VASCEPA- icosapent ethyl capsule
Amarin Pharma Inc.
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:
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
Capsules: 0.5-gram and 1-gram (3)
VASCEPA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to VASCEPA or any of its components. (4)
WARNINGS AND PRECAUTIONS
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.
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.
FULL PRESCRIBING INFORMATION: CONTENTS*
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.
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:
Patients should be advised to swallow VASCEPA capsules whole. Do not break open, crush, dissolve, or chew VASCEPA.
VASCEPA capsules are supplied in the following dosage form strengths:
VASCEPA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to VASCEPA or any of its components.
In patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored periodically during therapy with VASCEPA.
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.
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.
An additional adverse reaction from clinical studies was oropharyngeal pain.
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.
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.
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.
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.
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:
VASCEPA capsules also contain the following inactive ingredients: tocopherol, gelatin, glycerin, maltitol, sorbitol, and purified water.
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.
Gender: When administered VASCEPA in clinical trials, plasma total EPA concentrations did not differ significantly between men and women.
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).
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.
|Parameter||VASCEPA 4 g/day
|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|
|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.
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 52937-003-40
Bottles of 120 (1-gram): NDC 52937-001-20.
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
|This Patient Information has been approved by the U.S. Food and Drug Administration||Revised: 2/2017|
|VASCEPA® (vas-EE-puh) (icosapent ethyl)
|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:
|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?
|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?
|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.|
|What are the ingredients in VASCEPA?|
|Active ingredient: icosapent ethyl|
|Inactive ingredients: tocopherol, gelatin, glycerin, maltitol, sorbitol, and purified water|
|VASCEPA is a registered trademark of the Amarin group of companies.|
|©2016 Amarin Pharma, Inc. Bedminster NJ, 07921 All rights reserved|
|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).|
icosapent ethyl capsule
icosapent ethyl capsule
icosapent ethyl capsule
|Labeler - Amarin Pharma Inc. (896179731)|