Omega-3-acid Ethyl Esters

OMEGA-3-ACID ETHYL ESTERS- omega-3-acid ethyl esters capsule, liquid filled
Major Pharmaceuticals

1 INDICATIONS AND USAGE

Omega-3-acid ethyl esters capsules, USP are indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (greater than or equal to 500 mg per dL) hypertriglyceridemia (HTG).

Usage Considerations: Patients should be placed on an appropriate lipid-lowering diet before receiving omega-3-acid ethyl esters capsules, USP and should continue this diet during treatment with omega-3-acid ethyl esters capsules, USP.

Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal before instituting therapy with omega-3-acid ethyl esters. Every attempt should be made to control serum lipids with appropriate diet, exercise, weight loss in obese patients, and control of any medical problems such as diabetes mellitus and hypothyroidism that are contributing to the lipid abnormalities. Medications known to exacerbate hypertriglyceridemia (such as beta blockers, thiazides, estrogens) should be discontinued or changed if possible prior to consideration of triglyceride-lowering drug therapy.

Limitations of Use:

The effect of omega-3-acid ethyl esters capsules, USP on the risk for pancreatitis has not been determined.

The effect of omega-3-acid ethyl esters capsules, USP on cardiovascular mortality and morbidity has not been determined.

2 DOSAGE AND ADMINISTRATION

1.
Assess triglyceride levels carefully before initiating therapy. Identify other causes (e.g., diabetes mellitus, hypothyroidism, medications) of high triglyceride levels and manage as appropriate [see Indications and Usage (1)].
2.
Patients should be placed on an appropriate lipid-lowering diet before receiving omega-3-acid ethyl esters capsules, and should continue this diet during treatment with omega-3-acid ethyl esters capsules. In clinical studies, omega-3-acid ethyl esters capsules were administered with meals.

The daily dose of omega-3-acid ethyl esters capsules is 4 grams per day. The daily dose may be taken as a single 4-gram dose (4 capsules) or as two 2-gram doses (2 capsules given twice daily).

Patients should be advised to swallow omega-3-acid ethyl esters capsules whole. Do not break open, crush, dissolve, or chew omega-3-acid ethyl esters capsules.

3 DOSAGE FORMS AND STRENGTHS

Omega-3-acid ethyl esters capsules, USP are supplied as 1-gram transparent, soft gelatin capsules filled with light yellowish oil printed with white ink (Logo “APO900”).

4 CONTRAINDICATIONS

Omega-3-acid ethyl esters capsules are contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to omega-3-acid ethyl esters capsules or any of its components.

5 WARNINGS AND PRECAUTIONS

5.1 Monitoring: Laboratory Tests

In patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored periodically during therapy with omega-3-acid ethyl esters capsules. In some patients, increases in ALT levels without a concurrent increase in AST levels were observed.

In some patients, omega-3-acid ethyl esters capsule increases low-density lipoprotein cholesterol (LDL-C) levels. LDL-C levels should be monitored periodically during therapy with omega-3-acid ethyl esters.

Laboratory studies should be performed periodically to measure the patient’s TG levels during therapy with omega-3-acid ethyl esters.

5.2 Fish Allergy

Omega-3-acid ethyl esters capsules contain ethyl esters of omega-3 fatty acids (EPA and DHA) obtained from the oil of several fish sources. It is not known whether patients with allergies to fish and/or shellfish, are at increased risk of an allergic reaction to omega-3-acid ethyl esters capsules. Omega-3-acid ethyl esters capsules should be used with caution in patients with known hypersensitivity to fish and/or shellfish.

5.3 Recurrent Atrial Fibrillation (AF) or Flutter

In a double-blind, placebo-controlled trial of 663 subjects with symptomatic paroxysmal AF (n=542) or persistent AF (n=121), recurrent AF or flutter was observed in subjects randomized to omega-3-acid ethyl esters who received 8 grams per day for 7 days and 4 grams per day thereafter for 23 weeks at a higher rate relative to placebo. Subjects in this trial had median baseline triglycerides of 127 mg per dL, had no substantial structural heart disease, were taking no anti-arrhythmic therapy (rate control permitted), and were in normal sinus rhythm at baseline.

At 24 weeks, in the paroxysmal AF stratum, there were 129 (47%) first recurrent symptomatic AF or flutter events on placebo and 141 (53%) on omega-3-acid ethyl esters (primary endpoint, HR 1.19; 95% CI: 0.93, 1.35). In the persistent AF stratum, there were 19 (35%) events on placebo and 34 (52%) events on omega-3-acid ethyl esters (HR 1.63; 95% CI: 0.91, 2.18). For both strata combined, the HR was 1.25; 95% CI: 1.00, 1.40. Although the clinical significance of these results is uncertain, there is a possible association between omega-3-acid ethyl esters and more frequent recurrences of symptomatic atrial fibrillation or flutter in patients with paroxysmal or persistent atrial fibrillation, particularly within the first 2 to 3 months of initiating therapy.

Omega-3-acid ethyl esters capsules are not indicated for the treatment of AF or flutter.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions reported in at least 3% of subjects treated with omega-3-acid ethyl esters capsules and at a greater rate than placebo based on pooled data across 23 clinical trials are listed in Table 1.

Table 1. Adverse Reactions Occurring at Incidence ≥3% and Greater than Placebo in Clinical Trials of omega-3-acid ethyl esters capsules
*
Trials included subjects with HTG and severe HTG.


Adverse Reactions *

Omega-3-acid ethyl esters
capsules
(n = 655)

Placebo
(n = 370)

n

%

n

%

Eructation

29

4

5

1

Dyspepsia

22

3

6

2

Taste perversion

27

4

1

≤1

Additional adverse reactions from clinical trials are listed below:

Digestive System: Constipation, gastrointestinal disorder and vomiting.

Metabolic and Nutritional Disorders: Increased ALT and increased AST.

Skin: Pruritus and rash.

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