Epanova

CLINICAL PHARMACOLOGY

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.

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].

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.

Clinical Studies

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).

Table 2: Median Baseline (BL) and Median Percent (%) Change from Baseline in Lipid Parameters in Patients with Severe Hypertriglyceridemia ( ≥ 500 mg/dL)

Parameter (mg/dL) EPANOVA 2 g
N = 100
EPANOVA 4 g
N = 99
Placeboa
N = 99
EPANOVA 2 g vs. Placebo EPANOVA 4 g vs. Placebo
BL % Change BL % Change BL % Change Treatment Difference in % changeb
TG 717 -25 655 -31 682 -10 -16 ** c -21 *** d
Non-HDL-C 205 -8 225 -8 215 -1 -7 * -10 **
HDL-C 27 7 29 5 29 2 +5 † +4 †
TC 241 -6 254 -6 246 0 -6 -9
VLDL-C 123 -25 126 -35 125 -11 -14 -21
LDL-C 77 21 90 26 78 10 13 15
Apo B 114 6 118 6 110 2 3 2
a Placebo = Olive Oil
b Difference = Median of [EPANOVA % Change – Placebo % Change] (Hodges-Lehmann Estimate)
c 95% confidence interval of the treatment difference was (-26%, -6%) for EPANOVA 2 g vs. Placebo.
d 95% confidence interval of the treatment difference was (-31%, -11%) for EPANOVA 4 g vs. Placebo.
† not significant;
* for p < 0.05; ** for p < 0.01; *** for p < 0.001
Testing for statistical significance, with multiplicity adjustment where appropriate, was performed for TG, non-HDL-C, and HDL-C. P values were obtained from an ANCOVA model using rank-transformed data that included terms for treatment and use of lipid-altering drugs as factors and the baseline value as a covariate. Testing for statistical significance was not performed for TC, VLDL-C, LDL-C, or Apo B. Note: The results from the 3 gram arm were not meaningfully different than the 2 gram arm and are therefore not described.

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.

Last reviewed on RxList: 5/20/2014
This monograph has been modified to include the generic and brand name in many instances.

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