The available data from published case reports and the pharmacovigilance database on the use of omega-3-acid ethyl esters in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, omega-3-acid ethyl esters given orally to female rats prior to mating through lactation did not have adverse effects on reproduction or development when given at doses 5 times the maximum recommended human dose (MRHD) of 4 grams/day, based on a body surface area comparison. Omega-3-acid ethyl esters given orally to rats and rabbits during organogenesis was not teratogenic at clinically relevant exposures, based on body surface area comparison (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Animal Data : In female rats given oral doses of omega-3-acid ethyl esters (100 mg/kg/day, 600 mg/kg/day, or 2,000 mg/kg/day) beginning 2 weeks prior to mating through lactation, no adverse effects were observed at 2,000 mg/kg/day (5 times the MRHD based on body surface area [mg/m 2 ]). In a dose-ranging study, female rats given oral doses of omega-3-acid ethyl esters (1,000 mg/kg/day, 3,000 mg/kg/day, or 6,000 mg/kg/day) beginning 2 weeks prior to mating through Postpartum Day 7 had decreased live births (20% reduction) and pup survival to Postnatal Day 4 (40% reduction) at or greater than 3,000 mg/kg/day in the absence of maternal toxicity at 3,000 mg/kg/day (7 times the MRHD based on body surface area [mg/m 2 ]).
In pregnant rats given oral doses of omega-3-acid ethyl esters (1,000 mg/kg/day, 3,000 mg/kg/day, or 6,000 mg/kg/day) during organogenesis, no adverse effects were observed in fetuses at a maternally toxic dose (increased food consumption) of 6,000 mg/kg/day (14 times the MRHD based on body surface area [mg/m 2 ]). In pregnant rats given oral doses of omega-3-acid ethyl esters (100 mg/kg/day, 600 mg/kg/day, or 2,000 mg/kg/day) from Gestation Day 14 through Lactation Day 21, no adverse effects were observed at 2,000 mg/kg/day (5 times the MRHD based on body surface area [mg/m 2 ]).
In pregnant rabbits given oral doses of omega-3-acid ethyl esters (375 mg/kg/day, 750 mg/kg/day, or 1,500 mg/kg/day) during organogenesis, no adverse effects were observed in fetuses given 375 mg/kg/day (2 times the MRHD based on body surface area [mg/m 2 ]). However, at higher doses, increases in fetal skeletal variations and reduced fetal growth were evident at maternally toxic doses (reduced food consumption and body weight gain) greater than or equal to 750 mg/kg/day (4 times the MRHD), and embryolethality was evident at 1,500 mg/kg/day (7 times the MRHD).
Published studies have detected omega-3 fatty acids, including EPA and DHA, 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 available on the effects of omega3 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 omega-3-acid ethyl esters and any potential adverse effects on the breastfed child from omega-3-acid ethyl esters or from the underlying maternal condition.
Safety and effectiveness in pediatric patients have not been established.
A limited number of subjects older than 65 years were enrolled in the clinical trials of omega‑3‑acid ethyl esters. Safety and efficacy findings in subjects older than 60 years did not appear to differ from those of subjects younger than 60 years.
Omega-3-acid ethyl esters, a lipid-regulating agent, are supplied as a liquid-filled gel capsule for oral administration. Each 1 gram capsule of omega-3-acid ethyl esters contains at least 900 mg of the ethyl esters of omega-3 fatty acids sourced from fish oils. These are predominantly a combination of ethyl esters of eicosapentaenoic acid (EPA — approximately 465 mg) and docosahexaenoic acid (DHA — approximately 375 mg).
The empirical formula of EPA ethyl ester is C 22 H 34 O 2 , and the molecular weight of EPA ethyl ester is 330.51. The structural formula of EPA ethyl ester is:
The empirical formula of DHA ethyl ester is C 24 H 36 O 2 , and the molecular weight of DHA ethyl ester is 356.55. The structural formula of DHA ethyl ester is:
Omega-3-acid ethyl esters capsules, USP also contain 4 mg alpha-tocopherol as an inactive ingredient in the capsule fill. The capsule shell is composed of gelatin, glycerin and water. The capsules are printed with white ink composed of hypromellose, isopropyl alcohol, propylene glycol, titanium dioxide and water.
The mechanism of action of omega-3-acid ethyl esters is not completely understood. Potential mechanisms of action include inhibition of acyl-CoA:1,2-diacylglycerol acyltransferase, increased mitochondrial and peroxisomal β-oxidation in the liver, decreased lipogenesis in the liver, and increased plasma lipoprotein lipase activity. Omega-3-acid ethyl esters may reduce the synthesis of TG in the liver because EPA and DHA are poor substrates for the enzymes responsible for TG synthesis, and EPA and DHA inhibit esterification of other fatty acids.
In healthy volunteers and in subjects with hypertriglyceridemia, EPA and DHA were absorbed when administered as ethyl esters orally. Omega-3-acids administered as ethyl esters (Omega‑3‑Acid Ethyl Esters Capsules) induced significant dose-dependent increases in serum phospholipid EPA content, though increases in DHA content were less marked and not dose‑dependent when administered as ethyl esters.
Age: Uptake of EPA and DHA into serum phospholipids in subjects treated with omega-3-acid ethyl esters was independent of age (younger than 49 years versus 49 years and older).
Male and Female Patients: Females tended to have more uptake of EPA into serum phospholipids than males. The clinical significance of this is unknown.
Pediatric Patients: Pharmacokinetics of omega-3-acid ethyl esters have not been studied.
Patients with Renal or Hepatic Impairment: Omega-3-acid ethyl esters has not been studied in patients with renal or hepatic impairment.
Drug Interaction Studies
Simvastatin: In a 14-day trial of 24 healthy adult subjects, daily co-administration of simvastatin 80 mg with omega-3-acid ethyl esters 4 grams did not affect the extent (AUC) or rate (C max ) of exposure to simvastatin or the major active metabolite, beta‑hydroxy simvastatin, at steady state.
Atorvastatin: In a 14-day trial of 50 healthy adult subjects, daily co-administration of atorvastatin 80 mg with omega-3-acid ethyl esters 4 grams did not affect AUC or C max of exposure to atorvastatin, 2-hydroxyatorvastatin, or 4-hydroxyatorvastatin at steady state.
Rosuvastatin: In a 14-day trial of 48 healthy adult subjects, daily co-administration of rosuvastatin 40 mg with omega-3-acid ethyl esters 4 grams did not affect AUC or C max of exposure to rosuvastatin at steady state.
In vitro studies using human liver microsomes indicated that clinically significant cytochrome P450-mediated inhibition by EPA/DHA combinations are not expected in humans.
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