Icosapent Ethyl

RECENT MAJOR CHANGES Indications and Usage (1) 12/2019 Warnings and Precautions, Atrial Fibrillation/Flutter (5.1) 12/2019 Warnings and Precautions, Bleeding (5.3) 12/2019

1 INDICATIONS AND USAGE Icosapent ethyl capsules are indicated: • as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia. Limitations of Use: The effect of icosapent ethyl capsules on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined. Icosapent ethyl capsules are an ethyl ester of eicosapentaenoic acid (EPA) 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 icosapent ethyl capsules on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined. ( 1 )

2 DOSAGE AND ADMINISTRATION Assess lipid levels before initiating therapy. Identify other causes of high triglyceride levels and manage as appropriate. ( 2.1 ) Patients should engage in appropriate nutritional intake and physical activity before receiving icosapent ethyl capsules, which should continue during treatment. ( 2.1 ) The daily dose of icosapent ethyl capsules are 4 grams per day taken as either four 0.5 gram capsules twice daily with food or two 1 gram capsules twice daily with food. ( 2.2 ) Advise patients to swallow capsules whole. Do not break open, crush, dissolve, or chew icosapent ethyl capsules. ( 2.2 ) 2.1 Prior to Initiation of Icosapent Ethyl Capsules Assess lipid levels before initiating therapy. Identify other causes (e.g., diabetes mellitus, hypothyroidism, or medications) of high triglyceride levels and manage as appropriate. Patients should engage in appropriate nutritional intake and physical activity before receiving icosapent ethyl capsules, which should continue during treatment with icosapent ethyl capsules. 2.2 Dosage and Administration The daily dose of icosapent ethyl capsules are 4 grams per day taken as either: -four 0.5 gram capsules twice daily with food; or as -two 1 gram capsules twice daily with food. Advise patients to swallow icosapent ethyl capsules whole. Do not break open, crush, dissolve, or chew icosapent ethyl capsules.

2.1 Prior to Initiation of Icosapent Ethyl Capsules Assess lipid levels before initiating therapy. Identify other causes (e.g., diabetes mellitus, hypothyroidism, or medications) of high triglyceride levels and manage as appropriate. Patients should engage in appropriate nutritional intake and physical activity before receiving icosapent ethyl capsules, which should continue during treatment with icosapent ethyl capsules.

2.2 Dosage and Administration The daily dose of icosapent ethyl capsules are 4 grams per day taken as either: -four 0.5 gram capsules twice daily with food; or as -two 1 gram capsules twice daily with food. Advise patients to swallow icosapent ethyl capsules whole. Do not break open, crush, dissolve, or chew icosapent ethyl capsules.

3 DOSAGE FORMS AND STRENGTHS Icosapent ethyl capsules, 0.5 gm are oval, transparent, elastic soft gelatin capsule containing clear, light-yellow oil with a characteristic fish-like odour and with "1738" in white ink printed on the surface. Icosapent ethyl capsules, 1 gm are oblong, transparent, elastic soft gelatin capsule containing clear, light-yellow oil with a characteristic fish-like odour and with "1592" in white ink printed on the surface. Capsules: 0.5 gram and 1 gram ( 3 )

4 CONTRAINDICATIONS Icosapent ethyl capsules are contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to icosapent ethyl capsules or any of its components. Icosapent ethyl capsules are contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to icosapent ethyl capsules or any of its components. ( 4 )

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Atrial Fibrillation or Atrial Flutter [see Warnings and Precautions ( 5.1 )] Potential for Allergic Reactions in Patients with Fish Allergy [see Warnings and Precautions ( 5.2 )] Bleeding [see Warnings and Precautions ( 5.3 )] Common adverse reactions (incidence ≥3% and ≥1% more frequent than placebo): musculoskeletal pain, peripheral edema, constipation, gout, and atrial fibrillation ( 6.1 ) Common adverse reactions in the hypertriglyceridemia trials (incidence ≥1% more frequent than placebo): arthralgia and oropharyngeal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc. at 1-888-375-3784 or contact the 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Common adverse reactions (incidence ≥3% on icosapent ethyl and ≥1% more frequent than placebo) included musculoskeletal pain, peripheral edema, constipation, gout, and atrial fibrillation. Hypertriglyceridemia Trials In two randomized, double-blind, placebo-controlled trials in patients with triglyceride levels between 200 and 2000 mg/dL treated for 12 weeks, adverse reactions reported with icosapent ethyl at an incidence ≥1% more frequent than placebo based on pooled data included arthralgia and oropharyngeal pain. 6.2 Postmarketing Experience Additional adverse reactions have been identified during post-approval use of icosapent ethyl capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Diarrhea Blood triglycerides increased Abdominal discomfort Pain in the extremities

6.2 Postmarketing Experience Additional adverse reactions have been identified during post-approval use of icosapent ethyl capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Diarrhea Blood triglycerides increased Abdominal discomfort Pain in the extremities

7 DRUG INTERACTIONS Increased Bleeding Risk with Anticoagulants and Antiplatelet Agents: Some published studies with omega-3 fatty acids have demonstrated prolongation of bleeding time. Monitor patients receiving icosapent ethyl capsules and concomitant anticoagulants and/or antiplatelet agents for bleeding. ( 7 ) 7.1 Increased Bleeding Risk with Anticoagulants and Antiplatelet Agents Some published studies with omega-3 fatty acids have demonstrated prolongation of bleeding time. The prolongation of bleeding time reported in those studies has not exceeded normal limits and did not produce clinically significant bleeding episodes. Monitor patients receiving icosapent ethyl capsules and concomitant anticoagulants and/or antiplatelet agents for bleeding.

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 icosapent ethyl in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies in pregnant rats, non-dose-related imbalances for some minor developmental findings were observed with oral administration of icosapent ethyl during organogenesis at exposures that were equivalent to the clinical exposure at the human dose of 4 g/day, based on body surface area comparisons. In a study in pregnant rabbits orally administered icosapent ethyl during organogenesis, there were no clinically relevant adverse developmental effects at exposures that were 5 times the clinical exposure, based on body surface area comparisons ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 pregnant rats given oral gavage doses of 0.3, 1 and 2 g/kg/day icosapent ethyl from gestation through organogenesis all drug treated groups had non-dose-related imbalances in visceral and skeletal findings, including 13th reduced ribs, additional liver lobes, testes medially displaced and/or not descended, at human systemic exposures following a maximum oral dose of 4 g/day based on body surface comparisons. In a multigenerational developmental study in pregnant rats given doses of 0.3, 1, 3 g/kg/day icosapent ethyl by oral gavage from gestation day 7 to 17, icosapent ethyl did not affect viability in fetuses (F1 or F2). Non-dose-related imbalances in findings of absent optic nerves and unilateral testes atrophy at human exposures based on the maximum dose of 4 g/day and on body surface area comparisons. Additional variations consisting of early incisor eruption and increased percent cervical ribs were observed at the same exposures. Pups from high dose treated dams exhibited decreased copulation rates, delayed estrus, decreased implantations and decreased surviving fetuses (F2) suggesting potential multigenerational effects of icosapent ethyl at 7 times human systemic exposure following 4 g/day dose based on body surface area comparisons across species. In pregnant rabbits given oral gavage doses of 0.1, 0.3, and 1 g/kg/day icosapent ethyl from gestation through organogenesis, a decrease in body weight and food consumption was observed at the high dose of 1 g/kg/day (5 times the human exposure at the maximum dose of 4 g/day, based on body surface area comparisons). Slight increases in resorbed and dead fetuses were noted in the 1 g/kg/day group, but these were not significantly different from the control group. There were no differences between the icosapent ethyl groups and control group as to the number of corpora lutea , number of implantations, number of surviving fetuses, sex ratio, body weight of female fetuses or placental weight. There were no treatment-related malformations or skeletal anomalies. In pregnant rats given icosapent ethyl from gestation day 17 through lactation day 20 at 0.3, 1, 3 g/kg/day no adverse maternal or developmental effects were observed. However, complete litter loss (not dose-related) was noted in 2/23 litters at the low dose and 1/23 mid-dose dams by post-natal day 4 at human exposures at a maximum dose of 4 g/day, based on body surface area comparisons. 8.2 Lactation Risk Summary Published studies have detected omega-3 fatty acids, including EPA, 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 on t …

12.1 Mechanism of Action Studies suggest that EPA reduces hepatic very low-density lipoprotein triglycerides (VLDL-TG) synthesis and/or secretion and enhances TG clearance from circulating VLDL particles. Potential mechanisms of action include increased β-oxidation; inhibition of acyl-CoA:1,2-diacylglycerol acyltransferase (DGAT); decreased lipogenesis in the liver; and increased plasma lipoprotein lipase activity.

11 DESCRIPTION Icosapent ethyl capsules, a lipid-regulating agent, is supplied as either a 0.5 gram or a 1 gram liquid-filled clear, transparent soft gelatin capsules containing clear to light yellow colored solution for oral use. Each icosapent ethyl capsule contains either 0.5 grams of icosapent ethyl (in a 0.5 gram capsule) or 1 gram of icosapent ethyl (in a 1 gram capsule). Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). The empirical formula of icosapent ethyl is C 22 H 34 O 2 and the molecular weight is 330.50. The chemical name for icosapent ethyl is ethyl all-cis-5,8,11,14,17-icosapentaenoate with the following chemical structure: Icosapent ethyl capsules also contain the following inactive ingredients: bloom gelatin, glycerin, alpha tocopherol, medium chain triglycerides, and lecithin. The capsules are imprinted either with white imprinting ink containing titanium dioxide, propylene glycol, and hypromellose 2910, or by laser printing. structure

16 HOW SUPPLIED/STORAGE AND HANDLING Icosapent ethyl capsules, 0.5 gm are oval, transparent, elastic soft gelatin capsule containing clear, light-yellow oil with a characteristic fish-like odour and with "1738" in white ink printed on the surface and are supplied as follows: NDC 70710-1738-4 in bottle of 240 capsules with child-resistant closure Icosapent ethyl capsules, 1 gm are oblong, transparent, elastic soft gelatin capsule containing clear, light-yellow oil with a characteristic fish-like odour and with "1592" in white ink printed on the surface and are supplied as follows: NDC 70710-1592-7 in bottle of 120 capsules with child-resistant closure Store at 20° to 25° C (68° to 77°F); excursions permitted to 15° to 30° C (59° to 86°F) [see USP Controlled Room Temperature].