HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
`
` These highlights do not include all the information needed to use
` VASCEPA® safely and effectively. See full prescribing information for
`
`
`
` VASCEPA.
`
` VASCEPA® (icosapent ethyl) capsules, for oral use
`
`
`
` Initial U.S. Approval: 2012
`
`-------------------------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
`
`
`
`
`--------------------------INDICATIONS AND USAGE-----------------------------­
`
`
`
`VASCEPA is an ethyl ester of eicosapentaenoic acid (EPA) 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
`
`
`o
`
`
`
`
` diabetes mellitus and 2 or more additional risk factors
`
`o
` for cardiovascular disease. (1)
`
`
`
`
` as an adjunct to diet to reduce 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)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`•
`
`
`
`
`
`
`-----------------------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 VASCEPA, which should continue during
`
`
`
` treatment. (2.1)
`
`
` • The daily dose of VASCEPA is 4 grams per day taken as either
`
`
`
` four 0.5 gram capsules twice daily with food or
`
`
`
`
`o
`
`
` two 1 gram capsules twice daily with food. (2.2)
`
`
`
`
`o
` • Advise patients to swallow capsules whole. Do not break open, crush,
`
`
` dissolve, or chew VASCEPA. (2.2)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` ---------------------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)
`
`
`------------------------WARNINGS and PRECAUTIONS------------------------­
`
`
`
` Atrial Fibrillation/Flutter: VASCEPA was associated with an increased risk
` of atrial fibrillation or atrial flutter requiring hospitalization in a double-blind,
`
`
`
`
` placebo-controlled trial. The incidence of atrial fibrillation was greater in
`
`
`
` patients with a previous history of atrial fibrillation or atrial flutter. (5.1)
`
`
`
`
`
` Potential for Allergic Reactions in Patients with Fish Allergy: 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.
`
`
`
` Inform patients with known hypersensitivity to fish and/or shellfish about the
`
`
` potential for allergic reactions and advise them to discontinue VASCEPA and
`
`
` seek medical attention if any reactions occur. (5.2)
`
`
`
`
`
`
` Bleeding: VASCEPA was associated with an increased risk 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. (5.3)
`
`
`
`
`
`-------------------------------ADVERSE REACTIONS-----------------------------­
`
`
`Common adverse reactions in the cardiovascular outcomes trial (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 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-------------------------------­
`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 VASCEPA and concomitant
`
`
`anticoagulants and/or antiplatelet agents for bleeding. (7)
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`
`approved patient labeling.
`
`
`
`Revised: 12/2019
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`___________________________________________________________________________________________________________________________________
`
`
` 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 Atrial Fibrillation/Flutter
`
`
`
`
` 5.2 Fish Allergy
`
`
` 5.3 Bleeding
`
` 6 ADVERSE REACTIONS
`
`
`
`
` 6.1 Clinical Trials Experience
`
` 6.2 Postmarketing Experience
` 7 DRUG INTERACTIONS
`
`
` 7.1 Anticoagulants
`
`
` 8 USE IN SPECIFIC POPULATIONS
`
`
` 8.1 Pregnancy
`
` 8.2 Lactation
`
`
`
` 8.4 Pediatric Use
`
`
` 8.5 Geriatric Use
`
` 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 Prevention of Cardiovascular Events
`
` 14.2 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.
`
`
`
`
`
`
`
`
`Reference ID: 4533779
`
`
`
` Page 1 of 14
`
`
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1033, p. 1 of 14
`
`

`

`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` 1
`
` INDICATIONS AND USAGE
`
`
`
` 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
`
`
`
`
`o established cardiovascular disease or
`
`
`
`
`
`o 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.
`
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`2.1 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 as
`
`
`
`
`two 1 gram capsules twice daily with food.
`o
`
`• Advise patients to swallow VASCEPA capsules whole. Do not break open, crush,
`
`
`dissolve, or chew VASCEPA.
`
`
`
`3
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`VASCEPA capsules are supplied as:
`
`
`
`• 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 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
`
`
`
`
`Page 2 of 14
`
`
`Reference ID: 4533779
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1033, p. 2 of 14
`
`

`

`
`
` 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 Allergy
`
`
`
` 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. 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.
`
`
`
`
`
`
`ADVERSE REACTIONS
`6
`
`
`
`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)]
`
`
`
`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.
`
`
`
`Cardiovascular Outcomes Trial
`In 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 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
`
`
`
`
`Reference ID: 4533779
`
`
`
`
`
`Page 3 of 14
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1033, p. 3 of 14
`
`

`

`
`
` VASCEPA 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
`
`
`
`
` 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
`
`
`
`
`
` DRUG INTERACTIONS
` 7
`
`
` Increased Bleeding Risk with Anticoagulants and Antiplatelet Agents
` 7.1
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
` USE IN SPECIFIC POPULATIONS
` 8
`
`
` 8.1 Pregnancy
`
`
`
`
` Risk 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.
`
`
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4533779
`
`
`
`
`
`Page 4 of 14
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1033, p. 4 of 14
`
`

`

`
`
`
`
`
`
` 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 VASCEPA and any
`
`
`potential adverse effects on the breastfed child from VASCEPA 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 VASCEPA, 45%
`
`
`
`were 65 years of age and over. No overall differences in safety or effectiveness were observed
`
`
`
`
`Reference ID: 4533779
`
`
`
`
`
`Page 5 of 14
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1033, p. 5 of 14
`
`

`

`
`
` 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 VASCEPA.
`
`
`
`
`
`
`
`
`
`
`
` 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 use.
` 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:
`
`
`
`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.
`
`
`
`The mechanisms of action contributing to reduction of cardiovascular events with
`
`
`
`
`VASCEPA (icosapent ethyl) are not completely understood but are likely multi-factorial.
`
`
`
`
`
`
`Increased EPA lipid composition from carotid plaque specimens and increased circulating
`
`
`
`EPA/arachidonic acid ratio have been observed following EPA treatment. EPA inhibits platelet
`
`
`
`
`aggregation under some ex vivo conditions. However, the direct clinical meaning of individual
`
`findings is not clear.
`
`
`
`12.2 Pharmacodynamics
`
`In a 12-week, dose-ranging study in patients with severe hypertriglyceridemia and in the
`event-driven REDUCE-IT® trial, VASCEPA 4 grams per day reduced median TG from baseline
`
`
`
`relative to placebo [see Clinical Studies (14)].
`
`12.3 Pharmacokinetics
`
`
`Absorption
`
`
`
`
`
`Reference ID: 4533779
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`
`
`
`
`Page 6 of 14
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1033, p. 6 of 14
`
`

`

`
`
`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.
`
`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 (t1/2) of EPA is approximately 89 hours. VASCEPA does not undergo renal excretion.
`
`
`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 have not been studied in pediatric patients.
`
`
`Hepatic or Renal Impairment
`
`
`VASCEPA 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, 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.
`
`
`
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`Page 7 of 14
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`
`Reference ID: 4533779
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1033, p. 7 of 14
`
`

`

`
`
`
`
`
`
`
`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 at steady-state.
`
`
`
`13
`NONCLINICAL TOXICOLOGY
`
`
`
`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 Prevention of Cardiovascular Events
`
`
`REDUCE-IT (NCT01492361) was a multinational, double-blind, randomized, placebo-
`
`
`
`
`
`
`
`
`controlled, event-driven trial in 8,179 (4,089 VASCEPA, 4,090 placebo) statin-treated adult
`
`
`
`
`
`
`patients enrolled with LDL-C >40 mg/dL and ≤100 mg/dL and elevated TG levels (90% of
`
`
`
`
`
`
`
`enrolled patients had TG ≥ 150 mg/dL and <500 mg/dL) and either established cardiovascular
`
`
`
`
`
`
`
`
`
`disease (71%) or diabetes and other risk factors for cardiovascular disease (29%). Patients with
`
`
`
`
`
`
`
`established cardiovascular disease were defined as being at least 45 years of age and having a
`
`
`documented history of coronary artery disease, cerebrovascular or carotid disease, or peripheral
`
`
`
`
`
`artery disease. Patients with other risk factors for cardiovascular disease were defined as being
`
`
`at least 50 years of age with diabetes and at least one additional risk factor. Patients were
`
`
`
`
`randomly assigned 1:1 to receive either VASCEPA (4 grams daily) or placebo. The median
`
`
`
`
`follow-up duration was 4.9 years. Overall, 99.8% of patients were followed for vital status until
`
`the end of the trial or death.
`
`
`
`
`
`
`Page 8 of 14
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`Reference ID: 4533779
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1033, p. 8 of 14
`
`

`

`
`
`
`
`
`
` The median age at baseline was 64 years and 29% were women. The trial population was
`
`
`
`
`
`
`
`
`
`
` 90% White, 5% Asian, 2% Black; 4% identified as Hispanic ethnicity. Selected additional
` baseline risk factors included hypertension (87%), type 2 diabetes mellitus (58%), eGFR < 60
`
`
`
` mL/min per 1.73 m2 (22%), congestive heart failure (18%), and current daily cigarette smoking
`(15%).
`
`Most patients were taking moderate-intensity (63%) or high-intensity (31%) statin
`
`
`
`therapy at baseline. Most patients at baseline were taking at least one other cardiovascular
`
`
`
`
`medication, including anti-platelet agents (79%) or anti-hypertensives (95%), including beta
`
`
`
`
`blockers (71%), angiotensin converting enzyme (ACE) inhibitors (52%), or angiotensin receptor
`
`
`
`blockers (ARB; 27%).
`
`
`On stable background lipid-lowering therapy, the median [Q1, Q3] LDL-C at baseline
`
`
`
`was 75.0 [62.0, 89.0] mg/dL; the mean (SD) was 76.2 (20.3) mg/dL. The median [Q1, Q3]
`
`
`
`fasting TG was 216.0 [176.0, 272.5] mg/dL; the mean (SD) was 233.2 (80.1) mg/dL.
`
`
`VASCEPA significantly reduced the risk for the primary composite endpoint (time to
`
`first occurrence of cardiovascular death, myocardial infarction, stroke, coronary
`
`revascularization, or hospitalization for unstable angina; p<0.0001) and the key secondary
`
`
`composite endpoint (time to first occurrence of cardiovascular death, myocardial infarction, or
`
`stroke; p<0.0001). The results of the primary, key secondary, and other secondary efficacy
`
`
`
`
`endpoints in the prespecified testing hierarchy to control for type 1 error are shown in Table 2.
`
`
`
`
`
`The Kaplan-Meier estimates of the cumulative incidence of the primary composite endpoints
`
`
`
`over time are shown in Figure 1.
`
`
`
`
`Table 1. Effect of VASCEPA on Time to First Occurrence of Cardiovascular Events in
`
`
`
`
`
`Patients with Elevated Triglyceride Levels and Other Risk Factors for Cardiovascular
`
`
`
`
`
`Disease in REDUCE-IT
`
`
`
`
` VASCEPA
`
`
`Incidence
`
` Rate
`(per 100
`
`patient
`
`years)
`
`
`
` N = 4089
`
` n (%)
`
` Placebo
`
`
`Incidence
`
` Rate
`(per 100
`
`patient
`
`years)
`
`
` N = 4090
`
` n (%)
`
`VASCEPA
`
`vs Placebo
`
`
`
`Hazard Ratio
`(95% CI)
`
`
` 705
`
` (17.2)
`
`
`
`459
`
`(11.2)
`
`
`250
`
`(6.1)
`
`216
`
`(5.3)
`
`174
`
`(4.3)
`
`108
`
`(2.6)
`
`
`
` 4.3
`
`
`
` 2.7
`
`
`
` 1.5
`
`
`
` 1.3
`
`
`
` 1.0
`
`
`
` 0.6
`
`
`
` 901
`
` (22.0)
`
`
`
`
`606
`
`(14.8)
`
`
`355
`
`(8.7)
`
`321
`
`(7.8)
`
`213
`
`(5.2)
`
`157
`
`(3.8)
`
`
`
` 5.7
`
`
`
` 3.7
`
`
`
` 2.1
`
`
`
` 1.9
`
`
`
` 1.2
`
`
`
` 0.9
`
` 0.75
`
` (0.68, 0.83)
`
`
`
`
`0.74
`
`(0.65, 0.83)
`
`
`0.69
`
`(0.58, 0.81)
`
`0.65
`
`(0.55, 0.78)
`
`0.80
`
`(0.66, 0.98)
`
`0.68
`
`(0.53, 0.87)
`
`
`
`Page 9 of 14
`
`
`
`
`Primary composite endpoint
`
`
`Cardiovascular death, myocardial
` infarction, stroke, coronary
`
` revascularization, hospitalization for
`
`
`unstable angina (5-point MACE)
`
`Key secondary composite endpoint
`
`
`Cardiovascular death, myocardial
`
`infarction, stroke (3-point MACE)
`
`Other secondary endpoints
` Fatal or non-fatal myocardial infarction
`
`Emergent or urgent coronary
`
`revascularization
` Cardiovascular death [1]
`
`
`
`
`
`
`
`
`
` Hospitalization for unstable angina [2]
`
`
`
`
`
`
`
`
`Reference ID: 4533779
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1033, p. 9 of 14
`
`

`

`
`
` VASCEPA
`
`
`Incidence
`
` Rate
`(per 100
`patient
`
`
`years)
`
`
`134
`98
`
`
` 0.6
`Fatal or non-fatal stroke
`
`
`(3.3)
`(2.4)
`
`
`
`
`[1] Includes adjudicated cardiovascular deaths and deaths of undetermined causality.
` [2] Determined to be caused by myocardial ischemia by invasive/non-invasive testing and requiring emergent hospitalization.
`
`
`
`
`
`
` N = 4089
`
` n (%)
`
` N = 4090
`
`
` n (%)
`
` Placebo
`
`
`Incidence
`
` Rate
`(per 100
`patient
`
`
`years)
`
` 0.8
`
`VASCEPA
`
`vs Placebo
`
`
`
`Hazard Ratio
`(95% CI)
`
`
`
`0.72
`
`(0.55, 0.93)
`
`
`
`
`
` Figure 1. Kaplan-Meier Estimated Cumulative Incidence of Primary Composite Endpoint
`
`
` in REDUCE-IT
`
`
`
`
`
`
`
`
`
`
`
` CI=confidence interval
`
`
`
` The median TG and LDL-C baseline values were similar between the VASCEPA group and
`
`
`
`
`
`
` placebo group. The median change in TG from baseline to Year 1 was -39 mg/dL (-18%) in the
` VASCEPA group and 5 mg/dL (2%) in the placebo group. The median change in LDL-C from
`
`
`baseline to Year 1 was 2 mg/dL (3%) in the VASCEPA group and 7 mg/dL (10%) in the placebo
`group.
`
`
`14.2 Severe Hypertriglyceridemia
`
`
`
`
`
`
`
`
`Reference ID: 4533779
`
`
`
`
`
`Page 10 of 14
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1033, p. 10 of 14
`
`

`

`
`
`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
`
`
`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 st