omega-3 acid ethyl esters (USP) 1000 MG Oral Capsule [Lovaza]

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 )

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 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. • 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 )

WARNINGS AND PRECAUTIONS In patients with hepatic impairment, monitor ALT and AST levels periodically during therapy. ( 5.1 ) Omega-3-acid ethyl esters capsules may increase levels of low-density lipoprotein (LDL). Monitor LDL levels periodically during therapy. ( 5.1 ) Use with caution in patients with known hypersensitivity to fish and/or shellfish. ( 5.2 ) There is a possible association between omega-3-acid ethyl esters capsules and more frequent recurrences of symptomatic atrial fibrillation or flutter in patients with paroxysmal or persistent atrial fibrillation, particularly within the first months of initiating therapy. ( 5.3 ) 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 capsules increases low-density lipoprotein cholesterol (LDL-C) levels. LDL-C levels should be monitored periodically during therapy with omega-3-acid ethyl esters capsules. Laboratory studies should be performed periodically to measure the patient's TG levels during therapy with omega-3-acid ethyl esters capsules. 5.2 Fish Allergy Omega-3-acid ethyl esters capsules contains 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 capsules 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 TG levels 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 capsules (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 capsules (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 capsules and more frequent recurrences of symptomatic AF or flutter in patients with paroxysmal or persistent AF, 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.

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 )

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 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 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 (omega-3-acid ethyl esters capsules) 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 have 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 co-administration 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 co-administration 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 co-administration 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.