Icosapent (Page 2 of 3)

8.2 Lactation

Risk Summary

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 icosapent ethyl and any potential adverse effects on the breastfed child from icosapent ethyl or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of the total number of patients in well-controlled clinical studies of icosapent ethyl, 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.

8.7 Hepatic Impairment

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

11 DESCRIPTION

Icosapent ethyl capsules, a lipid-regulating agent, is supplied as a 1 gram transparent natural colored oblong shaped, liquid-filled soft gelatin capsule for oral use.

Each icosapent ethyl capsule contains 1 gram of icosapent ethyl (in a 1 gram capsule). Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). The empirical formula of icosapent ethyl is C22 H34 O2 and the molecular weight is 330.51. The chemical name for icosapent ethyl is ethyl all-cis-5,8,11,14,17-icosapentaenoate with the following chemical structure:

Chemical Structure

Icosapent ethyl capsules also contain the following inactive ingredients: alpha tocopherol, gelatin, glycerin, mannitol, sorbitol, and purified water.

The imprinting Opacode NSP-78-18022 White contains, ammonium hydroxide, macrogol, polyvinyl acetate phthalate, propylene glycol and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Studies suggest that EPA reduces hepatic very low-density lipoprotein triglycerides (VLDL-TG) synthesis and/or secretion and enhances TG clearance from circulating VLDL particles. Potential mechanisms of action include increased β-oxidation; inhibition of acyl-CoA:1,2-diacylglycerol acyltransferase (DGAT); decreased lipogenesis in the liver; and increased plasma lipoprotein lipase activity.

12.2 Pharmacodynamics

In a 12-week, dose-ranging study in patients with severe hypertriglyceridemia, icosapent ethyl 4 grams per day reduced median TG from baseline relative to placebo [see Clinical Studies (14)].

12.3 Pharmacokinetics

Absorption

After oral administration, icosapent ethyl is de-esterified during the absorption process and the active metabolite EPA is absorbed in the small intestine and enters the systemic circulation mainly via the thoracic duct lymphatic system. Peak plasma concentrations of EPA were reached approximately 5 hours following oral doses of icosapent ethyl. Icosapent ethyl capsules was administered with or following a meal in all clinical studies; no food effect studies were performed. Take icosapent ethyl capsules with or following a meal.

Distribution

The mean volume of distribution at steady state of EPA is approximately 88 liters. The majority of EPA circulating in plasma is incorporated in phospholipids, triglycerides and cholesteryl esters, and <1% is present as the unesterified fatty acid. Greater than 99% of unesterified EPA is bound to plasma proteins.

Elimination

Metabolism

EPA is mainly metabolized by the liver via beta-oxidation similar to dietary fatty acids. Beta oxidation splits the long carbon chain of EPA into acetyl Coenzyme A, which is converted into energy via the Krebs cycle. Cytochrome P450-mediated metabolism is a minor pathway of elimination of EPA.

Excretion

The total plasma clearance of EPA at steady state is 684 mL/hr. The plasma elimination half-life (t1/2) of EPA is approximately 89 hours. Icosapent ethyl does not undergo renal excretion.

Specific Populations

Gender

When administered icosapent ethyl in clinical trials, plasma total EPA concentrations did not differ significantly between men and women.

Pediatric

The pharmacokinetics of icosapent ethyl have not been studied in pediatric patients.

Hepatic or Renal Impairment

Icosapent ethyl has not been studied in patients with renal or hepatic impairment.

Drug Interaction Studies

Omeprazole

In a drug-drug interaction study with 28 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the steady-state AUCτ or Cmax of omeprazole when co- administered at 40 mg/day to steady-state.

Rosiglitazone

In a drug-drug interaction study with 28 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the single dose AUC or Cmax of rosiglitazone at 8 mg.

Warfarin

In a drug-drug interaction study with 25 healthy adult subjects, icosapent ethyl 4 g/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 warfarin when co-administered as racemic warfarin at 25 mg.

Atorvastatin

In a drug-drug interaction study of 26 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the steady-state AUCτ or Cmax of atorvastatin, 2-hydroxyatorvastatin, or 4-hydroxyatorvastatin when co-administered with atorvastatin 80 mg/day at steady-state.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year rat carcinogenicity study with oral gavage doses of 0.09, 0.27, and 0.91 g/kg/day icosapent ethyl, respectively, males did not exhibit drug-related neoplasms. Hemangiomas and hemangiosarcomas of the mesenteric lymph node, the site of drug absorption, were observed in females at clinically relevant exposures based on body surface area comparisons across species relative to the maximum clinical dose of 4 g/day. Overall incidence of hemangiomas and hemangiosarcomas in all vascular tissues did not increase with treatment.

In a 6-month carcinogenicity study in Tg.rasH2 transgenic mice with oral gavage doses of 0.5, 1, 2, and 4.6 g/kg/day icosapent ethyl, drug-related incidences of benign squamous cell papilloma in the skin and subcutis of the tail was observed in high dose male mice. The papillomas were considered to develop secondary to chronic irritation of the proximal tail associated with fecal excretion of oil and therefore not clinically relevant. Drug-related neoplasms were not observed in female mice.

Icosapent ethyl was not mutagenic with or without metabolic activation in the bacterial mutagenesis (Ames) assay or in the in vivo mouse micronucleus assay. A chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells was positive for clastogenicity with and without metabolic activation.

In an oral gavage rat fertility study, ethyl-EPA, administered at doses of 0.3, 1, and 3 g/kg/day to male rats for 9 weeks before mating and to female rats for 14 days before mating through day 7 of gestation, increased anogenital distance in female pups and increased cervical ribs were observed at 3 g/kg/day (7 times human systemic exposure with 4 g/day clinical dose based on a body surface area comparison).

14 CLINICAL STUDIES

14.2 Severe Hypertriglyceridemia

The effects of icosapent ethyl 4 grams per day were assessed in a randomized, placebo- controlled, double-blind, parallel-group study of adult patients (76 on icosapent ethyl, 75 on placebo) with severe hypertriglyceridemia. Patients whose baseline TG levels were between 500 and 2,000 mg/dL were enrolled in this study for 12 weeks. The median baseline TG and LDL-C levels in these patients were 684 mg/dL and 86 mg/dL, respectively. Median baseline HDL-C level was 27 mg/dL. The randomized population in this study was mostly Caucasian (88%) and male (76%). The mean age was 53 years and the mean body mass index was 31 kg/m2 . Twenty- five percent of patients were on concomitant statin therapy, 28% were diabetics, and 39% of the patients had TG levels >750 mg/dL.

The changes in the major lipoprotein lipid parameters for the groups receiving icosapent ethyl or 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 Icosapent Ethyl 4 g/day N=76 Placebo N=75 Difference (95% Confidence Interval)
Baseline % Change Baseline % Change
TG (mg/dL) 680 -27 703 +10 -33* (-47, -22)
LDL-C (mg/dL) 91 -5 86 -3 -2 (-13, +8)
Non-HDL-C (mg/dL) 225 -8 229 +8 -18 (-25, -11)
TC (mg/dL) 254 -7 256 +8 -16 (-22, -11)
HDL-C (mg/dL) 27 -4 27 0 -4 (-9, +2)
VLDL-C (mg/dL) 123 -20 124 +14 -29** (-43, -14)
Apo B (mg/dL) 121 -4 118 +4 -9**(-14, -3)

% Change= Median Percent Change from Baseline

Difference= Median of [Icosapent Ethyl % Change – Placebo % Change] (Hodges-Lehmann Estimate) p-values from Wilcoxon rank-sum test

*p-value < 0.001 (primary efficacy endpoint)

**p-value < 0.05 (key secondary efficacy endpoints determined to be statistically significant according to the pre-specified multiple comparison procedure)

Icosapent ethyl 4 grams per day reduced median TG, VLDL-C, and Apo B levels from baseline relative to placebo. The reduction in TG observed with Icosapent ethyl was not associated with elevations in LDL-C levels relative to placebo.

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