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 capsules and concomitant anticoagulants and/or antiplatelet agents for bleeding.

The available data from published case reports and the pharmacovigilance database on the use of icosapent ethyl capsules 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.

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 13 th 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.