acebo-controlled trial. the incidence of bleeding was greater in patients receiving concomitant antithrombotic medications, such as aspirin, clopidogrel, or warfarin. ( 5.3 ) 5.1 atrial fibrillation/flutter icosapent ethyl is associated with an increased risk of atrial fibrillation or atrial flutter requiring hospitalization. in a double-blind, placebo-controlled trial of 8,179 subjects, adjudicated atrial fibrillation or atrial flutter requiring hospitalization for 24 or more hours occurred in 127 (3%) patients treated with icosapent ethyl compared to 84 (2%) patients receiving placebo [hr= 1.5 (95% ci 1.14, 1.98)]. the incidence of atrial fibrillation was greater in patients with a previous history of atrial fibrillation or atrial flutter. 5.2 potential for allergic reactions in patients with fish allergy icosapent ethyl contains ethyl esters of the omega-3 fatty acid, eicosapentaenoic acid (epa), obtained from the oil of fish. it is not known whether patients with allergies to fish and/or shellfish are at increased risk of an allergic reaction to icosapent ethyl. inform patients with known hypersensitivity to fish and/or shellfish about the potential for allergic reactions to icosapent ethyl and advise them to discontinue icosapent ethyl and seek medical attention if any reactions occur. 5.3 bleeding icosapent ethyl is associated with an increased risk of bleeding. in a double-blind, placebo-controlled trial of 8,179 patients, 482 (12%) patients receiving icosapent ethyl experienced a bleeding event compared to 404 (10%) patients receiving placebo. serious bleeding events occurred in 111 (3%) of patients on icosapent ethyl vs. 85 (2%) of patients receiving placebo. the incidence of bleeding was greater in patients receiving concomitant antithrombotic medications, such as aspirin, clopidogrel, or warfarin.

ethyl. 2.2 dosage and administration • the daily dose of icosapent ethyl is 4 grams per day taken as: o 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.

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. 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

nown. 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 2-4% and 15-20%, 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 7-17, 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 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 icosapent ethyl and any potential adverse effects on the breastfed child from icosapent ethyl or from the underlying maternal condition. 8.4 pediatric use safety and effectiveness in pediatric patients have not been established. 8.5 geriatric use of the total number of patients in well-controlled clinical studies of icosapent ethyl, 45% were 65 years of age and over. no overall differences in safety or effectiveness were observed between these patients and younger groups. other reported clinical experience has not identified differences in responses between the elderly and younger patients. 8.7 hepatic impairment in patients with hepatic impairment, alanine aminotransferase (alt) and aspartate aminotransferase (ast) levels should be monitored periodically during therapy with icosapent ethyl.

ackground 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 2-4% and 15-20%, 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 7-17, 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.

urs following oral doses of icosapent ethyl. icosapent ethyl was administered with or following a meal in all clinical studies; no food effect studies were performed. take icosapent ethyl with or following a meal. distribution the mean volume of distribution at steady state of epa is approximately 88 liters. the majority of epa circulating in plasma is incorporated in phospholipids, triglycerides and cholesteryl esters, and <1% is present as the unesterified fatty acid. greater than 99% of unesterified epa is bound to plasma proteins. elimination metabolism epa is mainly metabolized by the liver via beta-oxidation similar to dietary fatty acids. beta oxidation splits the long carbon chain of epa into acetyl coenzyme a, which is converted into energy via the krebs cycle. cytochrome p450-mediated metabolism is a minor pathway of elimination of epa. excretion the total plasma clearance of epa at steady state is 684 ml/hr. the plasma elimination half-life (t 1/2 ) of epa is approximately 89 hours. icosapent ethyl does not undergo renal excretion. specific populations gender when administered icosapent ethyl in clinical trials, plasma total epa concentrations did not differ significantly between men and women. pediatric the pharmacokinetics of icosapent ethyl has not been studied in pediatric patients. hepatic or renal impairment icosapent ethyl has not been studied in patients with renal or hepatic impairment. drug interaction studies omeprazole: in a drug-drug interaction study with 28 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the steady-state auc τ or c max of omeprazole when co-administered at 40 mg/day to steady-state. rosiglitazone: in a drug-drug interaction study with 28 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the single dose auc or c max of rosiglitazone at 8 mg. warfarin: in a drug-drug interaction study with 25 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the single dose auc or c max of r - and s -warfarin or the anti-coagulation pharmacodynamics of warfarin when co-administered as racemic warfarin at 25 mg. atorvastatin: in a drug-drug interaction study of 26 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the steady-state auc τ or c max of atorvastatin, 2-hydroxyatorvastatin, or 4-hydroxyatorvastatin when co-administered with atorvastatin 80 mg/day at steady-state.

tion splits the long carbon chain of epa into acetyl coenzyme a, which is converted into energy via the krebs cycle. cytochrome p450-mediated metabolism is a minor pathway of elimination of epa. excretion the total plasma clearance of epa at steady state is 684 ml/hr. the plasma elimination half-life (t 1/2 ) of epa is approximately 89 hours. icosapent ethyl does not undergo renal excretion. specific populations gender when administered icosapent ethyl in clinical trials, plasma total epa concentrations did not differ significantly between men and women. pediatric the pharmacokinetics of icosapent ethyl has not been studied in pediatric patients. hepatic or renal impairment icosapent ethyl has not been studied in patients with renal or hepatic impairment. drug interaction studies omeprazole: in a drug-drug interaction study with 28 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the steady-state auc τ or c max of omeprazole when co-administered at 40 mg/day to steady-state. rosiglitazone: in a drug-drug interaction study with 28 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the single dose auc or c max of rosiglitazone at 8 mg. warfarin: in a drug-drug interaction study with 25 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the single dose auc or c max of r - and s -warfarin or the anti-coagulation pharmacodynamics of warfarin when co-administered as racemic warfarin at 25 mg. atorvastatin: in a drug-drug interaction study of 26 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the steady-state auc τ or c max of atorvastatin, 2-hydroxyatorvastatin, or 4-hydroxyatorvastatin when co-administered with atorvastatin 80 mg/day at steady-state.

al excretion of oil and therefore not clinically relevant. drug-related neoplasms were not observed in female mice. icosapent ethyl was not mutagenic with or without metabolic activation in the bacterial mutagenesis (ames) assay or in the in vivo mouse micronucleus assay. a chromosomal aberration assay in chinese hamster ovary (cho) cells was positive for clastogenicity with and without metabolic activation. in an oral gavage rat fertility study, ethyl-epa, administered at doses of 0.3, 1, and 3 g/kg/day to male rats for 9 weeks before mating and to female rats for 14 days before mating through day 7 of gestation, increased anogenital distance in female pups and increased cervical ribs were observed at 3 g/kg/day (7 times human systemic exposure with 4 g/day clinical dose based on a body surface area comparison).

erefore not clinically relevant. drug-related neoplasms were not observed in female mice. icosapent ethyl was not mutagenic with or without metabolic activation in the bacterial mutagenesis (ames) assay or in the in vivo mouse micronucleus assay. a chromosomal aberration assay in chinese hamster ovary (cho) cells was positive for clastogenicity with and without metabolic activation. in an oral gavage rat fertility study, ethyl-epa, administered at doses of 0.3, 1, and 3 g/kg/day to male rats for 9 weeks before mating and to female rats for 14 days before mating through day 7 of gestation, increased anogenital distance in female pups and increased cervical ribs were observed at 3 g/kg/day (7 times human systemic exposure with 4 g/day clinical dose based on a body surface area comparison).

seline in lipid parameters in patients with severe hypertriglyceridemia (≥500 mg/dl) parameter icosapent ethyl 4 g/day n=76 placebo n=75 difference (95% confidence interval) baseline % change baseline % change tg (mg/dl) 680 -27 703 +10 -33 1 (-47, -22) ldl-c (mg/dl) 91 -5 86 -3 -2 (-13, +8) non-hdl-c (mg/dl) 225 -8 229 +8 -18 (-25, -11) tc (mg/dl) 254 -7 256 +8 -16 (-22, -11) hdl-c (mg/dl) 27 -4 27 0 -4 (-9, +2) vldl-c (mg/dl) 123 -20 124 +14 -29 2 (-43, -14) apo b (mg/dl) 121 -4 118 +4 -9 2 (-14, -3) % change = median percent change from baseline difference = median of [icosapent ethyl % change – placebo % change] (hodges-lehmann estimate) p-values from wilcoxon rank-sum test icosapent ethyl 4 grams per day reduced median tg, vldl-c, and apo b levels from baseline relative to placebo. the reduction in tg observed with icosapent ethyl was not associated with elevations in ldl-c levels relative to placebo.

as soon as they remember. however, if they miss one day of icosapent ethyl, they should not double the dose when they take it. for more information about icosapent ethyl, please call northstar rx llc at 1-800-206-7821. manufactured for: northstar rx llc memphis, tn 38141 manufactured by: catalent pharma solutions, llc. st. petersburg, florida 33716 c50001298/01 revised october 2022

o fish or shellfish are also allergic to icosapent ethyl. • are pregnant, or planning to become pregnant. it is not known if icosapent ethyl will harm your unborn baby. • are breastfeeding or plan to breastfeed. icosapent ethyl can pass into your breast milk, and may harm your baby. talk to your doctor about the best way to feed your baby if you take icosapent ethyl. tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and dietary or herbal supplements. icosapent ethyl can interact with certain other medicines that you are taking. especially tell your doctor if you take medicines that affect your blood clotting (anticoagulants or blood thinners). how should i take icosapent ethyl? • take icosapent ethyl exactly as your doctor tells you to take it. • do not change your dose or stop taking icosapent ethyl without talking to your doctor. • do not take more capsules than what is prescribed by your doctor. o if you are prescribed the 1 gram capsules, you should not take more than 4 capsules each day with food. • take icosapent ethyl capsules whole. do not break, crush, dissolve, or chew icosapent ethyl capsules before swallowing. • if you miss a dose of icosapent ethyl, take it as soon as you remember. however, if you miss one day of icosapent ethyl, do not double your dose when you take it. • your doctor may start you on a diet that is low in saturated fat, cholesterol, carbohydrates, and low in added sugars before giving you icosapent ethyl. stay on this diet while taking icosapent ethyl. • your doctor may do blood tests to check your triglyceride and other lipid levels while you take icosapent ethyl. what are the possible side effects of icosapent ethyl? icosapent ethyl may cause serious side effects, including: • heart rhythm problems (atrial fibrillation and atrial flutter). heart rhythm problems which can be serious and cause hospitalization have happened in people who take icosapent ethyl, especially in people who have heart (cardiovascular) disease or diabetes with a risk factor for heart (cardiovascular) disease, or who have had heart rhythm problems in the past. tell your doctor if you get any symptoms of heart rhythm problems such as feeling as if your heart is beating fast and irregular, lightheadedness, dizziness, shortness of breath, chest discomfort, or you faint. • possible allergic reactions if you are allergic to fish or shellfish. stop taking icosapent ethyl and tell your doctor right away or get emergency medical help if you have any signs or symptoms of an allergic reaction. • bleeding . serious bleeding can happen in people who take icosapent ethyl. your risk of bleeding may increase if you are also taking a blood thinner medicine. if you have liver problems and are taking icosapent ethyl, your doctor should do blood tests during treatment. the most common side effects of icosapent ethyl include: • muscle and joint pain. • swelling of the hands, legs, or feet. • constipation • gout • heart rhythm problems (atrial fibrillation). these are not all the possible side effects of icosapent ethyl. 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 icosapent ethyl capsules? • store icosapent ethyl at room temperature between 68° to 77° f (20° to 25° c). • safely throw away medicine that is out of date or no longer needed. keep icosapent ethyl and all medicine out of the reach of children. general information about the safe and effective use of icosapent ethyl. medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. do not use icosapent ethyl for a condition for which it was not prescribed. do not give icosapent ethyl to other people, even if they have the same symptoms that you have. it may harm them. you can ask your pharmacist or healthcare provider for information about icosapent ethyl that is written for health professionals. what are the ingredients in icosapent ethyl capsules? active ingredient: icosapent ethyl inactive ingredients: gelatin, glycerin, purified water, sorbitol, sorbitan and tocopherol. the monogramming ink ingredients contain: ammonium hydroxide, iron oxide black, isopropyl alcohol, macrogol, polyvinyl acetate phthalate, propylene glycol, purified water and sda alcohol (ethanol and ethyl acetate). this patient information has been approved by the u.s. food and drug administration. manufactured for: northstar rx llc memphis, tn 38141 manufactured by: catalent pharma solutions, llc. st. petersburg, florida 33716 c50001298/01 revised october 2022