OMEGA-3-ACID ETHYL ESTERS

6 ADVERSE REACTIONS The most common adverse reactions (incidence >3% and greater than placebo) were eructation, dyspepsia, and taste perversion. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact [Epic Pharma LLC at 1-888-374-2791] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 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 Adverse Reaction * Omega-3-Acid Ethyl Esters (n = 655) Placebo (n = 370) n % n % Eructation 29 4 5 1 Dyspepsia 22 3 6 2 Taste perversion 27 4 1 <1 * Trials included subjects with hypertriglyceridemia and severe hypertriglyceridemia. 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. 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, urticaria.

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 or any of its components. Omega-3-acid ethyl esters capsules are contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to omega-3-acid ethyl esters or any of its components. ( 4 )

11 DESCRIPTION Omega-3-acid ethyl esters, USP, a lipid-regulating agent, is supplied as a liquid-filled gel capsule for oral administration. Each 1-gram capsule of omega-3-acid ethyl esters 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 22 H 34 O 2 , and the molecular weight of EPA ethyl ester is 330.51. The structural formula of EPA ethyl ester is: The empirical formula of DHA ethyl ester is C 24 H 36 O 2 , and the molecular weight of DHA ethyl ester is 356.55. The structural formula of DHA ethyl ester is: Omega-3-acid ethyl esters capsules USP also contain the following inactive ingredients: gelatin, glycerin and purified water. The imprinting ink contains the following: propylene glycol, shellac glaze and titanium dioxide. EPA.jpg DHA.jpg

2 DOSAGE AND ADMINISTRATION • Assess TG levels carefully before initiating therapy. Identify other causes (e.g., diabetes mellitus, hypothyroidism, medications) of high TG levels and manage as appropriate [see Indications and Usage (1) ]. • 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 was 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. • The daily dose of omega-3-acid ethyl esters capsules is 4 grams per day taken as a single 4-gram dose (4 capsules) or as two 2-gram doses (2 capsules given twice daily). ( 2 ) • 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. ( 2 )

1 INDICATIONS AND USAGE Omega-3-acid ethyl esters capsules are indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (greater than or equal to 500 mg/dL) hypertriglyceridemia. Usage Considerations: 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. Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal before instituting therapy with omega-3-acid ethyl esters capsules. 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 TG-lowering drug therapy. Limitations of Use: The effect of omega-3-acid ethyl esters capsules on the risk for pancreatitis has not been determined. The effect of omega-3-acid ethyl esters capsules on cardiovascular mortality and morbidity has not been determined. Omega-3-acid ethyl esters capsules are a combination of ethyl esters of omega 3 fatty acids, principally eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA),, indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia. ( 1 ) Limitations of Use: • The effect of omega-3-acid ethyl esters capsules on the risk for pancreatitis has not been determined. ( 1 ) • The effect of omega-3-acid ethyl esters capsules on cardiovascular mortality and morbidity has not been determined. ( 1 )

7 DRUG INTERACTIONS Omega-3-acids may prolong bleeding time. Patients taking omega-3-acid ethyl esters and an anticoagulant or other drug affecting coagulation (e.g., anti-platelet agents) should be monitored periodically. ( 7.1 ) 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.

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 -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 TG 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 Absorption 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 (younger than 49 years versus 49 years and older). Male and Female Patients: Females tended to have more uptake of EPA into serum phospholipids than males. The clinical significance of this is unknown. Pediatric Patients: Pharmacokinetics of omega-3-acid ethyl esters have not been studied. Patients with Renal or Hepatic Impairment: omega-3-acid ethyl esters has not been studied in patients with renal or hepatic impairment. Drug Interaction Studies 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.

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 -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 TG 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 Absorption 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 (younger than 49 years versus 49 years and older). Male and Female Patients: Females tended to have more uptake of EPA into serum phospholipids than males. The clinical significance of this is unknown. Pediatric Patients: Pharmacokinetics of omega-3-acid ethyl esters have not been studied. Patients with Renal or Hepatic Impairment: omega-3-acid ethyl esters has not been studied in patients with renal or hepatic impairment. Drug Interaction Studies 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.

20230921

1

3 DOSAGE FORMS AND STRENGTHS Omega-3-acid ethyl esters capsules USP are supplied as 1 gram oblong, clear, soft gelatin capsules filled with light yellow liquid and imprinted with "PC25" in white ink. Capsules: 1 gram ( 3 )

OMEGA-3-ACID ETHYL ESTERS OMEGA-3-ACID ETHYL ESTERS OMEGA-3-ACID ETHYL ESTERS OMEGA-3 FATTY ACIDS GELATIN, UNSPECIFIED GLYCERIN WATER PROPYLENE GLYCOL SHELLAC TITANIUM DIOXIDE light yellow PC25

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 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 mating and through lactation. No adverse effect on fertility was observed at 2,000 mg/kg/day (5 times the MRHD of 4 grams/day based on a body surface area [mg/m 2 ]).

13 NONCLINICAL TOXICOLOGY 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 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 mating and through lactation. No adverse effect on fertility was observed at 2,000 mg/kg/day (5 times the MRHD of 4 grams/day based on a body surface area [mg/m 2 ]).

ANDA210093

OMEGA-3-ACID ETHYL ESTERS

OMEGA-3-ACID ETHYL ESTERS

50090-6692

HUMAN PRESCRIPTION DRUG

ORAL

OMEGA-3-ACID ETHYL ESTERS Label Image

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Information for Patients: • Omega-3-acid ethyl esters capsules should be used with caution in patients with known sensitivity or allergy to fish and/or shellfish [see Warnings and Precautions (5.2) ]. • Advise patients that use of lipid-regulating agents does not reduce the importance of adhering to diet [see Dosage and Administration (2) ]. • Advise patients not to alter omega-3-acid ethyl esters capsules in any way and to ingest intact capsules only [see Dosage and Administration (2) ]. • Instruct patients to take omega-3-acid ethyl esters capsules as prescribed. If a dose is missed, advise patients to take it as soon as they remember. However, if they miss one day of omega-3-acid ethyl esters capsules, they should not double the dose when they take it. Manufactured by: Humanwell PuraCap Pharmaceutical Wuhan, Hubei 430206, China Distributed by: Epic Pharma, LLC Laurelton, NY 11413 Rev. 09-2020-00 OE2955

Patient Information OMEGA-3-ACID ETHYL ESTERS CAPSULES USP Rx Only 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 changes your risk of having inflammation of your pancreas (pancreatitis). It is not known if omega-3-acid ethyl esters capsules prevents you from having a heart attack or stroke. It is not known if omega-3-acid ethyl esters capsules is 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. Before taking omega-3-ethyl esters capsules, tell your healthcare provider about all your medical conditions, including 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. Talk to your healthcare provider about the best way to feed your baby if you take omega-3-acid ethyl esters capsules. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, 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. How should I take omega-3-acid ethyl esters capsules? • Take omega-3-acid ethyl esters capsules exactly as your healthcare provider 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 healthcare provider. • Take omega-3-acid ethyl esters capsules with 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 healthcare provider. You may need a different medicine. • If you miss a dose of omega-3-acid ethyl esters capsules, take the missed dose as soon as you remember. If you miss one day of omega-3-acid ethyl esters capsules, do not double your dose the next time you take it. • Your healthcare provider may start you on a cholesterol-lowing diet before giving you omega-3-acid ethyl esters capsules. Stay on this diet while taking omega-3-acid ethyl esters capsules. • Your healthcare provider should do blood tests to check your triglyceride, bad cholesterol (LDL-C) and liver function (ALT and AST) levels while you take omega-3-acid ethyl esters capsules. What are the possible side effects of omega-3-acid ethyl esters capsules? Omega-3-acid ethyl esters capsules may cause serious side effects, including: • changes in certain blood tests. Omega-3-acid ethyl esters capsules may cause an increase in the results of blood tests used to check your liver function and your bad cholesterol levels. • increased risk of a heart rhythm problem in people who have a heart rhythm problem. Omega-3-acid ethyl esters capsules may cause an increase in the frequency of a heart rhythm problem (atrial fibrillation or flutter), especially in the first few months of taking omega-3-acid ethyl esters capsules, if you already have a heart rhythm problem. The most common side effects of omega-3-acid ethyl esters capsules include: • burping • upset stomach • a change in your sense of taste. These are not all the possible side effects of omega-3-acid ethyl esters capsules. 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 between 68 ° to 77 ° F (20 ° to 25 ° C). • 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. You can ask your healthcare provider or pharmacist for information about omega-3-acid ethyl esters capsules that is written for health professionals. What are the ingredients in omega-3-acid ethyl esters capsules? Active Ingredient: omega-3-acid ethyl esters, USP, mostly EPA and DHA Inactive Ingredients: gelatin, glycerin and purified water. The imprinting ink contains the following: propylene glycol, shellac glaze and titanium dioxide. This patient labeling has been approved by the U.S. Food and Drug Administration. Manufactured by: Humanwell PuraCap Pharmaceutical Wuhan, Hubei 430206, China Distributed by: Epic Pharma, LLC Laurelton, NY 11413 Rev. 09-2020-00 OE2955

14 CLINICAL STUDIES 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 TG levels. Subjects whose baseline TG levels were between 500 and 2,000 mg/dL were enrolled in these 2 trials of 6 and 16 weeks’ duration. The median TG and LDL-C levels in these subjects were 792 mg/dL and 100 mg/dL, respectively. Median high-density lipoprotein cholesterol (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. Table 2. Median Baseline and Percent Change from Baseline in Lipid Parameters in Subjects with Severe Hypertriglyceridemia (≥500 mg/dL) Parameter Omega-3-Acid Ethyl Esters n = 42 Placebo n = 42 Difference BL % Change BL % Change TG 816 -44.9 788 +6.7 -51.6 Non-HDL-C 271 -13.8 292 -3.6 -10.2 TC 296 -9.7 314 -1.7 -8/0 WLDL-C 175 -41.7 175 -0.9 -40.8 HDL-C 22 +9.1 24 0.0 +9.1 LDL-C 89 +44.5 108 -4.8 +49.3 BL = Baseline (mg per dL); % Change = Median Percent Change from Baseline; Difference = Omega-3-acid ethyl esters Median % Change – Placebo Median % Change. TC = Total cholesterol. VLDL-C = Very-low-density lipoprotein (VLDL) cholesterol. 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.

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.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.1 Pregnancy Risk Summary The available data from published case reports and the pharmacovigilance database on the use of omega-3-acids ethyl esters in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, omega-3-acid ethyl esters given orally to female rats prior to mating through lactation did not have adverse effects on reproduction or development when given at doses 5 times the maximum recommended human dose (MRHD) of 4 grams/day, based on a body surface area comparison. Omega-3-acid ethyl esters given orally to rats and rabbits during organogenesis was not teratogenic at clinically relevant exposures, based on body surface area comparison (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data : In female rats given oral doses of omega-3-acid ethyl esters (100, 600, or 2,000 mg/kg/day) beginning 2 weeks prior to mating through lactation, no adverse effects were observed at 2,000 mg/kg/day (5 times the MRHD based on body surface area [mg/m 2 ]). In a dose-ranging study, female rats given oral doses of omega-3-acid ethyl esters (1,000, 3,000, or 6,000 mg/kg/day) beginning 2 weeks prior to mating through Postpartum Day 7 had decreased live births (20% reduction) and pup survival to Postnatal Day 4 (40% reduction) at or greater than 3,000 mg/kg/day in the absence of maternal toxicity at 3,000 mg/kg/day (7 times the MRHD based on body surface area [mg/m 2 ]). In pregnant rats given oral doses of omega-3-acid ethyl esters (1,000, 3,000, or 6,000 mg/kg/day) during organogenesis, no adverse effects were observed in fetuses at a maternally toxic dose (increased food consumption) of 6,000 mg/kg/day (14 times the MRHD based on body surface area [mg/m 2 ]). In pregnant rats given oral doses of omega-3-acid ethyl esters (100, 600, or 2,000 mg/kg/day) from Gestation Day 14 through Lactation Day 21, no adverse effects were observed at 2,000 mg/kg/day (5 times the MRHD based on body surface area [mg/m 2 ]). In pregnant rabbits given oral doses of omega-3-acid ethyl esters (375, 750, or 1,500 mg/kg/day) during organogenesis, no adverse effects were observed in fetuses given 375 mg/kg/day (2 times the MRHD based on body surface area [mg/m 2 ]). However, at higher doses, increases in fetal skeletal variations and reduced fetal growth were evident at maternally toxic doses (reduced food consumption and body weight gain) greater than or equal to 750 mg/kg/day (4 times the MRHD), and embryolethality was evident at 1,500 mg/kg/day (7 times the MRHD).

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary The available data from published case reports and the pharmacovigilance database on the use of omega-3-acids ethyl esters in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, omega-3-acid ethyl esters given orally to female rats prior to mating through lactation did not have adverse effects on reproduction or development when given at doses 5 times the maximum recommended human dose (MRHD) of 4 grams/day, based on a body surface area comparison. Omega-3-acid ethyl esters given orally to rats and rabbits during organogenesis was not teratogenic at clinically relevant exposures, based on body surface area comparison (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data : In female rats given oral doses of omega-3-acid ethyl esters (100, 600, or 2,000 mg/kg/day) beginning 2 weeks prior to mating through lactation, no adverse effects were observed at 2,000 mg/kg/day (5 times the MRHD based on body surface area [mg/m 2 ]). In a dose-ranging study, female rats given oral doses of omega-3-acid ethyl esters (1,000, 3,000, or 6,000 mg/kg/day) beginning 2 weeks prior to mating through Postpartum Day 7 had decreased live births (20% reduction) and pup survival to Postnatal Day 4 (40% reduction) at or greater than 3,000 mg/kg/day in the absence of maternal toxicity at 3,000 mg/kg/day (7 times the MRHD based on body surface area [mg/m 2 ]). In pregnant rats given oral doses of omega-3-acid ethyl esters (1,000, 3,000, or 6,000 mg/kg/day) during organogenesis, no adverse effects were observed in fetuses at a maternally toxic dose (increased food consumption) of 6,000 mg/kg/day (14 times the MRHD based on body surface area [mg/m 2 ]). In pregnant rats given oral doses of omega-3-acid ethyl esters (100, 600, or 2,000 mg/kg/day) from Gestation Day 14 through Lactation Day 21, no adverse effects were observed at 2,000 mg/kg/day (5 times the MRHD based on body surface area [mg/m 2 ]). In pregnant rabbits given oral doses of omega-3-acid ethyl esters (375, 750, or 1,500 mg/kg/day) during organogenesis, no adverse effects were observed in fetuses given 375 mg/kg/day (2 times the MRHD based on body surface area [mg/m 2 ]). However, at higher doses, increases in fetal skeletal variations and reduced fetal growth were evident at maternally toxic doses (reduced food consumption and body weight gain) greater than or equal to 750 mg/kg/day (4 times the MRHD), and embryolethality was evident at 1,500 mg/kg/day (7 times the MRHD). 8.2 Lactation Risk Summary Published studies have detected omega-3 fatty acids, including EPA and DHA, in human milk. Lactating women receiving oral omega-3 fatty acids for supplementation have resulted in higher levels of omega-3 fatty acids in human milk. There are no data available on the effects of omega-3 fatty acid ethyl esters on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for omega-3-acids ethyl esters and any potential adverse effects on the breastfed child from omega-3-acids ethyl esters or from the underlying maternal condition. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Product: 50090-6692 NDC: 50090-6692-0 120 CAPSULE, LIQUID FILLED in a BOTTLE