icosapent (Rx)

>10%

Bleeding event (12%)

1-10%

Musculoskeletal pain (≥3%)

Peripheral edema (≥3%)

Constipation (≥3%)

Gout (≥3%)

Atrial fibrillation or flutter (3%)

Serious bleeding event (3%)

Postmarketing Reports

Diarrhea

Blood TG increased

Abdominal discomfort

Pain in extremities

Contraindications

Hypersensitivity to drug or any of its components

Cautions

Associated with increased risk of atrial fibrillation or atrial flutter requiring hospitalization compared with placebo (3% vs 2%)

Contains ethyl esters of the omega-3 fatty acid, eicosapentaenoic acid (EPA), obtained from the oil of fish; unknown whether patients with allergies to fish and/or shellfish are at increased risk of an allergic reaction

Use associated with increased risk of bleeding; incidence is greater if taking concomitant antithrombotic medications (eg, aspirin, clopidogrel, or warfarin)

Drug interaction overview

• Some published studies with omega-3 fatty acids have demonstrated prolongation of bleeding time; bleeding time reported in those studies has not exceeded normal limits and did not produce clinically significant bleeding episodes
• Monitor patients receiving icosapent with anticoagulants and/or antiplatelet agents for bleeding

Pregnancy

Available data from published case reports and the pharmacovigilance database on the use in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes

Animal studies

• In animal reproduction studies in pregnant rats, nondose-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

Lactation

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

Consider developmental and health benefits of breastfeeding along with mother’s clinical need for drug and any potential adverse effects on breastfed child from drug or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Ethyl ester of eicosapentaenoic acid (EPA); EPA has been shown to reduce hepatic very low-density lipoprotein triglycerides (VLDL-TG) synthesis and/or secretion; enhances triglyceride clearance from circulating VLDL particle; may also increase beta-oxidation, inhibits acyl-CoA:1,2-diacylglycerol acyltransferase (DGAT), decrease lipogenesis in liver, and increase plasma lipoprotein lipase activity

The mechanisms of action contributing to reduction of cardiovascular events are not completely understood but are likely multifactorial; 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

Absorption

De-esterified during absorption to active EPA that is absorbed in small intestine

Peak Plasma Time: 5 hr

Distribution

Protein Bound: >99% of unesterified EPA

Vd: 88 L

Metabolism

Mainly metabolized by the liver via beta-oxidation similar to dietary fatty acids; minor CYP450 mediated metabolism

Elimination

Half-life: 89 hr

Does not undergo renal excretion

Total plasma clearance: 684 mL/hr

Oral Administration

Swallow capsule whole; do not break open, dissolve, crush, or chew

Storage

Store at controlled room temperature of 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)