Omega-3-acid Ethyl Esters (Page 3 of 4)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a rat carcinogenicity study with oral gavage doses of 100, 600, and 2,000 mg/kg/day, males were treated with omega-3-acid ethyl esters for 101 weeks and females for 89 weeks without an increased incidence of tumors (up to 5 times human systemic exposures following an oral dose of 4 grams/day based on a body surface area comparison). Standard lifetime carcinogenicity bioassays were not conducted in mice.

Omega-3-acid ethyl esters were 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 V79 lung cells or human lymphocytes. Omega-3-acid ethyl esters were negative in the in vivo mouse micronucleus assay.

In a rat fertility study with oral doses of 100, 600, and 2,000 mg/kg/day, males were treated for 10 weeks prior to mating and females were treated for 2 weeks prior to mating and through lactation. No adverse effect on fertility was observed at 2,000 mg/kg/day (5 times the MRHD of 4 grams/day based on body surface area [mg/m 2 ]).

14 CLINICAL STUDIES

14.1 Severe Hypertriglyceridemia

The effects of omega-3-acid ethyl esters 4 grams per day were assessed in 2 randomized, placebo-controlled, double-blind, parallel-group trials of 84 adult subjects (42 on omega-3-acid ethyl esters, 42 on placebo) with very high TG levels. Subjects whose baseline TG levels were between 500 and 2,000 mg/dL were enrolled in these 2 trials of 6 and 16 weeks’ duration. The median TG and LDL-C levels in these subjects were 792 mg/dL and 100 mg/dL, respectively. Median high-density lipoprotein cholesterol (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 2.

Table 2. Median Baseline and Percent Change from Baseline in Lipid Parameters in Subjects with Severe Hypertriglyceridemia (≥500 mg/dL)

BL = Baseline (mg/dL); % Change = Median Percent Change from Baseline;

Difference = Omega-3-acid ethyl esters Median % Change – Placebo Median % Change. TC = Total cholesterol. VLDL-C = Very-low-density lipoprotein (VLDL) cholesterol.

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

Omega-3-acid ethyl esters 4 grams per day reduced median TG, VLDL-C, and non-HDL-C levels and increased median 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 omega-3-acid ethyl esters on the risk of pancreatitis has not been determined.

The effect of omega-3-acid ethyl esters on cardiovascular mortality and morbidity has not been determined.

16 HOW SUPPLIED/STORAGE AND HANDLING

Omega-3-Acid Ethyl Esters Capsules, USP are supplied as 1-gram clear, natural colored oblong shaped soft gelatin capsules containing pale yellow colored oily liquid imprinted with ‘740’

Blister pack of 4 x 5: NDC 50268-676-12

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) Protect from light. [See USP Controlled Room Temperature]. Do not freeze. Keep out of reach of children.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Information for Patients

  • Omega-3-acid ethyl esters capsules should be used with caution in patients with known sensitivity or allergy to fish and/or shellfish [see Warnings and Precautions (5.2)].
  • Advise patients that use of lipid-regulating agents does not reduce the importance of adhering to diet [see Dosage and Administration (2)].
  • Advise patients not to alter omega-3-acid ethyl esters capsules in any way and to ingest intact capsules only [see Dosage and Administration (2)].
  • Instruct patients to take omega-3-acid ethyl esters capsules as prescribed. If a dose is missed, advise patients to take it as soon as they remember. However, if they miss one day of omega-3-acid ethyl esters capsules, they should not double the dose when they take it.

Manufactured by:

Strides Pharma Science Ltd.

Bengaluru — 562106, India

Distributed by:

AvKARE

Pulaski, TN 38478

Revised 03/2021

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