Omtryg

CLINICAL PHARMACOLOGY

Mechanism Of Action

The mechanism of action of OMTRYG is not completely understood. Potential mechanisms of action include inhibition of acyl-CoA:1,2-diacylglycerol acyltransferase, increased mitochondrial and peroxisomal -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 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

Systemic Bioavailability

When OMTRYG was administered under fasted condition, on average the peak (Cmax) and total (AUC0-72h) exposure were lower by up to 20 to 80-fold, respectively, for total plasma EPA, and lower by up to 2 to 4-fold, respectively, for total plasma DHA, in comparison to those observed under fed condition (high-fat high-calorie meal). Therefore, OMTRYG should be taken with food.

In healthy volunteers and in patients with hypertriglyceridemia, EPA and DHA were absorbed when administered as ethyl esters orally. Omega-3-acids administered as ethyl esters 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.

Specific Populations

Age: Uptake of EPA and DHA into serum phospholipids in subjects treated with omega-3-acid ethyl esters was independent of age ( < 49 years versus ≥ 49 years).

Gender: Females tended to have more uptake of EPA into serum phospholipids than males. The clinical significance of this is unknown.

Pediatric: Pharmacokinetics of OMTRYG have not been studied.

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

Drug-Drug Interactions

Simvastatin: In a 14-day study of 24 healthy adult subjects, daily coadministration of simvastatin 80 mg with 4 capsules of omega-3-acid ethyl esters did not affect the extent (AUC) or rate (Cmax) of exposure to simvastatin or the major active metabolite, betahydroxy simvastatin, at steady state.

Atorvastatin: In a 14-day study of 50 healthy adult subjects, daily co-administration of atorvastatin 80 mg with 4 capsules of omega-3-acid ethyl esters did not affect AUC or Cmax of exposure to atorvastatin, 2-hydroxyatorvastatin, or 4-hydrosyatorvastatin at steady state.

Rosuvastatin: In a 14-day study of 48 healthy adult subjects, daily co-administration of rosuvastatin 40 mg with 4 capsules of omega-3-acid ethyl esters did not affect AUC or Cmax 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.

Clinical Studies

Severe Hypertriglyceridemia

A randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy of OMTRYG compared with both placebo and an omega-3-acid ethyl esters product in 254 patients with severe hypertriglyceridemia (500-1500 mg/dL). Patients entered a 6-week wash-out/dietary lead-in period and then were randomized to 12-week treatment with either OMTRYG, omega-3acid ethyl esters, or placebo (vegetable oil), each administered as 4 capsules once daily. Each capsule of both OMTRYG and omega-3-acid ethyl esters contains, among other components, at least 900 mg of ethyl esters from omega-3 fatty acids sourced from fish oils. The primary endpoint was percent change in serum triglycerides (TG) from baseline to Week 12. The secondary endpoints were percent change in non-HDL-C, VLDL-C, LDL-C, and HDL-C from baseline to Week 12. Overall, the mean age was 51 years, 72% were men, 92% were Caucasian, the mean BMI was 33 kg/m², and 21% were taking a statin. The baseline median TG level was 675 mg/dL, mean LDL-C was 87 mg/dL, and mean HDL-C was 30 mg/dL.

OMTRYG statistically significantly reduced TG at Week 12 compared with placebo (pvalue < 0.05). The changes in the major lipid parameters for the groups receiving OMTRYG, omega-3-acid ethyl esters, and placebo are shown in Table 2.

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

Parameter OMTRYG
N = 104
Omega-3-Acid Ethyl Esters
N=103
Placebo
N = 43
Median difference from Placebo
BL % Change BL % Change BL % Change OMTRYG vs. Placebo Omega- 3-Acid EE vs. Placebo
TG 702 -24.7 655 -26.8 624 -17.4 -12.2* -14.0*
Non-HDL-C 237 -9.2 210 -3.6 222 -0.8 -8.5 -3.5
TC 270 -8.1 244 -1.0 250 -0.8 -6.9 -1.9
VLDL-C 153 -21.2 117 -18.0 114 +5.6 -28.7** -23.7*
HDL-C 28 0.0 30 0.0 30 0.0 +3.9 +5.2
LDL-C 78 +20.3 85 +12.8 94 -5.9 +24.7** +18.9*
BL = Baseline (mg/dL) median; % Change = Median Percent Change from Baseline; Median difference from placebo = Hodges Lehmann median of all pairwise differences from placebo
* p < 0.05, ** p < 0.01, statistically significant difference between treatment groups based on the pre-specified Hommel method for controlling Type 1 error among the secondary endpoints.

The effects of omega-3-acid ethyl esters 4 capsules per day were assessed in 2 randomized, placebo-controlled, double-blind, parallel-group studies of 84 adult patients (42 on omega-3-acid ethyl esters, 42 on placebo) with severe hypertriglyceridemia. Patients whose baseline TG levels were between 500 and 2,000 mg/dL were enrolled in these 2 studies of 6 and 16 weeks duration. The median triglyceride and LDL-C levels in these patients were 792 mg/dL and 100 mg/dL, respectively. Median HDL-C level was 23.0 mg/dL.

The changes in the major lipoprotein lipid parameters for the groups receiving omega-3-acid ethyl esters or placebo are shown in Table 3.

Table 3: Median Baseline and Percent Change From Baseline in Lipid Parameters in Patients with Severe Hypertriglyceridemia ( ≥ 500mg/dL)

Parameter Omega-3-Acid Ethyl Esters*
N = 42
Placebo
N = 42
Difference
BL % Change BL % Change
TG 816 -44.9 788 +6.7 -51.6
Non-HDL-C 271 -13.8 292 -3.6 -10.2
TC 296 -9.7 314 -1.7 -8.0
VLDL-C 175 -41.7 175 -0.9 -40.8
HDL-C 22 +9.1 24 0.0 +9.1
LDL-C 89 +44.5 108 -4.8 +49.3
BL = Baseline (mg/dL); % Change = Median Percent Change from Baseline; Difference = Omega-3-acid ethyl esters Median % Change – Placebo Median % Change
* OMTRYG and omega-3-acid ethyl esters each contain, among other components, at least 900 mg per capsule of ethyl esters from omega-3 fatty acids sourced from fish oils.

Omega-3-acid ethyl esters reduced median TG, VLDL-C, and non-HDL-C levels and increased HDL-C from baseline relative to placebo. Treatment with omega-3-acid ethyl esters to reduce very high TG levels may result in elevations in LDL-C and non-HDL-C in some individuals. Patients should be monitored to ensure that the LDL-C level does not increase excessively.

The effect of OMTRYG on the risk of pancreatitis has not been evaluated.

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

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

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