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warnings and cautions
5 WARNINGS AND PRECAUTIONS In patients with hepatic impairment, monitor ALT and AST levels periodically during therapy. (5.1) Omega-3-acid ethyl esters may increase levels of 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 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. In some patients, increases in ALT levels without a concurrent increase in AST levels were observed. In some patients, omega-3-acid ethyl esters increase 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 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. Omega-3-acid ethyl esters 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, 1.4. 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 are not indicated for the treatment of AF or flutter.
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 Amneal Pharmaceuticals at 1-877-835-5472 and or FDA at 1-800-FDA-1088 or www.amneal.com 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% and at a greater rate than placebo for subjects treated with omega-3-acid ethyl esters 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 a 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 Studies included subjects with HTG and severe HTG. a Additional adverse reactions from clinical trials are listed below: Constipation, gastrointestinal disorder and vomiting. Digestive System: Increased ALT and increased AST. Metabolic and Nutritional Disorders: Pruritus and rash. Skin: 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.