Case 1:20-cv-01630-RGA Document 1-6 Filed 11/30/20 Page 1 of 11 PageID #: 88
`
`Exhibit F
`
`

`

`Case 1:20-cv-01630-RGA Document 1-6 Filed 11/30/20 Page 2 of 11 PageID #: 89
`
`
`
`
`------------------------WARNINGS and PRECAUTIONS------------------------­
`In patients with hepatic impairment, monitor ALT and AST levels
`
`
`
`periodically during therapy. (5.1)
`
`
`
`Use with caution in patients with known hypersensitivity to fish and/or
`
`
`
`
`
`shellfish. (5.2)
`
`
`
`-------------------------------ADVERSE REACTIONS-----------------------------­
`
`The most common reported adverse reaction (incidence >2% and greater than
`
`placebo) was arthralgia. (6)
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Amarin
`
`
`
`Pharma Inc. at 1-855-VASCEPA (1-855-827-2372) or contact the FDA at
`
`
`
`
`
`1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`------------------------------DRUG INTERACTIONS-------------------------------­
`
`Omega-3 acids may prolong bleeding time. Patients receiving treatment with
`
`
`
`
`
`
`
`
`
`VASCEPA and other drugs affecting coagulation (e.g., anti-platelet agents)
`
`
`
`should be monitored periodically. (7)
`
`
`
`
`-------------------------USE IN SPECIFIC POPULATIONS---------------------­
`
`Pregnancy: Use during pregnancy only if the potential benefit justifies the
`
`potential risk to the fetus. (8.1)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`approved patient labeling.
`
`
`
`Revised: 2/2017
`
`
`
`
`
`
`
`9 DRUG ABUSE AND DEPENDENCE
`
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of
`
`
`
`
`Fertility
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Severe Hypertriglyceridemia
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`17.1 Information for Patients
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`
`listed.
`
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` VASCEPA® (icosapent ethyl) Capsules, for oral use
`
`
` Initial U.S. Approval: 2012
`
`These highlights do not include all the information needed to use
`
`
`
` VASCEPA® safely and effectively. See full prescribing information for
`
`
`
`
`
` VASCEPA.
` --------------------------INDICATIONS AND USAGE-----------------------------­
`
`VASCEPA is 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 VASCEPA on the risk for pancreatitis in patients with severe
`
`
`
`hypertriglyceridemia has not been determined. (1)
`
`
`
`•The effect of VASCEPA on cardiovascular mortality and morbidity in
`
`patients with severe hypertriglyceridemia has not been determined. (1)
`
`
`
`-----------------------DOSAGE AND ADMINISTRATION-----------------------­
`
`
`
`The daily dose of VASCEPA is 4 grams per day taken as four 0.5-gram
`
`
`
`capsules or two 1-gram capsules twice daily with food. (2)
`
`
`
`
`
`
`
`Patients should be advised to swallow VASCEPA capsules whole. Do not
`
`
`
`
`
`break open, crush, dissolve, or chew VASCEPA. (2)
`
`
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`Capsules: 0.5-gram and 1-gram (3)
`
`
`
`
`---------------------------------CONTRAINDICATIONS----------------------------­
`VASCEPA is contraindicated in patients with known hypersensitivity (e.g.,
`
`
`
`
`anaphylactic reaction) to VASCEPA or any of its components. (4)
`
`____________________________________________________________________________________________________________________
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION:
`
`
`
`CONTENTS*
`
`INDICATIONS AND USAGE
`1
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Monitoring: Laboratory Tests
`
`
`5.2 Fish Allergy
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`
`7.1 Anticoagulants
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4057318
`
`
`
`
`
` Page 1 of 8
`
`
`
`

`

`
`
`
`
`Case 1:20-cv-01630-RGA Document 1-6 Filed 11/30/20 Page 3 of 11 PageID #: 90
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` 1
`
`
`
` INDICATIONS AND USAGE
`VASCEPA® (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride
`
`
`
`
`(TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia.
`
`Usage Considerations: Patients should be placed on an appropriate lipid-lowering diet and
`
`
`
`
`
`exercise regimen before receiving VASCEPA and should continue this diet and exercise regimen
`
`with VASCEPA.
`Attempts should be made to control any medical problems such as diabetes mellitus,
`
`
`
`hypothyroidism, and alcohol intake that may contribute to 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 VASCEPA on the risk for pancreatitis in patients with severe
`
`
`hypertriglyceridemia has not been determined.
`
`The effect of VASCEPA on cardiovascular mortality and morbidity in patients with
`
`severe hypertriglyceridemia has not been determined.
`
`
`2
`
`
`
`DOSAGE AND ADMINISTRATION
`
`
`
`Assess lipid levels before initiating therapy. Identify other causes (e.g., diabetes mellitus,
`hypothyroidism, or medications) of high triglyceride levels and manage as appropriate. [see
`
`
`
`
`Indications and Usage (1)].
`
`
`
`Patients should engage in appropriate nutritional intake and physical activity before
`
`
`receiving VASCEPA, which should continue during treatment with VASCEPA.
`
`
`The daily dose of VASCEPA is 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
`
`•
`
`
`
`Patients should be advised to swallow VASCEPA capsules whole. Do not break open,
`
`
`crush, dissolve, or chew VASCEPA.
`
`
`3
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`VASCEPA capsules are supplied in the following dosage form strengths:
`
`
`• 0.5-gram amber-colored, oval, soft-gelatin capsules imprinted with V500.
`
`
`• 1-gram amber-colored, oblong, soft-gelatin capsules imprinted with VASCEPA.
`
`
`
`
`CONTRAINDICATIONS
`4
`
`
`
`VASCEPA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic
`
`
`reaction) to VASCEPA or any of its components.
`
`
`
`
`WARNINGS AND PRECAUTIONS
`5
`
`
`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 VASCEPA.
`
`
`
`Reference ID: 4057318
`
`
`
`
`
`
` Page 2 of 8
`
`

`

`
`
`
`
`Case 1:20-cv-01630-RGA Document 1-6 Filed 11/30/20 Page 4 of 11 PageID #: 91
`
`
`Fish Allergy
`5.2
`
` VASCEPA 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. VASCEPA should be used
`with caution in patients with known hypersensitivity to fish and/or shellfish.
`
`6
`ADVERSE REACTIONS
`
`
` 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.
`
`
`
`Adverse reactions reported in at least 2% and at a greater rate than placebo for patients
`
`
`
`
`treated with VASCEPA based on pooled data across two clinical studies are listed in Table 1.
`
`
`
`
`
`
`
`
`
`Table 1. Adverse Reactions Occurring at Incidence >2% and Greater than Placebo in
`
`
`Double-Blind, Placebo-Controlled Trials*
`
`
`
`
` VASCEPA
`
` Placebo
`
` (N=622)
`
` (N=309)
`
` %
`
` n
`
` Adverse Reaction
` %
`
`
` n
` 2.3
`
`
` 14
`
` 1.0
`
`
` Arthralgia 3
`
` *Studies included patients with triglycerides values of 200 to 2000 mg/dL.
`
`
`
`
`
`
`
`
`
` An additional adverse reaction from clinical studies was oropharyngeal pain.
`
`
`
`
`
`
`
` 7
`
` DRUG INTERACTIONS
`
` 7.1 Anticoagulants
`
`
`
`
`
` 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. Patients receiving
` treatment with VASCEPA and other drugs affecting coagulation (e.g., anti-platelet agents)
`
`
`
`
`
`
`should be monitored periodically.
`
`
`
` USE IN SPECIFIC POPULATIONS
` 8
`
`
`
` 8.1 Pregnancy
` Pregnancy Category C: There are no adequate and well-controlled studies in pregnant
`
`
`
` women. It is unknown whether VASCEPA can cause fetal harm when administered to a pregnant
`
`
`
` woman or can affect reproductive capacity. VASCEPA should be used during pregnancy only if
` the potential benefit to the patient justifies the potential risk to the fetus.
`
`
`
`
` 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 visceral or skeletal abnormalities
`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. Variations including incomplete or abnormal ossification of various
`
`
`
`
`skeletal bones were observed in the 2 g/kg/day group at 5 times human systemic exposure
`
`
`following an oral dose of 4 g/day based on body surface area comparison.
`
`
`
`In a multigenerational developmental study in pregnant rats given oral gavage doses of
`
`0.3, 1, 3 g/kg/day ethyl-EPA from gestation day 7-17, an increased incidence of absent optic
`
`
`
`
` Page 3 of 8
`
`Reference ID: 4057318
`
`
`

`

`
`
`
`
`Case 1:20-cv-01630-RGA Document 1-6 Filed 11/30/20 Page 5 of 11 PageID #: 92
`
`
` nerves and unilateral testes atrophy were observed at ≥0.3 g/kg/day at human systemic exposure
`
`
`
` following an oral dose of 4 g/day based on body surface area comparisons across species.
` 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 multigenerational effects of ethyl-EPA 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 from gestation
`
`
`
`through organogenesis there were increased dead fetuses at 1 g/kg/day secondary to maternal
`
`
`toxicity (significantly decreased food consumption and body weight loss).
`
`In pregnant rats given ethyl-EPA from gestation day 17 through lactation day 20 at 0.3, 1,
`
`
`3 g/kg/day complete litter loss was observed in 2/23 litters at the low dose and 1/23 mid-dose
`
`
`dams by post-natal day 4 at human exposures based on a maximum dose of 4 g/day comparing
`
`body surface areas across species.
`
`
`
`8.3 Nursing Mothers
`
`Studies with omega-3-acid ethyl esters have demonstrated excretion in human milk. The
`
`
`effect of this excretion on the infant of a nursing mother is unknown; caution should be exercised
`
`
`
`when VASCEPA is administered to a nursing mother. An animal study in lactating rats given
`oral gavage 14C-ethyl EPA demonstrated that drug levels were 6 to 14 times higher in milk than
`
`
`in plasma.
`
`
`
`8.4 Pediatric Use
`
`
`Safety and effectiveness in pediatric patients have not been established.
`
`
`
`
`8.5 Geriatric Use
`
`
`Of the total number of subjects in clinical studies of VASCEPA, 33% were 65 years of
`age and over. No overall differences in safety or effectiveness were observed between these
`
`subjects and younger subjects, and other reported clinical experience has not identified
`differences in responses between the elderly and younger patients, but greater sensitivity of some
`
`
`
`
`older individuals cannot be ruled out.
`
`
`9
`
`
`DRUG ABUSE AND DEPENDENCE
`
`VASCEPA does not have any known drug abuse or withdrawal effects.
`
`
`
`
`
`
`11
`
`
`DESCRIPTION
`
`VASCEPA, a lipid-regulating agent, is supplied as either a 0.5-gram or a 1-gram amber-
`
`
`
`colored, liquid-filled soft gelatin capsule for oral administration.
`
`
`
`
`Each VASCEPA 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
`
`
`C22H34O2 and the molecular weight is 330.51. The chemical name for icosapent ethyl is ethyl all-
`
`
`
`cis-5,8,11,14,17-icosapentaenoate with the following chemical structure:
`
`
`
`
`Reference ID: 4057318
`
`
`
`
`
`
` Page 4 of 8
`
`

`

`
`
`
`
`Case 1:20-cv-01630-RGA Document 1-6 Filed 11/30/20 Page 6 of 11 PageID #: 93
`
`
`VASCEPA capsules also contain the following inactive ingredients: tocopherol, gelatin,
`
` glycerin, maltitol, sorbitol, and purified water.
`
`CLINICAL PHARMACOLOGY
` 12
`
` 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.
`
`
`
`
`
`
`
`
`
` 12.3 Pharmacokinetics
`
` Absorption: After oral administration, VASCEPA is de-esterified during the absorption
`
`
` process and the active metabolite EPA is absorbed in the small intestine and enters the systemic
`
` circulation mainly via the thoracic duct lymphatic system. Peak plasma concentrations of EPA
`
`
` were reached approximately 5 hours following oral doses of VASCEPA.
` VASCEPA was administered with or following a meal in all clinical studies; no food
`
`
` effect studies were performed. Take VASCEPA 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.
`
`
`Metabolism and Excretion: 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. The total plasma clearance of EPA at
`
`
`steady state is 684 mL/hr. The plasma elimination half-life (t1/2) of EPA is approximately 89
`
`
`hours. VASCEPA does not undergo renal excretion.
` Drug-Drug Interactions
`
`
`
`
` VASCEPA was studied at the 4 g/day dose level with the following medications which
`
`are typical substrates of cytochrome P450 enzymes, and no drug-drug interactions were
`
`observed:
`
`
`Omeprazole: In a drug-drug interaction study with 28 healthy adult subjects, VASCEPA
` 4 g/day at steady-state did not significantly change the steady-state AUCτ or Cmax of omeprazole
`
`
`
`
` when co-administered at 40 mg/day to steady-state.
`
`
`
`
`
` Rosiglitazone: In a drug-drug interaction study with 28 healthy adult subjects,
`
`
`
`VASCEPA 4 g/day at steady-state did not significantly change the single dose AUC or Cmax of
`
`
`
`
`rosiglitazone at 8 mg.
`
`
`
`
`
`Reference ID: 4057318
`
`
`
`
`
`
` Page 5 of 8
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`

`

`
`
`
`
`Case 1:20-cv-01630-RGA Document 1-6 Filed 11/30/20 Page 7 of 11 PageID #: 94
`
`
`
` Warfarin: In a drug-drug interaction study with 25 healthy adult subjects, VASCEPA
`
`
`
`
`4 g/day at steady-state did not significantly change the single dose AUC or Cmax 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, VASCEPA 4
`
`
`
`
`
`
`
`g/day at steady-state did not significantly change the steady-state AUCτ or Cmax of atorvastatin,
`
`
`
`
`2-hydroxyatorvastatin, or 4-hydroxyatorvastatin when co-administered with atorvastatin
`
`
`
`80 mg/day to steady-state.
`
`
`
`Specific Populations
`
`
`
`
`Gender: When administered VASCEPA in clinical trials, plasma total EPA
`
`concentrations did not differ significantly between men and women.
`
`
`
`Pediatric: The pharmacokinetics of VASCEPA has not been studied in pediatric patients.
`
`
`Hepatic or Renal Impairment: VASCEPA has not been studied in patients with renal or
`
`
`hepatic impairment.
`
`
`
`NONCLINICAL TOXICOLOGY
`13
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`In a 2-year rat carcinogenicity study with oral gavage doses of 0.09, 0.27, and 0.91
`
`
`
`
`g/kg/day icosapent ethyl, respectively, males did not exhibit drug-related neoplasms.
`
`Hemangiomas and hemangiosarcomas of the mesenteric lymph node, the site of drug absorption,
`
`were observed in females at clinically relevant exposures based on body surface area
`
`comparisons across species relative to the maximum clinical dose of 4 g/day. Overall incidence
`
`of hemangiomas and hemangiosarcomas in all vascular tissues did not increase with treatment.
`
`
`
`
`In a 6-month carcinogenicity study in Tg.rasH2 transgenic mice with oral gavage doses
`
`
`of 0.5, 1, 2, and 4.6 g/kg/day icosapent ethyl, drug-related incidences of benign squamous cell
`
`papilloma in the skin and subcutis of the tail was observed in high dose male mice. The
`
`papillomas were considered to develop secondary to chronic irritation of the proximal tail
`
`
`
`associated with fecal 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).
`
`
`
`CLINICAL STUDIES
`14
`
`
`14.1 Severe Hypertriglyceridemia
`The effects of VASCEPA 4 grams per day were assessed in a randomized, placebo-
`
`controlled, double-blind, parallel-group study of adult patients (76 on VASCEPA, 75 on
`
`placebo) with severe hypertriglyceridemia. Patients whose baseline TG levels were between 500
`
`
`
`
` Page 6 of 8
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`Reference ID: 4057318
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`

`

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`
`
`
`Case 1:20-cv-01630-RGA Document 1-6 Filed 11/30/20 Page 8 of 11 PageID #: 95
`
`
`
` and 2,000 mg/dL were enrolled in this study for 12 weeks. The median baseline TG and LDL-C
` levels in these patients were 684 mg/dL and 86 mg/dL, respectively. Median baseline HDL-C
`
`
`
`
`
`
` level was 27 mg/dL. The randomized population in this study was mostly Caucasian (88%) and
` male (76%). The mean age was 53 years and the mean body mass index was 31 kg/m2 . Twenty-
`
`
`
`
`five percent of patients were on concomitant statin therapy, 28% were diabetics, and 39% of the
`
`
`patients had TG levels >750 mg/dL.
`
`The changes in the major lipoprotein lipid parameters for the groups receiving
`
`
`VASCEPA or placebo are shown in Table 2.
`
`
`
`
`
`
`
`
`
`
`Difference
`
` (95%
`
` Confidence
` Interval)
`
` -33* (-47, -22)
`
`
`
` -2 (-13, +8)
`
`
` -18 (-25, -11)
`
`
`
` -16 (-22, -11)
` -4 (-9, +2)
`
` -29** (-43, -14)
`
`
`
`
` -9**(-14, -3)
`
`
`
`Table 2. Median Baseline and Percent Change from Baseline in Lipid Parameters in
`
`
`
`
`
`Patients with Severe Hypertriglyceridemia (≥500 mg/dL)
`
` Placebo
`
`
` VASCEPA 4 g/day
` N=75
` N=76
`
`
` Parameter
`
`
` Baseline % Change
`
` Baseline % Change
` TG (mg/dL)
`
`
`
` 703
` +10
`
`
` 680
` -27
` LDL-C (mg/dL)
`
` 86
`
`
` -3
` 91
`
`
` -5
` Non-HDL-C (mg/dL)
` 229
`
` +8
`
` 225
`
` -8
`
`
` TC (mg/dL)
`
` 256
`
` +8
`
` 254
`
` -7
` HDL-C (mg/dL)
` 27
`
`
` 27
`
` -4
`
`
` 0
`
` 124
` +14
`
`
` 123
` -20
`
`
` VLDL-C (mg/dL)
`
` +4
`
` 118
`
` 121
`
`
` Apo B (mg/dL)
` -4
` % Change= Median Percent Change from Baseline
`
`
`
`
` Difference= Median of [VASCEPA % Change – Placebo % Change] (Hodges-Lehmann Estimate)
`
` p-values from Wilcoxon rank-sum test
`
`
`*p-value < 0.001 (primary efficacy endpoint)
`
`
`
`**p-value < 0.05 (key secondary efficacy endpoints determined to be statistically significant according to the pre-specified
`
`
`
`multiple comparison procedure)
`
`
`
`
`
`
`
`
` VASCEPA 4 grams per day reduced median TG, VLDL-C, and Apo B levels from
`
`
`
`
`
`baseline relative to placebo. The reduction in TG observed with VASCEPA was not associated
`with elevations in LDL-C levels relative to placebo.
`
`
`
`The effect of VASCEPA on the risk of pancreatitis in patients with severe
`
`
`hypertriglyceridemia has not been determined.
`
`
`The effect of VASCEPA on cardiovascular mortality and morbidity in patients with
`
`severe hypertriglyceridemia has not been determined.
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`
`
`VASCEPA (icosapent ethyl) capsules are supplied as 0.5-gram amber-colored soft-
`
`gelatin capsules imprinted with V500 or as 1-gram amber-colored soft-gelatin capsules imprinted
`
`
`
`with VASCEPA.
`
`Bottles of 240 (0.5-gram): NDC 52937-001-40.
`
`
`Bottles of 120 (1-gram): NDC 52937-001-20.
`
`
`
`
`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]. Keep out of reach of children.
`
`
`
`17
`
`17.1
`
`
`
`
`PATIENT COUNSELING INFORMATION
`
`Information for Patients
`VASCEPA should be used with caution in patients with known sens
`
`
`allergy to fish and/or shellfish [see Warnings and Precautions (5.2)].
`
`
`
`
`
`itivity or
`
`
`
` Page 7 of 8
`
`Reference ID: 4057318
`
`
`

`

`
`
`
`
`Case 1:20-cv-01630-RGA Document 1-6 Filed 11/30/20 Page 9 of 11 PageID #: 96
`
` Patients should be advised that use of lipid-regulating agents does not reduce the
`
`
` importance of appropriate nutritional intake and physical activity [see Dosage and
`
`
` Administration (2)].
`
`
`Patients should be advised not to alter VASCEPA capsules in any way and to
` ingest intact capsules only [see Dosage and Administration (2)].
`
`
`
` Instruct patients to take VASCEPA as prescribed. If a dose is missed, patients
`
`
`
`
`
` should take it as soon as they remember. However if they miss one day of VASCEPA,
` they should not double the dose when they take it.
`
`
` Distributed by:
`
`
` Amarin Pharma Inc.
`
`
` Bedminster, NJ, USA
`
`
`
` Manufactured for:
`
`
`
` Amarin Pharmaceuticals Ireland Limited
`
` Dublin, Ireland
`
`
` +1-855-VASCEPA (+1-855-827-2372)
`
`
` www.VASCEPA.com
`
`
`
`
`
`
` VASCEPA is a registered trademark of the Amarin group of companies
`
`
`
`
`
`
` ©2016 Amarin Pharma, Inc. Bedminster NJ 07921 All rights reserved
`
`
`
`
` P00120H
`
`8/2016
`
`
`
`
`
`Reference ID: 4057318
`
`
`
`
`
`
` Page 8 of 8
`
`

`

`
`
` What is VASCEPA?
`
`
` VASCEPA is a prescription medicine used along with a low-fat and low-cholesterol diet to lower high levels of
` triglycerides (fats) in adults.
`
`
`
` It is not known if VASCEPA changes your risk of having inflammation of your pancreas (pancreatitis).
`
` It is not known if VASCEPA prevents you from having a heart attack or stroke.
`
` It is not known if VASCEPA is safe and effective in children.
`
` Do not take VASCEPA if you are allergic to icosapent ethyl or any of the ingredients in VASCEPA. See the
`
`
`
`
`
` end of this leaflet for a complete list of ingredients in VASCEPA.
`
` Before taking VASCEPA, tell your doctor about all of your medical conditions, including if you:
`
`
`
`
` have diabetes.
`
`
` •
`
` •
` have a low thyroid problem (hypothyroidism).
`
` •
`
` have a liver problem.
`
` •
` have a pancreas problem.
`
`
` •
` are allergic to fish or shellfish. It is not known if people who are allergic to fish or shellfish are also allergic
`
` to VASCEPA.
`
` are pregnant, or planning to become pregnant. It is not known if VASCEPA will harm your unborn baby.
`
`
`
`
`
`
`
` are breastfeeding or plan to breastfeed. VASCEPA can pass into your milk, and may harm your baby.
` Talk to your doctor about the best way to feed your baby if you take VASCEPA.
`
`
`
`
`
`
`
` Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines,
`
`
`
`
`
`
` vitamins, and dietary or herbal supplements. VASCEPA 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 VASCEPA?
`
`
`
` Take VASCEPA exactly as your doctor tells you to take it.
`
`
`
`•
` • Do not change your dose or stop taking VASCEPA without talking to your doctor.
`
`
`
`
` • Do not take more capsules than what is prescribed by your doctor.
`
`
`
`
`
` If you are prescribed the 0.5 gram capsules, you should not take more than 8 capsules each day.
`
`
`
`•
`
` If you are prescribed the 1 gram capsules, you should not take more than 4 capsules per day.
`
`
`
`
`
`•
`Take VASCEPA capsules whole. Do not break, crush, dissolve, or chew VASCEPA capsules before
` swallowing.
`
`
`
` If you miss a dose of VASCEPA, take it as soon as you remember. However, if you miss one day of
` VASCEPA, 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 VASCEPA. Stay on this diet while taking VASCEPA.
`
`
`
`
`
` • Your doctor may do blood tests to check your triglyceride and other lipid levels while you take VASCEPA.
`
`
`
`
`
` What are the possible side effects of VASCEPA?
`
`
`
` If you have liver problems and are taking VASCEPA, your doctor should do blood tests during treatment.
`
` The most common side effect of VASCEPA is joint pain. As with all drugs, you may experience a serious side
`
`
`
`
` effect when taking VASCEPA. Talk to your doctor if you have a side effect that bothers you or does not go
`
`
`
`
`
`
` away.
`
`
` These are not all the possible side effects of VASCEPA. 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 VASCEPA?
`
`
`
` • Store VASCEPA 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 VASCEPA and all medicine out of the reach of children.
`
`
`
` General information about the safe and effective use of VASCEPA.
`
`
` Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do
`
` not use VASCEPA for a condition for which it was not prescribed. Do not give VASCEPA 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 VASCEPA that is written for health professionals.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Case 1:20-cv-01630-RGA Document 1-6 Filed 11/30/20 Page 10 of 11 PageID #: 97
`
`
` PATIENT INFORMATION
` VASCEPA (vas-EE-puh) (icosapent ethyl)
`
`
`capsules
`
`
`
`
`
`
` •
`
`•
`
`
`•
`
`
`•
`
`Reference ID: 4057318
`
`

`

`Case 1:20-cv-01630-RGA Document 1-6 Filed 11/30/20 Page 11 of 11 PageID #: 98
`
`
`
`
`
`
`
` What are the ingredients in VASCEPA?
`
` Active ingredient: icosapent ethyl
`
`
`Inactive ingredients: tocopherol, gelatin, glycerin, maltitol, sorbitol, and purified water
`
`
`
`
` Distributed by: Amarin Pharma Inc. Bedminster, NJ, USA
`
`
`
`
` Manufactured for: Amarin Pharmaceuticals Ireland Limited Dublin, Ireland +1-855-VASCEPA (+1-855-827-2372) www.vascepa.com
`
`
`
`
` For more information, go to www.vascepa.com or call 1-855-VASCEPA (1-855-827-2372).
`
`
`
`
`
`This Patient Information has been approved by the U.S. Food and Drug Administration
`
`
`
`
`
`
`Revised: 2/2017
`
`Reference ID: 4057318
`
`