VASCEPA- icosapent ethyl capsule
Amarin Pharma Inc.
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.
VASCEPA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to VASCEPA or any of its components.
5 WARNINGS AND PRECAUTIONS
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.
5.2 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. VASCEPA should be used with caution in patients with known hypersensitivity to fish and/or shellfish.
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.
8 USE IN SPECIFIC POPULATIONS
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 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 14 C-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.
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 C22 H34 O2 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.
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.
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.
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.
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.
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.
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).
14 CLINICAL STUDIES
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 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.
Table 2. Median Baseline and Percent Change from Baseline in Lipid Parameters in Patients with Severe Hypertriglyceridemia (≥500 mg/dL)
Parameter VASCEPA 4 g/dayN=76 PlaceboN=75 Difference (95% Confidence Interval)
Baseline % Change Baseline % Change
% 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)
TG (mg/dL) 680 -27 703 +10 -33* (-47, -22)
LDL-C (mg/dL) 91 -5 86 -3 -2 (-13, +8)
Non-HDL-C (mg/dL) 225 -8 229 +8 -18 (-25, -11)
TC (mg/dL) 254 -7 256 +8 -16 (-22, -11)
HDL-C (mg/dL) 27 -4 27 0 -4 (-9, +2)
VLDL-C (mg/dL) 123 -20 124 +14 -29� (-43, -14)
Apo B (mg/dL) 121 -4 118 +4 -9�(-14, -3)
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.
PATIENT COUNSELING INFORMATION
17.1 Information for Patients
VASCEPA should be used with caution in patients with known sensitivity or allergy to fish and/or shellfish [see Warnings and Precautions (5.2)].
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.
Amarin Pharma Inc.
Bedminster, NJ, USA
Amarin Pharmaceuticals Ireland Limited
VASCEPA is a registered trademark of the Amarin group of companies
�2016 Amarin Pharma, Inc. Bedminster NJ 07921 All rights reserved
VASCEPA� (pronounced vas-EE-puh)
The risk information provided here is not comprehensive. To learn more, talk about VASCEPA with your health care provider or pharmacist. Read this Patient Information before you start taking VASCEPA and each time you get a refill. To read the FDA-approved product labeling, go to www.VASCEPA.com and click on prescribing information or call 1-855 VASCEPA. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.
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.
Who should not take VASCEPA?
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.