REDUCINGCARDIOVASCULAR RISKTHE ROLE OF THE PHARMACIST

Pharmacists are among the most trusted and most accessible of all healthcare professionals (HCPs).7,8 In addition, they are one of the most frequently visited members of a healthcare team.8,9 Many of the frequent visitors of community pharmacies are patients with cardiovascular disease (CVD).10

Statin therapy, the fi rst-line option for high cholesterol, lowers levels of low-density lipoprotein cholesterol (LDL-C), or “bad” cholesterol, and has helped reduce the risk of developing life-threatening blockages in the arteries that can cause heart attacks and strokes.5,11-13 Despite the LDL-C–lowering effects of statin therapy, persistent CV risk remains.14 Other drugs, including but not limited to those listed below, are sometimes recommended in patients that cannot tolerate statins or in addition to statins for patients responding inadequately or with severe hypercholesterolemia.3,15

• Ezetimibe: An oral cholesterol absorption inhibitor taken in combination with statin therapy that has shown reduction in LDL-C levels and in the risk of heart attacks and ischemic strokes; however, it has not shown reduced risk of other CV events compared to when statin therapy is taken alone.16

• Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors: Recently shown to improve CV outcomes when added to statin therapy,17,18 these monoclonal antibodies are injectables and tend to be limited due to high-cost adoption.19,20

• VASCEPA (IPE): An oral medication containing an ethyl ester of omega-3 fatty acid that was recently FDA approved and clinically shown to reduce the risk of CV events.1,2 The American Diabetes Association has updated their 2019 guidelines to include IPE as a top-tier recommendation for CV risk reduction, and further recommendations to use IPE have been made by the European Society

PHARMACISTS CAN HELP PREVENT THE NEXT CARDIOVASCULAR EVENT

VASCEPA® (icosapent ethyl [IPE])—not your typical omega-3 fatty acid drug—could help millions of high-risk patients, including statin-treated patients and statin-intolerant patients, to reduce their cardiovascular (CV) risk.1,2

Multiple professional societies have updated guidelines or issued advisories recognizing IPE, including the American Diabetes Association, the European Society of Cardiology/European Atherosclerosis Society, the National Lipid Association, and the American Heart Association.3-6

MILLIONS TAKING STATIN-BASED STANDARD OF CARE EXPERIENCE PERSISTENT CVD

~39 MILLIONPEOPLE ARE

STATIN-TREATED

~6.3 MILLIONOF WHICH HAVE

CVD OR DIABETES (AND ≥2 RISK FACTORS)

~12 MILLIONOF WHICH HAVE TRIGLYCERIDE

LEVELS ≥150 mg/dL

INDICATIONS AND LIMITATIONS OF USE• VASCEPA® (icosapent ethyl) is indicated as an adjunct to maximally tolerated statin therapy to reduce the risk of

myocardial infarction, stroke, coronary revascularization and unstable angina requiring hospitalization in adult patients with elevated triglyceride (TG) levels (≥150 mg/dL) and established cardiovascular disease or diabetes mellitus and 2 or more additional risk factors for cardiovascular disease

• VASCEPA is indicated as an adjunct to diet to reduce TG levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia

The effect of VASCEPA on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined.IMPORTANT SAFETY INFORMATION• VASCEPA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to VASCEPA or any

of its components Please see additional Important Safety Information on inside pages and back cover.

of Cardiology/European Atherosclerosis Society, National Lipid Association, and American Heart Association.3-6

Encouragingly, studies have shown that during pharmacy visits, short educational interventions by pharmacists can positively infl uence their patients’ decision making,especially as it pertains to taking control and managing CV risk factors—highlighting the critical role of pharmacists in patient care.21 An example patient journey is presented to demonstrate the impact pharmacists have on patient outlook.

IMPORTANT SAFETY INFORMATION (continued)• VASCEPA was associated with an increased risk (3% vs 2%) of atrial fi brillation or atrial fl utter requiring hospitalization in

a double-blind, placebo-controlled trial. The incidence of atrial fi brillation was greater in patients with a previous history of atrial fi brillation or atrial fl utter

• It is not known whether patients with allergies to fi sh and/or shellfi sh are at an increased risk of an allergic reaction to VASCEPA. Patients with such allergies should discontinue VASCEPA if any reactions occur

Patient name:Ruth Collins

Medical history: • CV event within the past year• Dyslipidemia• Type 2 diabetes

Active prescriptions:MEDICATION

Atorvastatin 40 mg

Metformin 1000 mg

Empaglilfozin 25 mg

Liraglutide 1.8 mg

Lisinopril 40 mg

Clopidogrel 75 mg

Metoprolol 50 mg

Amiodarone 200 mg

TIMES/DAY

QD

BID

QD

QD

QD

QD

BID

QD

Age:62 years

Pharmacist: Hi! How are you doing today?

Patient: Same old. I’m here for my usual.

Pharmacist: You know, you might want to ask your doctor about whether the statin you’re taking is enough for protecting your heart. Research has shown that despite being on a statin, patients continue to be at risk. Maybe you can talk to your doctor about that.

Patient: Oh, really? I’ll ask during my upcoming checkup. Actually, I’ve heard about fi sh oils being good. Omega-3, right? Should I add that as a supplement to my medications?

Pharmacist: Many fi sh oil supplements have not been proven to benefi t the heart. The FDA does not regulate their manufacturing, purity, or content, and they have not shown evidence of effi cacy or safety in clinical trials. As such, fi sh oil products are not approved to treat, cure, or prevent any medical condition.

Patient: I didn’t know that! Well then, is there an alternative?

Pharmacist: There is something else that is FDA approved that might help you. It’s called VASCEPA. Let me write it down for you. It’s been proven in a large clinical trial with over 8000 people and has been shown to reduce the risk of cardiovascular events by 25%, including heart attacks and strokes when added to a statin.

Patient: Oh, I’m interested. I’ll be sure to ask my doctor about this and see if they’d recommend adding it to my treatment. Thanks!

Pharmacist: No problem! If you like, I can call your doctor directly and talk to them about prescribing it.

VASCEPA is a prescription medication and is the onlyomega-3 fatty acid product to show CV benefi t in a clinical trial.1.22

In December 2019, VASCEPA was granted a new indication based on the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT), which was conducted globally with an emphasis on a Western population and enrolled 8179 patients.1,22

The trial investigated the effects of VASCEPA on the occurrence of a major adverse CV event in adults 45 years of age or older who were on statin therapy with well-controlled LDL-C levels between 40 mg/dL and 100 mg/dL and elevated TG levels (90% of enrolled patients had TG levels between 150 mg/dL and 500 mg/dL), and either established CVD (71%) or diabetes and at least one additional CV risk factor (29%).1,22 Patients were randomized 1:1 VASCEPA 4 g/day (2 g twice a day with food; n=4089) or placebo (n=4090).1,22 The median follow-up duration was 4.9 years.1,22

VASCEPA 4 g/day administration resulted in a signifi cant reduction of 25% in risk of CV events relative to placebo (hazard ratio [HR] 0.75, 95% confi dence interval [CI] 0.68–0.83; p<0.001), evident after approximately 1 year of treatment.1,22 Treatment with VASCEPA for 1 year also signifi cantly lowered LDL-C and TG levels from baseline compared to placebo. The median change

VASCEPA: THE FIRST AND ONLY FDA-APPROVED, ORAL, SINGLE-AGENT IPE WITH PROVEN CV REDUCTION

in TG from baseline after 1 year of taking VASCEPA was-39 mg/dL (-18%) compared to 5 mg/dL (2%) in the placebo group.1 Moreover, the median change in LDL-C from baseline after 1 year of taking VASCEPA was 2 mg/dL (3%) compared to 7 mg/dL (10%) in the placebo group.1

VASCEPA has a well-established safety profi le.22 Common adverse reactions that occurred in the VASCEPA group during REDUCE-IT at a frequency of at least 3% and at least 1% more frequently than in the placebo group included musculoskeletal pain, peripheral edema, constipation, gout, and atrial fi brillation.1 VASCEPA has been associated with increased risks of bleeding and atrial fi brillation/fl utter, the latter being more prevalent in patients with a previous history of atrial fi brillation or fl utter.1,2

It should be noted that the exact mechanisms of action contributing to the reduction of CV events with VASCEPA are not completely understood but are likely multi-factorial.1

VASCEPA is indicated as an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization in adult patients with elevated triglyceride (TG) levels (≥150 mg/dL) and established CVD or diabetes mellitus and two or more additional risk factors for CVD.1

VASCEPA is also indicated as an adjunct to diet to reduce TG levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia.1

Common adverse reactions at a frequency of ≤3% and ≤1% more frequently in the VASCEPA group than in the placebo group include:

Musculoskeletal pain

Peripheral edema

Constipation Gout Atrial fi brillation

VASCEPA’S SAFETY PROFILE1

REDUCE-IT STUDY DESIGN1,22

8179 adults with:• Well-controlled LDL-C• Elevated TG levels

29% primary CVD prevention ≥50 yrs old + diabetes + ≥1 additional CV risk factor

71% secondary CVD prevention ≥45 yrs old + existing CVD

Placebo-controlled, double-blind trial

Median follow-up:4.9 years

Statin + VASCEPA 4 g/d

Statin + Placebo

Primary Endpoint 1st occurrence of a

Major Adverse CV Event (MACE)

(5-point MACE was defi ned as myocardial infarction, stroke, coronary

revascularization, unstable angina requiring hospitalization, and CV death)

VASCEPA’S EFFICACY1,22

reduction in risk of composite 1st occurrence of 5-point MACEwhen using VASCEPArelative to placebo

IMPORTANT SAFETY INFORMATION (continued)• VASCEPA was associated with an increased risk (12% vs 10%) of bleeding in a double-blind, placebo-controlled trial.

The incidence of bleeding was greater in patients receiving concomitant antithrombotic medications, such as aspirin, clopidogrel or warfarin

• Common adverse reactions in the cardiovascular outcomes trial (incidence ≥3% and ≥1% more frequent than placebo): musculoskeletal pain (4% vs 3%), peripheral edema (7% vs 5%), constipation (5% vs 4%), gout (4% vs 3%) and atrial fi brillation (5% vs 4%)

The results of VASCEPA in the REDUCE-IT trial cannot be extrapolated to generic omega-3 fatty acid products, which have failed to demonstrate an impact on the persistent risk of CV events in large-scale outcomes trials.22-27 However, it should be noted that no head-to-head trials have been conducted comparing VASCEPA and these generic omega-3 fatty acid drugs, and that cross-trial comparisons are subject to differences in populations, primary outcomes, and other trial design aspects.

It still stands that VASCEPA is the fi rst and only medication indicated to reduce CV risk in high-risk patients approved for treatment.1 VASCEPA is highly refi ned, naturally derived, and consists primarily of the omega-3 fatty

CV outcomes studies of prescription omega-3 mixture products, containing docosahexaenoic acid (DHA), have failed to demonstrate CV benefi t on top of statins.22-31

FDA-APPROVED VASCEPA IS NOT SUBSTITUTABLE WITH GENERIC OMEGA-3 FATTY ACID PRODUCTS

To learn more about how VASCEPA (IPE) can lower CVD risk, please see full Prescribing Information or visit www.vascepahcp.com.

VAS-02521 2/20

SINGLE-AGENT EPA, NO DHA

FDA APPROVEDand clinically proven

TWO 1-GRAM CAPSULES twice a day

NO REPORTED FISHY TASTE

PROVEN STABILITY

VASCEPA® (ICOSAPENT ETHYL)

CONTAINS EPA + DHA MIXTURE

NOT FDA APPROVEDnor clinically proven

10-40 CAPSULES a day to equal the EPA in a daily dose of VASCEPA

REPORTED FISHY TASTE

PRONE TO DETERIORATION

COMMON FISH OIL

1gEPAOnly active ingredient

Not actual depiction of product.

References: 1. VASCEPA [prescribing information]. Bedminster, NJ: Amarin Pharma Inc; 2019. 2. Amarin Corporation (December 13, 2019) [press release]. https://investor.amarincorp.com/node/18451/pdf. Accessed January 9, 2020. 3. Mach F, Baigent C, Catapano AL, et al. Eur Heart J. 2019:1-78. 4. Skulas-Ray AC, Wilson PWF, Harris WS, et al. Circulation. 2019;140(12):e673-e691. 5. American Diabetes Association. Diabetes Care. 2019;42(suppl 1):S103-S123. 6. Orringer CE, Jacobson TA, Maki KC. J Clin Lipidol. 2019;13(6):860-872. 7. Norman J. Social and Policy Issues: Americans Rate Healthcare Providers High on Honesty, Ethics. GALLUP. https://news.gallup.com/poll/200057/americans-rate-healthcare-providers-high-honesty-ethics.aspx. Last updated December 19, 2016. Accessed February 12, 2020. 8. Kelling SE, Rondon-Begazo A, DiPietro Mager NA, Murphy BL, Bright DR. Prev Chronic Dis. 2016;13:E149. 9. Manolakis PG, Skelton JB. Am J Pharm Educ. 2010;74(10):S7. 10. Santschi V, Chiolero A, Burnand B, Colosimo AL, Paradis G. Arch Intern Med. 2011;171(16):1441-1453. 11. Arnett DK, Blumenthal RS, Albert MA, et al. Circulation. 2019;140:e596-e646. 12. Gaudette É, Goldman DP, Messali A, Sood N. Pharmacoeconomics. 2015;33(7):723-734. 13. US National Library of Medicine. Statins. MedlinePlus website. https://medlineplus.gov/statins.html. Accessed January 9, 2020. 14. Ridker PM. J Am Coll Cardiol. 2018;72(25):3320-3331. 15. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. J Am Coll Cardiol. 2017;70(14):1785-1822. 16. Cannon CP, Blazing MA, Giugliano RP, et al. N Engl J Med. 2015;372(25):2387-2397. 17. Sabatine MS, Giugliano RP, Keech AC, et al. N Engl J Med. 2017;376(18):1713-1722. 18. Schwartz GG, Steg PG, Szarek M, et al. N Engl J Med. 2018;379(22):2097-2107. 19. Chaudhary R, Garg J, Shah N, Sumner A. World J Cardiol.2017;9(2):76-91. 20. Dixon DL, Trankle C, Buckley L, et al. J Clin Lipidol. 2016;10(5):1073-1080. 21. Taitel M, Jiang J, Rudkin K, Ewing S, Duncan I. Patient Prefer Adherence. 2012;6:323-329. 22. Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2019;380(1):11-22. 23. Ganda OP, Bhatt DL, Mason RP, Miller M, Boden WE. J Am Coll Cardiol. 2018;72(3):330-343. 24. Bosch J, Gerstein HC, Dagenais GR, et al. N Engl J Med. 2012;367(4):309-318. 25. Rauch B, Schiele R, Schneider S, et al. Circulation. 2010;122(21):2152-2159. 26. Bowman L, Mafham M, Wallendszus K, et al. N Engl J Med. 2018;379(16):1540-1550. 27. Manson JE, Cook NR, Lee IM, et al. N Engl J Med. 2019;380(1):33-44. 28. Data on fi le. Amarin Pharma, Inc; 2018. 29. Mason RP, Sherratt SCR. Biochem Biophys Res Commun. 2017;483(1):425-429. 30. Ishida T, Ohta M, Nakakuki M, et al. Prostaglandins Leukot Essent Fatty Acids. 2013;88(4):281-288. 31. Dawson K, Zhao L, Adkins Y, et al. J Nutr Biochem. 2012;23(6):616-621.

0.15 g OTHER

0.38gDHA

0.47 gEPA

acid eicosapentaenoic acid (EPA).1,28 Unlike VASCEPA, generic omega-3 fatty acid drugs contain both EPA and DHA.29 While use of either VASCEPA or generic omega-3 fatty acid drugs have demonstrated lower TG levels, DHA-containing products may raise LDL-C in patients with elevated TG.1,23-27,30,31 Moreover, DHA-containing products are not FDA approved for co-administration with statins to affect lipid, lipoprotein, or infl ammation parameters with the aim of reducing CV mortality or morbidity.

VASCEPA is IPE, the only FDA-approved EPA that has undergone a proprietary purifi cation process to extract toxins, saturated fats, and LDL-raising DHA, and—once again—it is the only EPA approved to reduce CV risk.1,28

IMPORTANT SAFETY INFORMATION (continued)• Common adverse reactions in the hypertriglyceridemia trials (incidence ≥1% more frequent than placebo): arthralgia

(2% vs 1%) and oropharyngeal pain (1% vs 0.3%)• Adverse events may be reported by calling 1-855-VASCEPA or the FDA at 1-800-FDA-1088• Patients receiving VASCEPA and concomitant anticoagulants and/or anti-platelet agents for bleeding should

be monitoredPlease see adjacent page for brief summary of full Prescribing Information or visit www.vascepahcp.com.

VASCEPA (Icosapent ethyl) Capsules, for oral use Brief Summary of Prescribing InformationPlease see Full Prescribing information for additional information about VASCEPA.

1 INDICATIONS AND USAGEVASCEPA® (icosapent ethyl) is indicated:• as an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial

infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization in adult patients with elevated triglyceride (TG) levels (≥ 150 mg/dL) ando established cardiovascular disease oro diabetes mellitus and 2 or more additional risk factors for cardiovascular disease.

• as an adjunct to diet to reduce TG levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia.

Limitations of Use:The effect of VASCEPA on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined.

2 DOSAGE AND ADMINISTRATION2.1 Prior to Initiation of VASCEPA

• 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 VASCEPA, which should continue during treatment with VASCEPA.

2.2 Dosage and Administration• The daily dose of VASCEPA is 4 grams per day taken as either:

o four 0.5 gram capsules twice daily with food; or aso two 1 gram capsules twice daily with food.

• Advise patients to swallow VASCEPA capsules whole. Do not break open, crush, dissolve, or chew VASCEPA.

4 CONTRAINDICATIONSVASCEPA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to VASCEPA or any of its components.

5 WARNINGS AND PRECAUTIONS5.1 Atrial Fibrillation/Flutter

VASCEPA is associated with an increased risk of atrial fibrillation or atrial flutter requiring hospitalization. In a double-blind, placebo-controlled trial of 8,179 statin-treated subjects with established cardiovascular disease (CVD) or diabetes plus an additional risk factor for CVD, adjudicated atrial fibrillation or atrial flutter requiring hospitalization for 24 or more hours occurred in 127 (3%) patients treated with VASCEPA 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 AllergyVASCEPA 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 VASCEPA. Inform patients with known hypersensitivity to fish and/or shellfish about the potential for allergic reactions to VASCEPA and advise them to discontinue VASCEPA and seek medical attention if any reactions occur.

5.3 Bleeding VASCEPA is associated with an increased risk of bleeding. In a double-blind, placebo-controlled cardiovascular outcomes trial of 8,179 patients, 482 (12%) patients receiving VASCEPA experienced a bleeding event compared to 404 (10%) patients receiving placebo. Serious bleeding events occurred in 111 (3%) of patients on VASCEPA 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.

6 ADVERSE REACTIONSThe 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)]

6.1 Clinical Trials ExperienceBecause 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.

Cardiovascular Outcomes TrialIn a double-blind, randomized, placebo-controlled cardiovascular outcomes trial, 8,179 statin-stabilized patients were randomized to receive VASCEPA or placebo and followed for a median of 4.9 years [see Clinical Studies (14.1)]. The median age at baseline was 64 years, 29% were women, 90% White, 5% Asian, 2% were Black, and 4% identified as Hispanic ethnicity. Common adverse reactions (incidence ≥3% on VASCEPA and ≥1% more frequent than placebo) included musculoskeletal pain, peripheral edema, constipation, gout, and atrial fibrillation.

Hypertriglyceridemia TrialsIn 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 VASCEPA at an incidence ≥1% more frequent than placebo based on pooled data included arthralgia and oropharyngeal pain.

6.2 Postmarketing ExperienceAdditional adverse reactions have been identified during post-approval use of VASCEPA. 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 INTERACTIONS7.1 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 VASCEPA and concomitant anticoagulants and/or antiplatelet agents for bleeding.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyRisk Summary

The available data from published case reports and the pharmacovigilance database on the use of VASCEPA 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 2-4% and 15-20%, respectively.

DataAnimal 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 LactationRisk 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 VASCEPA and any potential adverse effects on the breastfed child from VASCEPA or from the underlying maternal condition.

8.4 Pediatric UseSafety and effectiveness in pediatric patients have not been established.

8.5 Geriatric UseOf the total number of patients in well-controlled clinical studies of VASCEPA, 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 ImpairmentIn patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored periodically during therapy with VASCEPA.

17 PATIENT COUNSELING INFORMATIONAdvise the patient to read the FDA-approved patient labeling before starting VASCEPA (Patient Information).

VASCEPA® (icosapent ethyl)Distributed by: Manufactured for: Amarin Pharma, Inc. Amarin Pharmaceuticals Ireland Limited Bridgewater, NJ, USA Dublin, Ireland

VASCEPA is a registered trademark of the Amarin group of companies.©2020 Amarin Pharma, Inc. Bridgewater NJ 08807. All rights reserved. PP00120M 12/19

VAS-02464 01/20

VASCEPA (Icosapent ethyl) Capsules, for oral use Brief Summary of Prescribing InformationPlease see Full Prescribing information for additional information about VASCEPA.

1 INDICATIONS AND USAGEVASCEPA® (icosapent ethyl) is indicated:• as an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial

infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization in adult patients with elevated triglyceride (TG) levels (≥ 150 mg/dL) ando established cardiovascular disease oro diabetes mellitus and 2 or more additional risk factors for cardiovascular disease.

• as an adjunct to diet to reduce TG levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia.

Limitations of Use:The effect of VASCEPA on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined.

2 DOSAGE AND ADMINISTRATION2.1 Prior to Initiation of VASCEPA

• 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 VASCEPA, which should continue during treatment with VASCEPA.

2.2 Dosage and Administration• The daily dose of VASCEPA is 4 grams per day taken as either:

o four 0.5 gram capsules twice daily with food; or aso two 1 gram capsules twice daily with food.

• Advise patients to swallow VASCEPA capsules whole. Do not break open, crush, dissolve, or chew VASCEPA.

4 CONTRAINDICATIONSVASCEPA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to VASCEPA or any of its components.

5 WARNINGS AND PRECAUTIONS5.1 Atrial Fibrillation/Flutter

VASCEPA is associated with an increased risk of atrial fibrillation or atrial flutter requiring hospitalization. In a double-blind, placebo-controlled trial of 8,179 statin-treated subjects with established cardiovascular disease (CVD) or diabetes plus an additional risk factor for CVD, adjudicated atrial fibrillation or atrial flutter requiring hospitalization for 24 or more hours occurred in 127 (3%) patients treated with VASCEPA 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 AllergyVASCEPA 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 VASCEPA. Inform patients with known hypersensitivity to fish and/or shellfish about the potential for allergic reactions to VASCEPA and advise them to discontinue VASCEPA and seek medical attention if any reactions occur.

5.3 Bleeding VASCEPA is associated with an increased risk of bleeding. In a double-blind, placebo-controlled cardiovascular outcomes trial of 8,179 patients, 482 (12%) patients receiving VASCEPA experienced a bleeding event compared to 404 (10%) patients receiving placebo. Serious bleeding events occurred in 111 (3%) of patients on VASCEPA 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.

6 ADVERSE REACTIONSThe 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)]

6.1 Clinical Trials ExperienceBecause 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.

Cardiovascular Outcomes TrialIn a double-blind, randomized, placebo-controlled cardiovascular outcomes trial, 8,179 statin-stabilized patients were randomized to receive VASCEPA or placebo and followed for a median of 4.9 years [see Clinical Studies (14.1)]. The median age at baseline was 64 years, 29% were women, 90% White, 5% Asian, 2% were Black, and 4% identified as Hispanic ethnicity. Common adverse reactions (incidence ≥3% on VASCEPA and ≥1% more frequent than placebo) included musculoskeletal pain, peripheral edema, constipation, gout, and atrial fibrillation.

Hypertriglyceridemia TrialsIn 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 VASCEPA at an incidence ≥1% more frequent than placebo based on pooled data included arthralgia and oropharyngeal pain.

6.2 Postmarketing ExperienceAdditional adverse reactions have been identified during post-approval use of VASCEPA. 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 INTERACTIONS7.1 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 VASCEPA and concomitant anticoagulants and/or antiplatelet agents for bleeding.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyRisk Summary

The available data from published case reports and the pharmacovigilance database on the use of VASCEPA 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 2-4% and 15-20%, respectively.

DataAnimal 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 LactationRisk 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 VASCEPA and any potential adverse effects on the breastfed child from VASCEPA or from the underlying maternal condition.

8.4 Pediatric UseSafety and effectiveness in pediatric patients have not been established.

8.5 Geriatric UseOf the total number of patients in well-controlled clinical studies of VASCEPA, 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 ImpairmentIn patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored periodically during therapy with VASCEPA.

17 PATIENT COUNSELING INFORMATIONAdvise the patient to read the FDA-approved patient labeling before starting VASCEPA (Patient Information).

VASCEPA® (icosapent ethyl)Distributed by: Manufactured for: Amarin Pharma, Inc. Amarin Pharmaceuticals Ireland Limited Bridgewater, NJ, USA Dublin, Ireland

VASCEPA is a registered trademark of the Amarin group of companies.©2020 Amarin Pharma, Inc. Bridgewater NJ 08807. All rights reserved. PP00120M 12/19

VAS-02464 01/20