Omega-3-Acid Ethyl Esters

RECENT MAJOR CHANGES Indications and Usage, Limitations of Use (1) 05/2014

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 per 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. 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 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 )

2 DOSAGE AND ADMINISTRATION 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 )]. 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, USP are 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)

3 DOSAGE FORMS AND STRENGTHS Omega-3-acid ethyl esters capsules USP are supplied as 1-gram oblong, clear, soft gel capsules filled with slightly yellow to yellow liquid and imprinted with "GLW" in white ink across one side. Capsules: 1 gram ( 3 )

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. 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. ( 4 )

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 Strides Pharma, Inc. at 1-877-244-9825 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 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 a Trials included subjects with hypertriglyceridemia and severe hypertriglyceridemia. Adverse Reaction a Omega-3-Acid Ethyl Esters Capsules (n=655) Placebo (n=370) n % n % Eructation Dyspepsia Taste perversion 29 22 27 4 3 4 5 6 1 1 2 <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, urticaria.

7 DRUG INTERACTIONS Omega-3-acids may prolong bleeding time. Patients taking omega-3-acid ethyl esters capsules 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.

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-acid ethyl esters capsules 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 omega3 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-acid ethyl esters capsules and any potential adverse effects on the breastfed child from Omega-3-acid ethyl esters capsules 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 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.

11 DESCRIPTION Omega-3-acid ethyl esters capsules, USP, a lipid-regulating agent, are supplied as a liquid-filled gel capsule for oral administration. Each 1-gram capsule of omega-3-acid ethyl esters capsules, USP 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, purified water and opacode white ink (contains shellac glaze, titanium dioxide, purified water, N-butyl alcohol, lecithin and simethicone). EPA chemical structure DHA chemical structure

16 HOW SUPPLIED/STORAGE AND HANDLING Omega-3-Acid Ethyl Esters Capsules, USP are supplied as 1-gram clear, natural colored oblong shaped soft gelatin capsules containing pale yellow colored oily liquid imprinted with '740' Bottles of 120: NDC 64380-761-11 Blister card of 10's: NDC 64380-761-01 Carton of 50 capsules containing 5 blister cards of 10 capsules per blister card: NDC 64380-761-02 Store at 20° to 25°C (68° to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) Protect from light. [See USP Controlled Room Temperature]. Do not freeze. Keep out of reach of children.