`
`Exhibit K
`
`
`
`Case 1:20-cv-01630-RGA Document 1-11 Filed 11/30/20 Page 2 of 15 PageID #: 120
`ICOSAPENT ETHYL- icosapent ethyl capsule
`Hikma Pharmaceuticals USA Inc.
`----------
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use ICOSAPENT ETHYL CAPSULES safely and
`effectively. See full prescribing information for ICOSAPENT ETHYL CAPSULES.
`
`ICOSAPENT ETHYL capsules, for oral use
`Initial U.S. Approval: 2012
`
`RECENT MAJOR CHANGES
`
`Warnings and Precautions, Atrial Fibrillation/Flutter (5.1)
`Warnings and Precautions, Bleeding (5.3)
`
`12/2019
`12/2019
`
`INDICATIONS AND USAGE
`Icosapent ethyl capsules are an ethyl ester of eicosapentaenoic acid (EPA) indicated:
`
`•
`
`as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥ 500 mg/dL)
`hypertriglyceridemia. (1)
`
`Limitations of Use:
`
`The effect of icosapent ethyl 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 icosapent ethyl
`capsules, which should continue during treatment. (2.1)
`The daily dose of icosapent ethyl is 4 grams per day taken as
`
`o two 1-gram capsules twice daily with food. (2.2)
`
`Advise patients to swallow capsules whole. Do not break open, crush, dissolve, or chew icosapent ethyl capsules. (2.2)
`
`•
`
`• • •
`
`•
`
`Capsules: 1 gram (3)
`
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`Icosapent ethyl is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to icosapent ethyl or
`any of its components. (4)
`
`WARNINGS AND PRECAUTIONS
`Atrial Fibrillation/Flutter: Icosapent ethyl 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: Icosapent ethylcontains ethyl esters of the omega-3 fatty
`acid, eicosapentaenoic acid (EPA), obtained from the oil of fish. It is not known whether patients with allergies to fish and/or
`shellfish are at increased risk of an allergic reaction to icosapent ethyl. Inform patients with known hypersensitivity to fish
`and/or shellfish about the potential for allergic reactions and advise them to discontinue icosapent ethyl and seek medical
`attention if any reactions occur. (5.2)
`Bleeding: Icosapent ethylwas 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 (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
`
`
`
`Case 1:20-cv-01630-RGA Document 1-11 Filed 11/30/20 Page 3 of 15 PageID #: 121
`oropharyngeal pain. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or
`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 icosapent ethyl capsules and concomitant
`anticoagulants and/or antiplatelet agents for bleeding. (7)
`See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
`
`Revised: 1/2020
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Prior to Initiation of Icosapent Ethyl
`2.2 Dosage and Administration
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Atrial Fibrillation/Flutter
`5.2 Potential for Allergic Reactions in Patients with Fish Allergy
`5.3 Bleeding
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`7.1 Increased Bleeding Risk with Anticoagulants and Antiplatelet Agents
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.7 Hepatic Impairment
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.2 Severe Hypertriglyceridemia
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`*
`Sections or subsections omitted from the full prescribing information are not listed.
`
`FULL PRESCRIBING INFORMATION
`
`
`
`Case 1:20-cv-01630-RGA Document 1-11 Filed 11/30/20 Page 4 of 15 PageID #: 122
`1 INDICATIONS AND USAGE
`Icosapent ethyl is indicated:
`
`•
`
`as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL)
`hypertriglyceridemia.
`
`Limitations of Use
`The effect of icosapent ethyl on the risk for pancreatitis in patients with severe hypertriglyceridemia
`has not been determined.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Prior to Initiation of Icosapent Ethyl
`
`Assess lipid levels before initiating therapy. Identify other causes (e.g., diabetes mellitus,
`hypothyroidism, or medications) of high triglyceride levels and manage as appropriate.
`Patients should engage in appropriate nutritional intake and physical activity before receiving
`icosapent ethyl, which should continue during treatment with icosapent ethyl.
`
`• •
`
`2.2 Dosage and Administration
`
`•
`
`•
`
`The daily dose of icosapent ethyl is 4 grams per day taken as:
`
`o
`
`two 1 gram capsules twice daily with food.
`
`Advise patients to swallow icosapent ethyl capsules whole. Do not break open, crush, dissolve,
`or chew icosapent ethyl capsules.
`
`3 DOSAGE FORMS AND STRENGTHS
`Icosapent Ethyl Capsules are supplied as a 1 gram, clear, oblong capsule with product identification “54
`648” on one side.
`
`4 CONTRAINDICATIONS
`Icosapent ethyl is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to
`icosapent ethyl or any of its components.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Atrial Fibrillation/Flutter
`Icosapent ethyl is associated with an increased risk of atrial fibrillation or atrial flutter requiring
`hospitalization. In a double-blind, placebo-controlled trial of 8,179 subjects, adjudicated atrial
`fibrillation or atrial flutter requiring hospitalization for 24 or more hours occurred in 127 (3%) patients
`treated with icosapent ethyl compared to 84 (2%) patients receiving placebo [HR= 1.5 (95% CI 1.14,
`1.98)]. The incidence of atrial fibrillation was greater in patients with a previous history of atrial
`fibrillation or atrial flutter.
`
`5.2 Potential for Allergic Reactions in Patients with Fish Allergy
`Icosapent ethyl contains ethyl esters of the omega-3 fatty acid, eicosapentaenoic acid (EPA), obtained
`
`
`
`Case 1:20-cv-01630-RGA Document 1-11 Filed 11/30/20 Page 5 of 15 PageID #: 123
`from the oil of fish. It is not known whether patients with allergies to fish and/or shellfish are at
`increased risk of an allergic reaction to icosapent ethyl. Inform patients with known hypersensitivity to
`fish and/or shellfish about the potential for allergic reactions to icosapent ethyl and advise them to
`discontinue icosapent ethyl and seek medical attention if any reactions occur.
`
`5.3 Bleeding
`Icosapent ethyl is associated with an increased risk of bleeding. In a double-blind, placebo-controlled
`trial of 8,179 patients, 482 (12%) patients receiving icosapent ethyl experienced a bleeding event
`compared to 404 (10%) patients receiving placebo. Serious bleeding events occurred in 111 (3%) of
`patients on icosapent ethyl vs. 85 (2%) of patients receiving placebo. The incidence of bleeding was
`greater in patients receiving concomitant antithrombotic medications, such as aspirin, clopidogrel, or
`warfarin.
`
`6 ADVERSE REACTIONS
`The following important adverse reactions are described below and elsewhere in the labeling:
`
`Atrial Fibrillation or Atrial Flutter [see Warnings and Precautions (5.1)]
`Potential for Allergic Reactions in Patients with Fish Allergy [see Warnings and Precautions (5.2)]
`Bleeding [see Warnings and Precautions (5.3)]
`
`•••
`
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed
`in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug
`and may not reflect the rates observed in practice.
`Common adverse reactions (incidence ≥3% on icosapent ethyl and ≥1% more frequent than placebo)
`included musculoskeletal pain, peripheral edema, constipation, gout, and atrial fibrillation.
`Hypertriglyceridemia Trials
`In two randomized, double-blind, placebo-controlled trials in patients with triglyceride levels between
`200 and 2000 mg/dL treated for 12 weeks, adverse reactions reported with icosapent ethyl at an
`incidence ≥1% more frequent than placebo based on pooled data included arthralgia and oropharyngeal
`pain.
`
`6.2 Postmarketing Experience
`Additional adverse reactions have been identified during post-approval use of icosapent ethyl. Because
`these reactions are reported voluntarily from a population of uncertain size, it is generally not possible
`to reliably estimate their frequency or establish a causal relationship to drug exposure.
`
`Diarrhea
`Blood triglycerides increased
`Abdominal discomfort
`Pain in the extremities
`
`••••
`
`7 DRUG INTERACTIONS
`
`7.1 Increased Bleeding Risk with Anticoagulants and Antiplatelet Agents
`Some published studies with omega-3 fatty acids have demonstrated prolongation of bleeding time. The
`prolongation of bleeding time reported in those studies has not exceeded normal limits and did not
`produce clinically significant bleeding episodes. Monitor patients receiving icosapent ethyl and
`
`
`
`Case 1:20-cv-01630-RGA Document 1-11 Filed 11/30/20 Page 6 of 15 PageID #: 124
`concomitant anticoagulants and/or antiplatelet agents for bleeding.
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`Risk Summary
`The available data from published case reports and the pharmacovigilance database on the use of
`icosapent ethyl in pregnant women are insufficient to identify a drug-associated risk for major birth
`defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies in pregnant
`rats, non-dose-related imbalances for some minor developmental findings were observed with oral
`administration of icosapent ethyl during organogenesis at exposures that were equivalent to the clinical
`exposure at the human dose of 4 g/day, based on body surface area comparisons. In a study in pregnant
`rabbits orally administered icosapent ethyl during organogenesis, there were no clinically relevant
`adverse developmental effects at exposures that were 5 times the clinical exposure, based on body
`surface area comparisons (see Data).
`The estimated background risk of major birth defects and miscarriage for the indicated population is
`unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In
`the U.S. general population, the estimated background risk of major birth defects and miscarriage in
`clinically recognized pregnancies is 2-4% and 15-20%, respectively.
`Data
`Animal Data
`In pregnant rats given oral gavage doses of 0.3, 1 and 2 g/kg/day icosapent ethyl from gestation through
`organogenesis all drug treated groups had non-dose-related imbalances in visceral and skeletal
`findings, including 13th reduced ribs, additional liver lobes, testes medially displaced and/or not
`descended, at human systemic exposures following a maximum oral dose of 4 g/day based on body
`surface comparisons.
`In a multigenerational developmental study in pregnant rats given doses of 0.3, 1, 3 g/kg/day icosapent
`ethyl by oral gavage from gestation day 7-17, icosapent ethyl did not affect viability in fetuses (F1 or
`F2). Non-dose-related imbalances in findings of absent optic nerves and unilateral testes atrophy at
`human exposures based on the maximum dose of 4 g/day and on body surface area comparisons.
`Additional variations consisting of early incisor eruption and increased percent cervical ribs were
`observed at the same exposures. Pups from high dose treated dams exhibited decreased copulation
`rates, delayed estrus, decreased implantations and decreased surviving fetuses (F2) suggesting potential
`multigenerational effects of icosapent ethyl at 7 times human systemic exposure following 4 g/day dose
`based on body surface area comparisons across species.
`In pregnant rabbits given oral gavage doses of 0.1, 0.3, and 1 g/kg/day icosapent ethyl from gestation
`through organogenesis, a decrease in body weight and food consumption was observed at the high dose
`of 1 g/kg/day (5 times the human exposure at the maximum dose of 4 g/day, based on body surface area
`comparisons). Slight increases in resorbed and dead fetuses were noted in the 1 g/kg/day group, but
`these were not significantly different from the control group. There were no differences between the
`icosapent ethyl groups and control group as to the number of corpora lutea, number of implantations,
`number of surviving fetuses, sex ratio, body weight of female fetuses or placental weight. There were
`no treatment-related malformations or skeletal anomalies.
`In pregnant rats given icosapent ethyl from gestation day 17 through lactation day 20 at 0.3, 1, 3 g/kg/day
`no adverse maternal or developmental effects were observed. However, complete litter loss (not dose-
`related) was noted in 2/23 litters at the low dose and 1/23 mid-dose dams by post-natal day 4 at human
`exposures at a maximum dose of 4 g/day, based on body surface area comparisons.
`
`8.2 Lactation
`
`
`
`Case 1:20-cv-01630-RGA Document 1-11 Filed 11/30/20 Page 7 of 15 PageID #: 125
`Risk Summary
`Published studies have detected omega-3 fatty acids, including EPA, in human milk. Lactating women
`receiving oral omega-3 fatty acids for supplementation have resulted in higher levels of omega-3 fatty
`acids in human milk. There are no data on the effects of omega-3 fatty acid ethyl esters on the breastfed
`infant or on milk production. The developmental and health benefits of breastfeeding should be
`considered along with the mother’s clinical need for icosapent ethyl and any potential adverse effects
`on the breastfed child from icosapent ethyl or from the underlying maternal condition.
`
`8.4 Pediatric Use
`Safety and effectiveness in pediatric patients have not been established.
`
`8.5 Geriatric Use
`Of the total number of patients in well-controlled clinical studies of icosapent ethyl, 45% were 65 years
`of age and over. No overall differences in safety or effectiveness were observed between these
`patients and younger groups. Other reported clinical experience has not identified differences in
`responses between the elderly and younger patients.
`
`8.7 Hepatic Impairment
`In patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase
`(AST) levels should be monitored periodically during therapy with icosapent ethyl.
`
`11 DESCRIPTION
`Icosapent ethyl, a lipid-regulating agent, is supplied as a 1 gram, liquid-filled soft gelatin capsule for
`oral administration.
`Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). The empirical
`formula of icosapent ethyl is C H O and the molecular weight is 330.51. The chemical name for
`22 34 2
`icosapent ethyl is ethyl all-cis-5,8,11,14,17-icosapentaenoate with the following chemical structure:
`
`
`
`Case 1:20-cv-01630-RGA Document 1-11 Filed 11/30/20 Page 8 of 15 PageID #: 126
`
`Each capsule contains the following inactive ingredients: gelatin, glycerin, purified water, sorbitol,
`sorbitan and tocopherol. The monogramming ink ingredients contain: ammonium hydroxide, iron oxide
`black, isopropyl alcohol, macrogol, polyvinyl acetate phthalate, propylene glycol, purified water and
`SDA alcohol (ethanol and ethyl acetate).
`
`12 CLINICAL PHARMACOLOGY
`
`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.
`
`12.2 Pharmacodynamics
`In a 12-week, dose-ranging study in patients with severe hypertriglyceridemia, icosapent ethyl 4 grams
`per day reduced median TG from baseline relative to placebo [see Clinical Studies (14)].
`
`12.3 Pharmacokinetics
`Absorption
`After oral administration, icosapent ethyl 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 icosapent ethyl.
`Icosapent ethyl was administered with or following a meal in all clinical studies; no food effect studies
`
`
`
`Case 1:20-cv-01630-RGA Document 1-11 Filed 11/30/20 Page 9 of 15 PageID #: 127
`were performed. Take icosapent ethyl with or following a meal.
`Distribution
`The mean volume of distribution at steady state of EPA is approximately 88 liters. The majority of EPA
`circulating in plasma is incorporated in phospholipids, triglycerides and cholesteryl esters, and <1% is
`present as the unesterified fatty acid. Greater than 99% of unesterified EPA is bound to plasma proteins.
`Elimination
`Metabolism
`EPA is mainly metabolized by the liver via beta-oxidation similar to dietary fatty acids. Beta oxidation
`splits the long carbon chain of EPA into acetyl Coenzyme A, which is converted into energy via the
`Krebs cycle. Cytochrome P450-mediated metabolism is a minor pathway of elimination of EPA.
`Excretion
`The total plasma clearance of EPA at steady state is 684 mL/hr. The plasma elimination half-life (t
`1/2
`of EPA is approximately 89 hours. Icosapent ethyl does not undergo renal excretion.
`Specific Populations
`Gender
`When administered icosapent ethyl in clinical trials, plasma total EPA concentrations did not differ
`significantly between men and women.
`Pediatric
`The pharmacokinetics of icosapent ethyl has not been studied in pediatric patients.
`Hepatic or Renal Impairment
`Icosapent ethyl has not been studied in patients with renal or hepatic impairment.
`Drug Interaction Studies
`Omeprazole: In a drug-drug interaction study with 28 healthy adult subjects, icosapent ethyl 4 g/day at
`steady-state did not significantly change the steady-state AUC or C
` of omeprazole when co-
`τ
`max
`administered at 40 mg/day to steady-state.
`Rosiglitazone: In a drug-drug interaction study with 28 healthy adult subjects, icosapent ethyl 4 g/day at
`steady-state did not significantly change the single dose AUC or C
` of rosiglitazone at 8 mg.
`max
`Warfarin: In a drug-drug interaction study with 25 healthy adult subjects, icosapent ethyl 4 g/day at
`steady-state did not significantly change the single dose AUC or C
` of R- and S-warfarin or the anti-
`max
`coagulation pharmacodynamics of warfarin when co-administered as racemic warfarin at 25 mg.
`Atorvastatin: In a drug-drug interaction study of 26 healthy adult subjects, icosapent ethyl 4 g/day at
`steady-state did not significantly change the steady-state AUC or C
` of atorvastatin, 2-
`τ
`max
`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.
`
`
`
`Case 1:20-cv-01630-RGA Document 1-11 Filed 11/30/20 Page 10 of 15 PageID #: 128
`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).
`
`14 CLINICAL STUDIES
`
`14.2 Severe Hypertriglyceridemia
`The effects of icosapent ethyl 4 grams per day were assessed in a randomized, placebo-controlled,
`double-blind, parallel-group study of adult patients (76 on icosapent ethyl, 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 study was mostly Caucasian (88%) and male (76%). The mean age was 53 years and
`2
`the mean body mass index was 31 kg/m . 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 icosapent ethyl or
`placebo are shown in Table 2.
`
`Table2. Median Baseline and Percent Change from Baseline in Lipid Parameters in Patients with
`Severe Hypertriglyceridemia (≥500 mg/dL)
`Icosapent Ethyl 4 g/day
`Placebo
`N=76
`N=75
`Baseline % Change
`Baseline % Change
`Parameter
`680
`-27
`703
`+10
`TG (mg/dL)
`91
`-5
`86
`-3
`LDL-C (mg/dL)
`225
`-8
`229
`+8
`Non-HDL-C (mg/dL)
`254
`-7
`256
`+8
`TC (mg/dL)
`27
`-4
`27
`0
`HDL-C (mg/dL)
`123
`-20
`124
`+14
`VLDL-C (mg/dL)
`121
`-4
`118
`+4
`Apo B (mg/dL)
`% Change = Median Percent Change from Baseline
`Difference = Median of [Icosapent ethyl % Change – Placebo % change] (Hodges-Lehmann Estimate)
`p-values from Wilcoxon rank-sum test
`
`Difference
`(95% Confidence
`Interval)
`1
`-33 , -47, -22)
`-2 (-13, +8)
`-18 (-25, -11)
`-16 (-22, -11)
`-4 (-9, +2)
`-29 (-43, -14)
`-9 (-14, -3)
`
`2 2
`
`Icosapent ethyl 4 grams per day reduced median TG, VLDL-C, and Apo B levels from baseline relative
`to placebo. The reduction in TG observed with icosapent ethyl was not associated with elevations in
`LDL-C levels relative to placebo.
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`Case 1:20-cv-01630-RGA Document 1-11 Filed 11/30/20 Page 11 of 15 PageID #: 129
`Icosapent Ethyl Capsules
`1 gram capsules are supplied as a clear, oblong capsule filled with colorless to pale yellow oily
`liquid and printed with “54 648” in black ink on one side.
`NDC 0054-0508-23: Bottle of 120 Capsules
`Store at 20° to 25° C (68° to 77°F). [See USP Controlled Room Temperature.] Keep out of reach of
`children.
`
`17 PATIENT COUNSELING INFORMATION
`Advise the patient to read the FDA-approved patient labeling before starting icosapent ethyl (Patient
`Information).
`Inform patients that icosapent ethyl may increase their risk for atrial fibrillation or atrial flutter [see
`Warnings and Precautions (5.1)].
`Inform patients with known hypersensitivity to fish and/or shellfish about the potential for allergic
`reactions to icosapent ethyl and advise them to discontinue icosapent ethyl and seek medical attention if
`any reactions occur [see Warnings and Precautions (5.2)].
`Inform patients that icosapent ethyl may increase their risk for bleeding, especially if they are receiving
`other antithrombotic agents [see Warnings and Precautions (5.3)].
`Advise patients to swallow icosapent ethyl capsules whole. Do not break open, crush, dissolve, or
`chew icosapent ethyl [see Dosage and Administration (2.2)].
`Instruct patients to take icosapent ethyl as prescribed. If a dose is missed, patients should take it as soon
`as they remember. However, if they miss one day of icosapent ethyl, they should not double the dose
`when they take it.
`For more information about icosapent ethyl, please call Hikma Pharmaceuticals USA Inc. at 1-800-962-
`8364.
`Mfg. by:
`Catalent Pharma Solutions, LLC.
`St. Petersburg, Florida 33716
`Distr. by: Hikma
`Pharmaceuticals USA Inc.
`Eatontown, NJ 07724
`C50000421/01
`Revised January 2020
`
`PATIENT INFORMATION
`
`Icosapent Ethyl
`Capsules
`(eye koe’ sa pent eth’ il)
`Rx Only
`
`What is icosapent ethyl?
`Icosapent ethyl is a prescription medicine used:
`
`•
`
`along with a low-fat and low-cholesterol diet to lower high levels of triglycerides (fats) in
`
`
`
`Case 1:20-cv-01630-RGA Document 1-11 Filed 11/30/20 Page 12 of 15 PageID #: 130
`adults.
`
`It is not known if icosapent ethyl changes your risk of having inflammation of your pancreas
`(pancreatitis).
`It is not known if icosapent ethyl is safe and effective in children.
`Do not take icosapent ethyl capsules if you are allergic to icosapent ethyl or any of the ingredients in
`icosapent ethyl capsules. See the end of this leaflet for a complete list of ingredients in icosapent ethyl
`capsules.
`Before taking icosapent ethyl, 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 icosapent ethyl.
`are pregnant, or planning to become pregnant. It is not known if icosapent ethyl will harm your
`unborn baby.
`are breastfeeding or plan to breastfeed. Icosapent ethyl can pass into your breast milk, and may
`harm your baby. Talk to your doctor about the best way to feed your baby if you take icosapent
`ethyl.
`
`••••• • •
`
`Tell your doctor about all the medicines you take, including prescription and over-the-counter
`medicines, vitamins, and dietary or herbal supplements.
`Icosapent ethyl can interact with certain other medicines that you are taking.
`Especially tell your doctor if you take medicines that affect your blood clotting (anticoagulants or
`blood thinners).
`How should I take icosapent ethyl?
`
`Take icosapent ethyl exactly as your doctor tells you to take it.
`Do not change your dose or stop taking icosapent ethyl without talking to your doctor.
`Do not take more capsules than what is prescribed by your doctor.
`
`o
`
`If you are prescribed the 1 gram capsules, you should not take more than 4 capsules each
`day with food.
`
`Take icosapent ethyl capsules whole. Do not break, crush, dissolve, or chew icosapent ethyl
`capsules before swallowing.
`If you miss a dose of icosapent ethyl, take it as soon as you remember. However, if you miss one
`day of icosapent ethyl, do not double your dose when you take it.
`Your doctor may start you on a diet that is low in saturated fat, cholesterol, carbohydrates, and
`low in added sugars before giving you icosapent ethyl. Stay on this diet while taking icosapent
`ethyl.
`Your doctor may do blood tests to check your triglyceride and other lipid levels while you take
`icosapent ethyl.
`
`•••
`
`• • • •
`
`What are the possible side effects of icosapent ethyl?
`Icosapent ethyl may cause serious side effects, including:
`
`•
`
`Heart rhythm problems (atrial fibrillation and atrial flutter). Heart rhythm problems which can
`
`
`
`Case 1:20-cv-01630-RGA Document 1-11 Filed 11/30/20 Page 13 of 15 PageID #: 131
`be serious and cause hospitalization have happened in people who take icosapent ethyl, especially
`in people who have heart (cardiovascular) disease or diabetes with a risk factor for heart
`(cardiovascular) disease, or who have had heart rhythm problems in the past. Tell your doctor if
`you get any symptoms of heart rhythm problems such as feeling as if your heart is beating fast and
`irregular, lightheadedness, dizziness, shortness of breath, chest discomfort, or you faint.
`Possible allergic reactions if you are allergic to fish or shellfish. Stop taking icosapent ethyl
`and tell your doctor right away or get emergency medical help if you have any signs or symptoms
`of an allergic reaction.
`Bleeding. Serious bleeding can happen in people who take icosapent ethyl. Your risk of bleeding
`may increase if you are also taking a blood thinner medicine.
`
`• •
`
`If you have liver problems and are taking icosapent ethyl, your doctor should do blood tests during
`treatment.
`The most common side effects of icosapent ethyl include:
`
`Muscle and joint pain.
`Swelling of the hands, legs, or feet.
`Constipation
`Gout
`Heart rhythm problems (atrial fibrillation).
`
`•••••
`
`These are not all the possible side effects of icosapent ethyl. Call your doctor for medical advice
`about side effects. You may report side effects to FDA at 1-800-FDA-1088.
`How should I store Icosapent Ethyl Capsules?
`
`Store icosapent ethyl at room temperature between 68° to 77° F (20° to 25° C).
`Safely throw away medicine that is out of date or no longer needed.
`
`••
`
`Keep icosapent ethyl and all medicine out of the reach of children.
`General information about the safe and effective use of icosapent ethyl.
`Medicines are sometimes prescribed for purposes other than those listed in a Patient Information
`leaflet. Do not use icosapent ethyl for a condition for which it was not prescribed. Do not give
`icosapent ethyl to other people, even if they have the same symptoms that you have. It may harm them.
`You can ask your pharmacist or healthcare provider for information about icosapent ethyl that is written
`for health professionals.
`What are the ingredients in Icosapent Ethyl Capsules?
`Active ingredient: icosapent ethyl
`Inactive ingredients: gelatin, glycerin, purified water, sorbitol, sorbitan and tocopherol. The
`monogramming ink ingredients contain: ammonium hydroxide, iron oxide black, isopropyl alcohol,
`macrogol, polyvinyl acetate phthalate, propylene glycol, purified water and SDA alcohol (ethanol and
`ethyl acetate).
`
`This Patient Information has been approved by the U.S. Food and Drug Administration.
`Mfg. by:
`Catalent Pharma Solutions, LLC.
`St. Petersburg, Florida 33716
`Distr. by: Hikma
`Pharmaceuticals USA Inc.
`Eatontown, NJ 07724
`
`
`
`Case 1:20-cv-01630-RGA Document 1-11 Filed 11/30/20 Page 14 of 15 PageID #: 132
`C50000421/01
`Revised January 2020
`
`PACKAGE/LABEL PRINCIPAL DISPLAY PANEL
`Icosapent Ethyl Capsules, 1 gram
`NDC 0054-0508-23: Bottle of 120 Capsules
`
`Rx Only
`
`ICOSAPENT ETHYL
`icosapent ethyl capsule
`
`Product Information
`Product T ype
`
`HUMAN PRESCRIPTION DRUG
`
`Ite m Code (Source )
`
`NDC:0 0 54-0 50 8
`
`Route of Administration
`
`ORAL
`
`Active Ingredient/Active Moiety
`
`
`
`Case 1:20-cv-01630-RGA Document 1-11 Filed 11/30/20 Page 15 of 15 PageID #: 133
`Ingredient Name
`Basis of Strength
`Strength
`ICO SAPENT ETHYL (UNII: 6 GC8 A4PAYH) (ICOSAPENT - UNII:AAN7QOV9 EA)
`ICOSAPENT ETHYL
`1 g
`
`Inactive Ingredients
`
`Ingredient Name
`GELATIN, UNSPECIFIED (UNII: 2G8 6 QN327L)
`GLYCERIN (UNII: PDC6 A3C0 OX)
`SO RBITO L (UNII: 50 6 T6 0 A25R)
`.ALPHA.-TO CO PHERO L (UNII: H4N8 55PNZ1)
`AMMO NIA (UNII: 5138 Q19 F1X)
`FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)
`ISO PRO PYL ALCO HO L (UNII: ND2M416 30 2)
`PO LYETHYLENE GLYCO L 4 0 0 (UNII: B6 9 78 9 4SGQ)
`PO LYVINYL ACETATE PHTHALATE (UNII: 58 QVG8 5GW3)
`ALCO HO L (UNII: 3K9 9 58 V9 0 M)
`ETHYL ACETATE (UNII: 76 8 45O8 NMZ)
`SO RBITAN (UNII: 6 O9 2ICV9 RU