5.1 Monitoring: Laboratory Tests

In some patients, EPANOVA increases LDL-C levels. LDL-C levels should be monitored periodically during therapy with EPANOVA.

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

5.2 Fish Allergy

EPANOVA contains polyunsaturated free fatty acids derived from fish oils. It is not known whether patients with allergies to fish and/or shellfish, are at increased risk of an allergic reaction to EPANOVA. EPANOVA should be used with caution in patients with known hypersensitivity to fish and/or shellfish.

6.1 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 by at least 3% of EPANOVA-treated individuals and with a higher incidence than placebo (olive oil), based on pooled data from two clinical trials of 6- and 12-week duration involving subjects with hypertriglyceridemia, are listed in Table 1.

In a pool of two longer-term (≥52 weeks) placebo-controlled clinical trials involving 748 patients (376 EPANOVA 4 grams per day; 372 placebo) with chronic gastrointestinal disease, additional common adverse reactions reported more often by EPANOVA-treated patients included abdominal distension, constipation, vomiting, fatigue, nasopharyngitis, arthralgia, and dysguesia.

7.1 Anticoagulants or Other Drugs Affecting Coagulation

Patients taking anti-platelet agents or anticoagulants were excluded from EPANOVA clinical trials involving patients with hypertriglyceridemia. 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. Nonetheless, patients receiving treatment with EPANOVA and drugs affecting coagulation (e.g., anti-platelet agents) should be monitored periodically.

8.1 Pregnancy

Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. It is unknown whether EPANOVA can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. EPANOVA should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus.

In female rats given oral gavage doses of 100, 600, and 2,000 mg/kg/day beginning 2 weeks prior to mating and continuing through day 6 of gestation, no adverse effects were observed in the high-dose group (5 times human systemic exposure following an oral dose of 4 grams/day based on body surface area comparison).

In pregnant rats given oral gavage doses of 100, 600, and 2,000 mg/kg/day from gestation day 6 through organogenesis , late embryonic deaths and embryos with skeletal variations were observed (5 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).

In pregnant rabbits given oral gavage doses of 100, 500, and 750 mg/kg/day from gestation day 6 through organogenesis, skeletal malformations, variations in ossification, and visceral variations were observed in the fetuses in groups given up to 500 mg/kg/day (2 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison). At 750 mg/kg/day, several rabbits aborted and evidence of maternal toxicity was observed, and there was an increase in the incidence of fetuses with malformations and variations (4 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).

In a multigenerational developmental study in pregnant rats given oral gavage doses of 100, 600, and 2,000 mg/kg/day from gestation day 6 through lactation day 21, difficulties during and shortly after parturition led to morbidity/mortality in 9 of 24 dams given the highest dose (5 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison). There were no abnormalities observed in offspring (F1) from treated dams. However, survival was decreased from day 10 of lactation onward in second generation offspring (F2) from dams given 600 mg/kg/day (1.5 times the human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).

8.2 Labor and Delivery

There are no human studies that have investigated the effects of EPANOVA on preterm labor or labor at term. However, animal studies showed that omega-3 fatty acids caused delayed parturition and associated fetal death in rats (5 times the human systemic exposure following an oral dose of 4 g/day based on body surface area comparison), and premature birth and abortion in rabbits (4 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).

8.3 Nursing Mothers

Studies with omega-3 fatty acids derived from fish oil have demonstrated excretion in human milk at levels higher than that in plasma. The effect of this excretion on the infant of a nursing mother is unknown; caution should be exercised when EPANOVA is administered to a nursing mother.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been studied.

8.5 Geriatric Use

Clinical studies of EPANOVA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

12.1 Mechanism of Action

The mechanism of action of EPANOVA 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. EPANOVA may reduce the synthesis of triglycerides 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.

12.3 Pharmacokinetics

Absorption: After oral administration, EPANOVA is directly absorbed in the small intestine, subsequently entering the systemic circulation mainly via the thoracic duct lymphatic system. Following repeat dosing with EPANOVA 4 grams per day under low-fat meal conditions for approximately 2 weeks, maximum plasma concentrations are achieved between 5-8 hours after dosing for total EPA and between 5-9 hours after dosing for total DHA. Steady-state concentrations of EPA and DHA in plasma are achieved within 2 weeks of repeat daily dosing with EPANOVA.

Single-dose administration of EPANOVA with a high-fat meal resulted in an increase in overall exposure of total and free baseline-adjusted EPA by approximately 140% and 80%, respectively, compared to fasting conditions. There was no change in overall exposure of baseline-adjusted total DHA; however, there was a 40% increase in AUC for baseline-adjusted free DHA. Overall exposures of unadjusted total and free EPA increased by 80% and 50%, respectively, although there was no change in overall exposure for unadjusted total and free DHA.

EPANOVA was administered without regard to meals in all clinical trials.

Distribution: Following a single 4-gram dose of EPANOVA under fasted conditions, the vast majority of EPA and DHA in plasma is incorporated in phospholipids, triglycerides and cholesteryl esters, with the free unesterified fatty acid representing approximately 0.8% and 1.1% of the total measured amount for EPA and DHA, respectively.

Metabolism and Excretion: EPA and DHA from EPANOVA are mainly oxidized in the liver similar to fatty acids derived from dietary sources. Following repeat dosing under low-fat meal conditions, the total apparent plasma clearance (CL/F) and half-life of baseline-adjusted EPA from EPANOVA at steady-state are 548 mL/hr and 37 hours, respectively. Under the same conditions, the CL/F and half-life of baseline-adjusted DHA are 518 mL/hr and approximately 46 hours, respectively. EPANOVA does not undergo renal excretion.

Specific Populations

Pediatric: Pharmacokinetics of EPANOVA in pediatric patients have not been studied [see Use in Specific Populations (8.4)].

Renal or Hepatic Impairment: EPANOVA has not been studied in patients with renal or hepatic impairment.

Drug-Drug Interactions

Simvastatin: In a 14-day study of 52 healthy adult subjects, daily co-administration of simvastatin 40 mg with EPANOVA 4 grams did not affect the extent (AUC) or rate (Cmax) of exposure to simvastatin or its major active metabolite, beta-hydroxy simvastatin, at steady state.

Warfarin: In a 14-day study of 52 healthy adult subjects, EPANOVA 4 grams/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 25 mg warfarin.

In vitro studies of cytochrome P450 inhibition with EPANOVA indicated that EPANOVA administration at clinically relevant doses should not result in inhibition of CYP450 enzymes. In vitro, EPANOVA did not affect multidrug resistance associated protein (MRP) or breast cancer resistance protein (BCRP) transporters.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a Sprague-Dawley rat carcinogenicity study with oral gavage doses of 100, 600, and 2,000 mg/kg/day omega-3 carboxylic acid, males were treated for 84 to 95 weeks without an increased incidence of tumors. In female rats treated for 66 to 95 weeks at 2000 mg/kg/day, an increased incidence of benign ovarian sex cord stromal tumors were observed (up to 5 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison). In a 6-month carcinogenicity study, Tg.rasH2 transgenic mice were treated with oral gavage doses of 500, 1000, 2000, and 4000 mg/kg/day omega-3 carboxylic acid without any increase in the incidence of tumors.

EPANOVA was not mutagenic or clastogenic with or without metabolic activation in the bacterial mutagenesis (Ames) test with Salmonella typhimurium and Escherichia coli or in the chromosomal aberration assay in Chinese hamster ovary cells. EPANOVA was negative in the in vivo rat bone marrow micronucleus assay.

In a rat fertility study with oral gavage doses of 100, 600, and 2,000 mg/kg/day, males were treated from 4 weeks prior to mating, and females were treated for 2 weeks prior to and throughout mating until day 6 of gestation. No adverse effect on male or female fertility was observed at 2,000 mg/kg/day (5 times human systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).

14.1 Severe Hypertriglyceridemia

The effects of EPANOVA in severe hypertriglyceridemia were assessed in a 12-week randomized, placebo (olive oil)-controlled, double-blind, parallel-group trial. After a wash-out period of lipid-altering medications other than statins and ezetimibe, patients whose TG levels were between 500 and 2,000 mg/dL were randomly assigned to placebo or EPANOVA 2, 3, or 4 grams per day. Overall, the median baseline triglyceride level was 694 mg/dL. Median baseline non-HDL-C, LDL-C, and HDL-C levels were 217 mg/dL, 81 mg/dL, and 28 mg/dL, respectively. The study population was mostly Caucasian (92%) and male (77%). The mean age was 52 years and the mean BMI was 31 kg/m2. Thirty-seven percent of patients had diabetes, 35% were treated with a statin and/or ezetimibe, and 29% had baseline TG > 885 mg/dL.

Treatment with EPANOVA led to statistically significant reductions in fasting TG levels (Table 2). Treatment with EPANOVA also resulted in statistically significant reductions in non-HDL-C levels compared with placebo, but increased LDL-C levels (Table 2).

The effect of EPANOVA on the risk for pancreatitis has not been determined.

The effect of EPANOVA on cardiovascular mortality and morbidity has not been determined.