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 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/day for 7 days and 4 grams/day thereafter for 23 weeks at a higher rate relative to placebo. Subjects in this trial had median baseline triglycerides of 127 mg/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.

6.1 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% and at a greater rate than placebo for subjects treated with omega-3-acid ethyl esters capsules based on pooled data across 23 clinical trials are listed in Table 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.            

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 capsules. 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.

7.1  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.

8.1 Pregnancy

Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. It is unknown whether omega-3-acid ethyl esters capsules can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Omega-3-acid ethyl esters capsules should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus.

Animal Data: 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.            

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 capsules are administered to a nursing mother. An animal study in lactating rats given oral gavage 14C-ethyl EPA demonstrated that drug levels were 6 to 14 times higher in milk than in plasma.

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 capsules. Safety and efficacy findings in subjects older than 60 years did not appear to differ from those of subjects younger than 60 years.

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  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.

Specific Populations: Age: 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).            

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

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

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

Drug-Drug Interactions: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 (C max) 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 C max 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 C max 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.  

13.1 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 gavage 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 and throughout mating, gestation, and lactation. No adverse effect on fertility was observed at 2,000 mg/kg/day (5 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).

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 triglyceride levels. Subjects whose baseline triglyceride levels were between 500 and 2,000 mg/dL were enrolled in these 2 trials of 6 and 16 weeks' duration. The median triglyceride and LDL-C levels in these subjects were 792 mg/dL and 100 mg/dL, respectively. Median 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.

BL = Baseline (mg/dL); % Change = Median Percent Change from Baseline; Difference = omega-3-acid ethyl esters Median % Change - Placebo Median % Change.

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.

Manufactured for:
AvKARE, Inc.
Pulaski, TN  38478

Mfg. Rev. 05/14
AV 05/15 (P)

PATIENT INFORMATION

Omega-3-Acid Ethyl Esters

(oh-may-ga-as-id-eth-il-es-ters)

Capsules, USP 

Read this Patient Information before you start taking omega-3-acid ethyl esters capsules, and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.  

What are omega-3-acid ethyl esters capsules?

Omega-3-acid ethyl esters capsules are a prescription medicine used along with a low fat and low cholesterol diet to lower very high triglyceride (fat) levels in adults.  

It is not known if omega-3-acid ethyl esters capsules change your risk of having inflammation of your pancreas (pancreatitis).

It is not known if omega-3-acid ethyl esters capsules prevent you from having a heart attack or stroke.

It is not known if omega-3-acid ethyl esters capsules are safe and effective in children.  

Who should not take omega-3-acid ethyl esters capsules?

Do not take omega-3-acid ethyl esters capsules if you are allergic to omega-3-acid ethyl esters or any of the ingredients in omega-3-acid ethyl esters capsules. See the end of this leaflet for a complete list of ingredients in omega-3-acid ethyl esters capsules. 

What should I tell my doctor before taking omega-3-acid ethyl esters capsules?
Before you take omega-3-acid ethyl esters capsules, tell your doctor if you: 

• have diabetes.
• have a low thyroid problem (hypothyroidism).
• have a liver problem.
• have a pancreas problem.
• have a certain heart rhythm problem called atrial fibrillation or flutter.
• are allergic to fish or shellfish. It is not known if people who are allergic to fish or shellfish are also allergic to omega-3-acid ethyl esters capsules.
• are pregnant or plan to become pregnant. It is not known if omega-3-acid ethyl esters capsules will harm your unborn baby.
• are breastfeeding or plan to breastfeed. Omega-3-acid ethyl esters can pass into your breast milk. You and your doctor should decide if you will take omega-3-acid ethyl esters capsules or breastfeed.  

Tell your doctor about all the medicines you take, including prescription and non-prescription medicine, vitamins, and herbal supplements.

Omega-3-acid ethyl esters capsules can interact with certain other medicines that you are taking. Using omega-3-acid ethyl esters capsules with medicines that affect blood clotting (anticoagulants or blood thinners) may cause serious side effects.  

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take omega-3-acid ethyl esters capsules?

• Take omega-3-acid ethyl esters capsules exactly as your doctor tells you to take it.
• You should not take more than 4 capsules of omega-3-acid ethyl esters capsules each day. Either take all 4 capsules at one time, or 2 capsules two times a day.
• Do not change your dose or stop omega-3-acid ethyl esters capsules without talking to your doctor.
• Take omega-3-acid ethyl esters capsules with or without food.
• Take omega-3-acid ethyl esters capsules whole. Do not break, crush, dissolve, or chew omega-3-acid ethyl esters capsules before swallowing. If you cannot swallow omega-3-acid ethyl esters capsules whole, tell your doctor. You may need a different medicine.
• Your doctor may start you on a diet that is low in saturated fat, cholesterol, carbohydrates, and low in added sugars before giving you omega-3-acid ethyl esters capsules. Stay on this diet while taking omega-3-acid ethyl esters capsules.
• Your doctor should do blood tests to check your triglyceride, bad cholesterol and liver function levels while you take omega-3-acid ethyl esters capsules.

What are the possible side effects of o mega-3-acid ethyl esters capsules?

Omega-3-acid ethyl esters capsules may cause serious side effects, including:

• increases in the results of blood tests used to check your liver function (ALT and AST) and your bad cholesterol levels (LDL-C).
• increases in the frequency of a heart rhythm problem (atrial fibrillation or flutter) may especially happen in the first few months of taking omega-3-acid ethyl esters capsules if you already have that problem.

The most common side effects of omega-3-acid ethyl esters capsules include:

• burping
• upset stomach
• a change in your sense of taste

Talk to your doctor if you have a side effect that bothers you or does not go away.  

These are not all the possible side effects of omega-3-acid ethyl esters capsules. For more information, ask your doctor or pharmacist.  

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store omega-3-acid ethyl esters capsules?

• Store omega-3-acid ethyl esters capsules at room temperature, 59° to 86° F (15° to 30° C). Protect from light.
• Do not freeze omega-3-acid ethyl esters capsules.
• Safely throw away medicine that is out of date or no longer needed.

Keep omega-3-acid ethyl esters capsules and all medicines out of the reach of children.  

General information about the safe and effective use of omega-3-acid ethyl esters capsules

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use omega-3-acid ethyl esters capsules for a condition for which it was not prescribed. Do not give omega-3-acid ethyl esters capsules to other people, even if they have the same symptoms you have. It may harm them.

This Patient Information Leaflet summarizes the most important information about omega-3-acid ethyl esters capsules. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about omega-3-acid ethyl esters capsules that is written for health professionals. 

For more information please call 1-855-361-3993.

What are the ingredients in omega-3-acid ethyl esters capsules?

Active Ingredient: omega-3-acid ethyl esters, mostly EPA and DHA

Inactive Ingredients: alpha-tocopherol (in soybean oil), gelatin, glycerin, purified water and white ink. The capsule imprinting ink contains ammonium hydroxide, propylene glycol, shellac glaze, simethicone and titanium dioxide.

This patient labeling has been approved by the U.S. Food and Drug Administration.

Manufactured for:
AvKARE, Inc.
Pulaski, TN  38478

Mfg. Rev. 05/14
AV 05/15 (P)