omega-3 acid ethyl esters 1 GM Oral Capsule
Generic Name: OMEGA-3-ACID ETHYL ESTERS
Brand Name: Omega-3-acid ethyl esters
- Substance Name(s):
- OMEGA-3-ACID ETHYL ESTERS
DRUG INTERACTIONS
7 Omega-3-acids may prolong bleeding time.
Patients taking omega-3-acid ethyl esters capsules and an anticoagulant or other drug affecting coagulation (e.g., anti-platelet agents) should be monitored periodically.
( 7.1 ) 7.1 Anticoagulants or Other Drugs Affecting Coagulation Some trials with omega-3-acids demonstrated prolongation of bleeding time.
The prolongation of bleeding time reported in these trials has not exceeded normal limits and did not produce clinically significant bleeding episodes.
Clinical trials have not been done to thoroughly examine the effect of omega-3-acid ethyl esters and concomitant anticoagulants.
Patients receiving treatment with omega-3-acid ethyl esters and an anticoagulant or other drug affecting coagulation (e.g., anti-platelet agents) should be monitored periodically.
DESCRIPTION
11 Omega-3-acid ethyl esters capsules, USP, a lipid-regulating agent, are supplied as a liquid-filled gel capsule for oral administration.
Each 1-gram capsule of omega-3-acid ethyl esters capsules, USP contains at least 900 mg of the ethyl esters of omega-3 fatty acids sourced from fish oils.
These are predominantly a combination of ethyl esters of eicosapentaenoic acid (EPA – approximately 465 mg) and docosahexaenoic acid (DHA – approximately 375 mg).
The molecular formula of EPA ethyl ester is C 22 H 34 O 2 , and the molecular weight of EPA ethyl ester is 330.51.
The structural formula of EPA ethyl ester is: The molecular formula of DHA ethyl ester is C 24 H 36 O 2 , and the molecular weight of DHA ethyl ester is 356.55.
The structural formula of DHA ethyl ester is: Omega-3-acid ethyl esters capsules, USP also contain the following inactive ingredients: 4 mg α-tocopherol (in a carrier of soybean oil), and gelatin, glycerin, purified water, and white ink (components of the capsule shell).
The capsule imprinting ink contains ammonium hydroxide, propylene glycol, shellac glaze, simethicone and titanium dioxide.
CLINICAL STUDIES
14 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) 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; TC = Total cholesterol; VLDL-C = Very-low-density lipoprotein (VLDL) cholesterol.
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.
HOW SUPPLIED
16 /STORAGE AND HANDLING Omega-3-acid ethyl esters capsules, USP are supplied as 1-gram transparent, oblong soft gelatin capsules with light yellowish oil printed with white ink (Logo “APO900”).
They are supplied as follows: Bottles of 30s (NDC 60505-3170-3) Bottles of 60s (NDC 60505-3170-6) Bottles of 120s (NDC 60505-3170-7) Store in tight, light-resistant containers at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Protect from light.
Do not freeze.
Keep out of reach of children.
GERIATRIC USE
8.5 Geriatric Use A limited number of subjects older than 65 years were enrolled in the clinical trials of omega-3-acid ethyl esters capsules.
Safety and efficacy findings in subjects older than 60 years did not appear to differ from those of subjects younger than 60 years.
DOSAGE FORMS AND STRENGTHS
3 Omega-3-acid ethyl esters capsules, USP are supplied as 1-gram transparent, soft gelatin capsules filled with light yellowish oil printed with white ink (Logo “APO900”).
Capsules: 1 gram ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action The mechanism of action of omega-3-acid ethyl esters 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.
Omega-3-acid ethyl esters may reduce the synthesis of TG 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.
INDICATIONS AND USAGE
1 Omega-3-acid ethyl esters capsules, USP are indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (greater than or equal to 500 mg/dL) hypertriglyceridemia.
Usage Considerations: Patients should be placed on an appropriate lipid-lowering diet before receiving omega-3-acid ethyl esters capsules, USP and should continue this diet during treatment with omega-3-acid ethyl esters capsules, USP.
Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal before instituting therapy with omega-3-acid ethyl esters.
Every attempt should be made to control serum lipids with appropriate diet, exercise, weight loss in obese patients, and control of any medical problems such as diabetes mellitus and hypothyroidism that are contributing to the lipid abnormalities.
Medications known to exacerbate hypertriglyceridemia (such as beta blockers, thiazides, estrogens) should be discontinued or changed, if possible, prior to consideration of TG-lowering drug therapy.
Limitations of Use: The effect of omega-3-acid ethyl esters capsules, USP on the risk for pancreatitis has not been determined.
The effect of omega-3-acid ethyl esters capsules, USP on cardiovascular mortality and morbidity has not been determined.
Omega-3-acid ethyl esters, USP is a combination of ethyl esters of omega 3 fatty acids, principally eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia.
( 1 ) Limitations of Use: The effect of omega-3-acid ethyl esters capsules, USP on the risk for pancreatitis has not been determined.
( 1 ) The effect of omega-3-acid ethyl esters capsules, USP on cardiovascular mortality and morbidity has not been determined.
( 1 )
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.
PREGNANCY
8.1 Pregnancy Risk Summary The available data from published case reports and the pharmacovigilance database on the use of omega-3-acid ethyl esters capsules in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes.
In animal studies, omega-3-acid ethyl esters given orally to female rats prior to mating through lactation did not have adverse effects on reproduction or development when given at doses 5 times the maximum recommended human dose (MRHD) of 4 grams/day, based on a body surface area comparison.
Omega-3-acid ethyl esters given orally to rats and rabbits during organogenesis was not teratogenic at clinically relevant exposures, based on body surface area comparison (see Data) .
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data Animal Data: In female rats given oral doses of omega-3-acid ethyl esters (100, 600, or 2,000 mg/kg/day) beginning 2 weeks prior to mating through lactation, no adverse effects were observed at 2,000 mg/kg/day (5 times the MRHD based on body surface area [mg/m 2 ]).
In a dose-ranging study, female rats given oral doses of omega-3-acid ethyl esters (1,000, 3,000, or 6,000 mg/kg/day) beginning 2 weeks prior to mating through Postpartum Day 7 had decreased live births (20% reduction) and pup survival to Postnatal Day 4 (40% reduction) at or greater than 3,000 mg/kg/day in the absence of maternal toxicity at 3,000 mg/kg/day (7 times the MRHD based on body surface area [mg/m 2 ]).
In pregnant rats given oral doses of omega-3-acid ethyl esters (1,000, 3,000, or 6,000 mg/kg/day) during organogenesis, no adverse effects were observed in fetuses at a maternally toxic dose (increased food consumption) of 6,000 mg/kg/day (14 times the MRHD based on body surface area [mg/m 2 ]).
In pregnant rats given oral doses of omega-3-acid ethyl esters (100, 600, or 2,000 mg/kg/day) from Gestation Day 14 through Lactation Day 21, no adverse effects were observed at 2,000 mg/kg/day (5 times the MRHD based on body surface area [mg/m 2 ]).
In pregnant rabbits given oral doses of omega-3-acid ethyl esters (375, 750, or 1,500 mg/kg/day) during organogenesis, no adverse effects were observed in fetuses given 375 mg/kg/day (2 times the MRHD based on body surface area [mg/m 2 ]).
However, at higher doses, increases in fetal skeletal variations and reduced fetal growth were evident at maternally toxic doses (reduced food consumption and body weight gain) greater than or equal to 750 mg/kg/day (4 times the MRHD), and embryolethality was evident at 1,500 mg/kg/day (7 times the MRHD).
NUSRING MOTHERS
8.2 Lactation Risk Summary Published studies have detected omega-3 fatty acids, including EPA and DHA, 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 available 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 omega-3-acid ethyl esters capsules and any potential adverse effects on the breastfed child from omega-3-acid ethyl esters capsules or from the underlying maternal condition.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS In patients with hepatic impairment, monitor ALT and AST levels periodically during therapy.
( 5.1 ) Omega-3-acid ethyl esters capsules may increase levels of low-density lipoprotein (LDL).
Monitor LDL levels periodically during therapy.
( 5.1 ) Use with caution in patients with known hypersensitivity to fish and/or shellfish.
( 5.2 ) There is a possible association between omega-3-acid ethyl esters and more frequent recurrences of symptomatic atrial fibrillation or flutter in patients with paroxysmal or persistent atrial fibrillation, particularly within the first months of initiating therapy.
( 5.3 ) 5.1 Monitoring: Laboratory Tests In patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored periodically during therapy with omega-3-acid ethyl esters capsules.
In some patients, increases in ALT levels without a concurrent increase in AST levels were observed.
In some patients, omega-3-acid ethyl esters capsule increases low-density lipoprotein cholesterol (LDL-C) levels.
LDL-C levels should be monitored periodically during therapy with omega-3-acid ethyl esters.
Laboratory studies should be performed periodically to measure the patient’s TG levels during therapy with omega-3-acid ethyl esters.
5.2 Fish Allergy Omega-3-acid ethyl esters capsules contain ethyl esters of omega-3 fatty acids (EPA and DHA) obtained from the oil of several fish sources.
It is not known whether patients with allergies to fish and/or shellfish, are at increased risk of an allergic reaction to omega-3-acid ethyl esters capsules.
Omega-3-acid ethyl esters capsules should be used with caution in patients with known hypersensitivity to fish and/or shellfish.
5.3 Recurrent Atrial Fibrillation (AF) or Flutter In a double-blind, placebo-controlled trial of 663 subjects with symptomatic paroxysmal AF (n = 542) or persistent AF (n = 121), recurrent AF or flutter was observed in subjects randomized to omega-3-acid ethyl esters who received 8 grams/day for 7 days and 4 grams/day thereafter for 23 weeks at a higher rate relative to placebo.
Subjects in this trial had median baseline TG levels of 127 mg/dL, had no substantial structural heart disease, were taking no anti-arrhythmic therapy (rate control permitted), and were in normal sinus rhythm at baseline.
At 24 weeks, in the paroxysmal AF stratum, there were 129 (47%) first recurrent symptomatic AF or flutter events on placebo and 141 (53%) on omega-3-acid ethyl esters (primary endpoint, HR: 1.19; 95% CI: 0.93, 1.35).
In the persistent AF stratum, there were 19 (35%) events on placebo and 34 (52%) events on omega-3-acid ethyl esters (HR: 1.63; 95% CI: 0.91, 2.18).
For both strata combined, the HR was 1.25; 95% CI: 1.00, 1.40.
Although the clinical significance of these results is uncertain, there is a possible association between omega-3-acid ethyl esters and more frequent recurrences of symptomatic AF or flutter in patients with paroxysmal or persistent AF, particularly within the first 2 to 3 months of initiating therapy.
Omega-3-acid ethyl esters capsules are not indicated for the treatment of AF or flutter.
INFORMATION FOR PATIENTS
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 Dispense with Patient Information available at ww1.apotex.com/products/us APOTEX INC.
Omega-3-Acid Ethyl Esters Capsules, USP 1 gram Manufactured in Canada for: Apotex Corp.
Weston, FL.
33326 USA Revision: 7 Revised: July 2021
DOSAGE AND ADMINISTRATION
2 Assess TG levels carefully before initiating therapy.
Identify other causes (e.g., diabetes mellitus, hypothyroidism, medications) of high TG levels and manage as appropriate [see Indications and Usage (1)] .
Patients should be placed on an appropriate lipid-lowering diet before receiving omega-3-acid ethyl esters capsules and should continue this diet during treatment with omega-3-acid ethyl esters capsules.
In clinical studies, omega-3-acid ethyl esters capsules were administered with meals.
The daily dose of omega-3-acid ethyl esters capsules is 4 grams per day.
The daily dose may be taken as a single 4-gram dose (4 capsules) or as two 2-gram doses (2 capsules given twice daily).
Patients should be advised to swallow omega-3-acid ethyl esters capsules whole.
Do not break open, crush, dissolve, or chew omega-3-acid ethyl esters capsules.
The daily dose of omega-3-acid ethyl esters is 4 grams per day taken as a single 4-gram dose (4 capsules) or as two 2-gram doses (2 capsules given twice daily).
( 2 ) Patients should be advised to swallow omega-3-acid ethyl esters capsules whole.
Do not break open, crush, dissolve, or chew omega-3-acid ethyl esters capsules.
( 2 )