Source: FDA, National Drug Code (US) Revision Year: 2020
VASCEPA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to VASCEPA or any of its components.
VASCEPA is associated with an increased risk of atrial fibrillation or atrial flutter requiring hospitalization. In a double-blind, placebo-controlled trial of 8,179 statin-treated subjects with established cardiovascular disease (CVD) or diabetes plus an additional risk factor for CVD, adjudicated atrial fibrillation or atrial flutter requiring hospitalization for 24 or more hours occurred in 127 (3%) patients treated with VASCEPA compared to 84 (2%) patients receiving placebo [HR=1.5 (95% CI 1.14, 1.98)]. The incidence of atrial fibrillation was greater in patients with a previous history of atrial fibrillation or atrial flutter.
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. Inform patients with known hypersensitivity to fish and/or shellfish about the potential for allergic reactions to VASCEPA and advise them to discontinue VASCEPA and seek medical attention if any reactions occur.
VASCEPA is associated with an increased risk of bleeding. In a double-blind, placebo-controlled cardiovascular outcomes trial of 8,179 patients, 482 (12%) patients receiving VASCEPA experienced a bleeding event compared to 404 (10%) patients receiving placebo. Serious bleeding events occurred in 111 (3%) of patients on VASCEPA vs. 85 (2%) of patients receiving placebo. The incidence of bleeding was greater in patients receiving concomitant antithrombotic medications, such as aspirin, clopidogrel, or warfarin.
The following important adverse reactions are described below and elsewhere in the labeling:
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.
In a double-blind, randomized, placebo-controlled cardiovascular outcomes trial, 8,179 statin-stabilized patients were randomized to receive VASCEPA or placebo and followed for a median of 4.9 years [see Clinical Studies (14.1)]. The median age at baseline was 64 years, 29% were women, 90% White, 5% Asian, 2% were Black, and 4% identified as Hispanic ethnicity.
Common adverse reactions (incidence ≥3% on VASCEPA and ≥1% more frequent than placebo) included musculoskeletal pain, peripheral edema, constipation, gout, and atrial fibrillation.
In two randomized, double-blind, placebo-controlled trials in patients with triglyceride levels between 200 and 2000 mg/dL treated for 12 weeks, adverse reactions reported with VASCEPA at an incidence ≥1% more frequent than placebo based on pooled data included arthralgia and oropharyngeal pain.
Additional adverse reactions have been identified during post-approval use of VASCEPA. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
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 VASCEPA and concomitant anticoagulants and/or antiplatelet agents for bleeding.
The available data from published case reports and the pharmacovigilance database on the use of VASCEPA 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 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.
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.
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. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VASCEPA and any potential adverse effects on the breastfed child from VASCEPA or from the underlying maternal condition.
Safety and effectiveness in pediatric patients have not been established.
Of the total number of patients in well-controlled clinical studies of VASCEPA, 45% were 65 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger groups. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
In patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored periodically during therapy with VASCEPA.
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