Omacor

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).

General

Laboratory studies should be performed to ascertain that the patient’s TG levels are consistently abnormal before instituting Omacor therapy. Every attempt should be made to control serum TG levels with appropriate diet, exercise, weight loss in overweight patients, and control of any medical problems (such as diabetes mellitus and hypothyroidism) that may be contributing to the patient’s TG abnormalities. Medications known to exacerbate HTG (such as beta blockers, thiazides, and estrogens) should be discontinued or changed, if possible, before considering TG–lowering drug therapy.

Laboratory studies should be performed periodically to measure the patient’s TG levels during Omacor therapy. Omacor therapy should be withdrawn in patients who do not have an adequate response after 2 months of treatment.

Information for Patients

Omacor should be used with caution in patients with known sensitivity or allergy to fish.

Patients should be advised that use of lipid-regulating agents does not reduce the importance of adhering to diet.

Laboratory Tests

In some patients, increases in alanine aminotransferase (ALT) levels without a concurrent increase in aspartate aminotransferase (AST) levels were observed. Alanine aminotransferase levels should be monitored periodically during Omacor therapy.

In some patients, Omacor increased low-density lipoprotein cholesterol (LDL-C) levels. As with any lipid-regulating product, LDL-C levels should be monitored periodically during Omacor therapy.

Drug Interactions

Some studies with omega-3-acids demonstrated prolongation of bleeding time. The prolongation of bleeding time reported in these studies has not exceeded normal limits and did not produce clinically significant bleeding episodes. Clinical studies have not been done to thoroughly examine the effect of Omacor and concomitant anticoagulants. Patients receiving treatment with both Omacor and anticoagulants should be monitored periodically.

Omega-3-fatty acid containing products have been shown to increase hepatic concentrations of cytochrome P450 and activities of certain P450 enzymes in rats. The potential of Omacor to induce P450 activities in humans has not been studied.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a rat carcinogenicity study with oral gavage doses of 100, 600, 2000 mg/kg/day by oral gavage, 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 g/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 gavage doses of 100, 600, 2000 mg/kg/day, males were treated for 10 weeks prior to mating and females were treated for 2 weeks prior to and throughout mating, gestation and lactation. No adverse effect on fertility was observed at 2000 mg/kg/day (5 times human systemic exposure following an oral dose of 4 g/day based on a body surface area comparison).

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. It is unknown whether Omacor can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Omacor should be used during pregnancy only if the potential benefit 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 g/day based on a body surface area comparison.

In female rats given oral gavage doses of 100, 600, 2000 mg/kg/day beginning two 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 g/day based on body surface area comparison).

In pregnant rats given oral gavage doses of 1000, 3000, 6000 mg/kg/day from gestation day 6 thorough 15, no adverse effects were observed (14 times human systemic exposure following an oral dose of 4 g/day based on a body surface area comparison).

In pregnant rats given oral gavage doses of 100, 600, 2000 mg/kg/day from gestation day 14 through lactation day 21, no adverse effects were seen at 2000 mg/kg/day (5 times the human systemic exposure following an oral dose of 4 g/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 3000mg/kg/day (7 times the human systemic exposure following an oral dose of 4 g/day based on a body surface area comparison).

In pregnant rabbits given oral gavage doses of 375, 750, 1500 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 g/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 g/day based on a body surface area comparison).

Nursing Mothers

It is not known whether omega-3-acid ethyl esters are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Omacor is administered to a woman who is breastfeeding.

Pediatric Use

Safety and effectiveness in pediatric patients under 18 years of age have not been established.

Geriatric Use

A limited number of patients over 65 years of age were enrolled in the clinical studies. In the pooled analyses, safety and efficacy findings in subjects over 60 years of age (approximately 25% of the study population) did not appear to differ from those of subjects less than 60 years of age.

In the event of an overdose, the patient should be treated symptomatically, and general supportive care measures instituted, as required.

Patients should be placed on an appropriate lipid-lowering diet before receiving Omacor, and should continue this diet during treatment with Omacor. In clinical studies, Omacor was administered with meals.

The daily dose of Omacor is 4 g per day. The daily dose may be taken as a single 4-g dose (4 capsules) or as two 2-g doses (2 capsules given twice daily).

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using Omacor and call your doctor at once if you have any of these serious side effects:

• fever, chills, body aches, flu symptoms;

• chest pain; or

• uneven heartbeats.

Less serious Omacor side effects may include:

• back pain;

• unusual or unpleasant taste in your mouth;

• upset stomach, belching; or

• mild skin rash.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.