 
The empirical formula of DHA ethyl ester is C24H36O2, and the molecular weight of DHA ethyl ester is 356.55.
Omacor capsules also contain the following inactive ingredients: 4 mg α-tocopherol (in a carrier of partially hydrogenated vegetable oils including soybean oil), and gelatin, glycerol, and purified water (components of the capsule shell).
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CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism of action of Omacor is not completely understood. Potential mechanisms of action include inhibition of acyl CoA:1,2-diacylglycerol acyltransferase and increased peroxisomal β-oxidation in the liver. Omacor may reduce the synthesis of triglycerides (TGs) 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.
Pharmacokinetic and Bioavailability Studies
In healthy volunteers and in patients with hypertriglyceridemia (HTG), EPA and DHA were absorbed when administered as ethyl esters orally. Omega-3-acids administered as ethyl esters (Omacor) 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 Omacor was independent of age (<49 years vs. ≥49 years). Females tended to have more uptake of EPA into serum phospholipids than males. Pharmacokinetic data on Omacor in children are not available.
Drug Interactions
Cytochrome P450-Dependent Monooxygenase Activities
The effect of a mixture of free fatty acids (FFA), EPA/DHA and their FFA-albumin conjugate on cytochrome P450-dependent monooxygenase activities was assessed in human liver microsomes. At the 23 μM concentration, FFA resulted in a less than 32% inhibition of CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A. At the 23 μM concentration, the FFA-albumin conjugate resulted in a less than 20% inhibition of CYP2A6, 2C19, 2D6, and 3A, with a 68% inhibition being seen for CYP2E1. Since the free forms of the EPA and DHA are undetectable in the circulation (<1 μM), clinically significant drug-drug interactions due to inhibition of P450 mediated metabolism EPA/DHA combinations are not expected in humans.
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CLINICAL STUDIES
The effects of Omacor 4 g per day were assessed in two randomized, placebo-controlled, double-blind, parallel-group studies of 84 adult patients (42 on Omacor, 42 on placebo) with very high triglyceride levels (Table 1). Patients whose baseline triglyceride levels were between 500 and 2000 mg/dL were enrolled in these two studies of 6 and 16 weeks duration. The median triglyceride and LDL-C levels in these patients were 792 mg/dL and 100 mg/dL, respectively. Median HDL-C level was 23.0 mg/dL.
Table 1. Median Baseline and Percent Change From Baseline in Lipid Parameters in Patients with Very High TG Levels (≥ 500 mg/dL) |
| TG | LDL-C | CHOL | HDL-C | VLDL-C | non-HDL-C |
| BL | % Chg | BL | % Chg | BL | % Chg | BL | % Chg | BL | % Chg | BL | % Chg |
| Placebo | 788 | +6.7 | 108 | -4.8 | 314 | -1.7 | 24 | 0.0 | 175 | -0.9 | 292 | -3.6 |
| Omacor 4g/day | 816 | -44.9 | 89 | +44.5 | 296 | -9.7 | 22 | +9.1 | 175 | -41.7 | 271 | -13.8 |
| Difference | | -51.6 | | +49.3 | | -8.0 | | +9.1 | | -40.8 | | -10.2 |
BL = Baseline (mg/dL); % Chg = Percent Change from Baseline; Difference = Omacor - Placebo
Omacor 4 g per day reduced median TG, VLDL-C, and non HDL-C levels and increased median HDL-C from baseline relative to placebo. Omacor treatment 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 Omacor on the risk of pancreatitis in patients with very high TG levels has not been evaluated. The effect of Omacor on cardiovascular mortality and morbidity in patients with very high TG levels has not been determined.
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