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Icosapent Ethyl Capsules

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). The chemical name for icosapent ethyl is ethyl all-cis-5,8,11,14,17-icosapentaenoate with the following chemical structure:

Empirical formula: C22H34O2- Molecular weight: 330.51

Icosapent ethyl, a lipid-regulating agent, is supplied as a 1-gram amber-colored, liquid-filled soft gelatin capsule for oral administration. Each icosapent ethyl capsule contains 1 gram of icosapent ethyl.

Inactive ingredients: tocopherol, gelatin, glycerin, maltitol, sorbitol, and purified water.

2. 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.

Usage Considerations: Patients should be placed on an appropriate lipid-lowering diet and exercise regimen before receiving icosapent ethyl and should continue this diet and exercise regimen with icosapent ethyl.

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 icosapent ethyl on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined.

The effect of icosapent ethyl on cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined.

3. 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].

Patients should engage in appropriate nutritional intake and physical activity before receiving icosapent ethyl, which should continue during treatment with icosapent ethyl.

The daily dose of icosapent ethyl is 4 grams per day taken as 2 capsules twice daily with food.

Patients should be advised to swallow icosapent ethyl capsules whole. Do not break open, crush, dissolve, or chew icosapent ethyl.

4. CONTRAINDICATIONS

Icosapent ethyl is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to icosapent ethyl or any of its components.

5. 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.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. It is unknown whether icosapent ethyl can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Icosapent ethyl 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.

6.2 Nursing Mothers

Studies with omega-3-acid ethyl esters have demonstrated excretion in human milk. The effect of this excretion is unknown; caution should be exercised when icosapent ethyl is administered to a nursing mother. In lactating rats, given oral gavage 14C-ethyl EPA, drug levels were 6 to 14 times higher in milk than in plasma.

6.3 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

6.4 Geriatric Use

Of the total number of subjects in clinical studies of icosapent ethyl, 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.

7. WARNINGS AND PRECAUTIONS

7.1 Monitoring: Laboratory Tests

In patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored periodically during therapy with icosapent ethyl.

7.2 Fish Allergy

Icosapent ethyl 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 icosapent ethyl. Icosapent ethyl should be used with caution in patients with known hypersensitivity to fish and/or shellfish.

8. ADVERSE REACTIONS

8.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions reported in at least 2% and at a greater rate than placebo for patients treated with icosapent ethyl based on pooled data across two clinical studies are listed in Table 1.

Table 1. Adverse Reactions Occurring at Incidence >2% and Greater than Placebo in Double-Blind, Placebo-Controlled Trials*

* Studies included patients with triglycerides values of 200 to 2000 mg/dL.

An additional adverse reaction from clinical studies was oropharyngeal pain.

9. OVERDOSAGE

No overdosage information is available.

10. DRUG INTERACTIONS

Icosapent ethyl 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, icosapent ethyl 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, icosapent ethyl 4 g/day at steady-state did not significantly change the single dose AUC or Cmax of rosiglitazone at 4 mg.

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 Cmax of R- and S warfarin or the anti-coagulation pharmacodynamics of warfarin when co-administered as racemic warfarin at 25 mg.

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 icosapent ethyl and other drugs affecting coagulation (e.g., anti-platelet agents) should be monitored periodically.

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 AUCτ or Cmax of atorvastatin, 2-hydroxyatorvastatin, or 4-hydroxyatorvastatin when co-administered with atorvastatin 80 mg/day to steady-state.

11. 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 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.

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 (t½) 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.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: VASCEPA, by Amarin Pharms.

b) Generic drugs: None.

2) How Supplied:

VASCEPA (icosapent ethyl) capsules are supplied as 1-gram amber-colored soft-gelatin capsules imprinted with VASCEPA.

Bottles of 120: NDC 52937-001-20.

3) Storage and Handling:

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30° C (59° to 86°F) [see USP Controlled Room Temperature].

Keep out of reach of children.

Rx only

Rev 07/12