Label: OMEGA-3 WELL PACK kit

Omega-3-acid ethyl esters capsules, USP are indicated as an adjunct to diet to reduce triglyceride (TG)
levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia (HTG).

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 triglyceride-lowering drug therapy.

Limitations of Use:
Sections or subsections omitted from the full prescribing information are not listed.
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.

Assess triglyceride levels carefully before initiating therapy. Identify other causes (e.g., diabetes
mellitus, hypothyroidism, medications) of high triglyceride 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.

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”).

Omega-3-acid ethyl esters capsules are contraindicated in patients with known hypersensitivity (e.g.,
anaphylactic reaction) to omega-3-acid ethyl esters capsules or any of its components.

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 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 triglycerides 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 atrial
fibrillation or flutter in patients with paroxysmal or persistent atrial fibrillation, 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.

6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed
in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another
drug and may not reflect the rates observed in practice.
Adverse reactions reported in at least 3% and at a greater rate than placebo for subjects treated with
omega-3-acid ethyl esters capsules based on pooled data across 23 clinical trials are listed in Table 1.
Table 1. Advers e Reactions Occurring at Incidence ≥3%
and Greater than Placebo in Clinical Trials of omega-3-
acid ethylesters capssules

Adverse Reactions
Omega-3-acid ethylesters capsules
(N = 655)
Placebo
(N = 370)
n % n %
Eructation 29 4 5 1
Dyspepsia 22 3 6 2
Taste
perversion 27 4 1 ≤1

Additional adverse reactions from clinical trials are listed below:
Digestive System: Constipation, gastrointestinal disorder and vomiting.
Metabolic and Nutritional Disorders: Increased ALT and increased AST.
Skin: Pruritus and rash.
6.2 Pos tmarketing Experience
In addition to adverse reactions reported from clinical trials, the events described below have been
identified during post-approval use of omega-3-acid ethyl esters capsules. Because these events are
reported voluntarily from a population of unknown size, it is not possible to reliably estimate their
Trials included subjects with HTG and severe HTG.

frequency or to always establish a causal relationship to drug exposure.
The following events have been reported: anaphylactic reaction, hemorrhagic diathesis.

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.

8.1 Pregnancy
Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. It is
unknown whether omega-3-acid ethyl esters capsules can cause fetal harm when administered to a
pregnant woman or can affect reproductive capacity. Omega-3-acid ethyl esters capsules should be
used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus.

Animal Data: Omega-3-acid ethyl esters have been shown to have an embryocidal effect in pregnant rats
when given in doses resulting in exposures 7 times the recommended human dose of 4 grams/day based
on a body surface area comparison.
In female rats given oral gavage doses of 100, 600, and 2,000 mg/kg/day beginning 2 weeks prior to
mating and continuing through gestation and lactation, no adverse effects were observed in the highdose
group (5 times human systemic exposure following an oral dose of 4 grams/day based on body
surface area comparison).

In pregnant rats given oral gavage doses of 1,000, 3,000, and 6,000 mg/kg/day from gestation day 6
through 15, no adverse effects were observed (14 times human systemic exposure following an oral
dose of 4 grams/day based on a body surface area comparison).
In pregnant rats given oral gavage doses of 100, 600, and 2,000 mg/kg/day from gestation day 14
through lactation day 21, no adverse effects were seen at 2,000 mg/kg/day (5 times the human systemic
exposure following an oral dose of 4 grams/day based on a body surface area comparison). However,
decreased live births (20% reduction) and decreased survival to postnatal day 4 (40% reduction) were
observed in a dose-ranging study using higher doses of 3,000 mg/kg/day (7 times the human systemic
exposure following an oral dose of 4 grams/day based on a body surface area comparison).

In pregnant rabbits given oral gavage doses of 375, 750, and 1,500 mg/kg/day from gestation day 7
through 19, no findings were observed in the fetuses in groups given 375 mg/kg/day (2 times human
systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).
However, at higher doses, evidence of maternal toxicity was observed (4 times human systemic
exposure following an oral dose of 4 grams/day based on a body surface area comparison).

8.3 Nursing Mothers
Studies with omega-3-acid ethyl esters have demonstrated excretion in human milk. The effect of this
excretion on the infant of a nursing mother is unknown; caution should be exercised when omega-3-acid
ethyl esters capsules are administered to a nursing mother. An animal study in lactating rats given oral
gavage C-ethyl EPA demonstrated that drug levels were 6 to 14 times higher in milk 14 than in plasma.

8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.

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.

Omega-3-acid ethyl esters capsules do not have any known drug abuse or withdrawal effects.

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 H O , and the molecular weight of EPA ethyl ester is
330.51.

The molecular formula of DHA ethyl ester is C H O , and the molecular weight of DHA ethyl ester
is 356.55.

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.

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
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.

12.3 Pharmacokinetics
In healthy volunteers and in subjects 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 omega-3-acid ethyl esters have not been studied.
Renal or Hepatic Impairment: Omega-3-acid ethyl esters has not been studied in patients with renal or
hepatic impairment.
Drug-Drug Interactions:Simvastatin: In a 14-day trial of 24 healthy adult subjects, daily coadministration
of simvastatin 80 mg with omega-3-acid ethyl esters 4 grams did not affect the extent (AUC) or rate
(C ) of exposure to simvastatin or the major active metabolite, beta-hydroxy simvastatin at steady
state.
Atorvastatin: In a 14-day trial of 50 healthy adult subjects, daily coadministration of atorvastatin 80 mg
with omega-3-acid ethyl esters 4 grams did not affect AUC or C of exposure to atorvastatin, 2-
hydroxyatorvastatin, or 4-hydroxyatorvastatin at steady state.
Rosuvastatin: In a 14-day trial of 48 healthy adult subjects, daily coadministration of rosuvastatin 40 mg
with omega-3-acid ethyl esters 4 grams did not affect AUC or C 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.

13.1 Carcinogenes is , Mutagenes is , 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 gavage 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 and throughout mating,
gestation, and lactation. No adverse effect on fertility was observed at 2,000 mg/kg/day (5 times human
systemic exposure following an oral dose of 4 grams/day based on a body surface area comparison).

14.1 Severe Hypertriglyceridemia
The effects of omega-3-acid ethyl esters 4 grams per day were assessed in 2 randomized, placebomax
controlled, double-blind, parallel-group trials of 84 adult subjects (42 on omega-3-acid ethyl esters, 42
on placebo) with very high triglyceride levels. Subjects whose baseline triglyceride levels were
between 500 and 2,000 mg/dL were enrolled in these 2 trials of 6 and 16 weeks' duration. The median
triglyceride and LDL-C levels in these subjects 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 2. (Refer to actual table in package insert in product )
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.
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.

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° to 30°C (59° to
86°F) [see USP Controlled Room Temperature]. Protect from light. Do not freeze. Keep out of reach
of children.

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.

APOTEX INC.
Omega-3-Acid Ethyl Esters Capsules , USP
1 gram

Manufactured by:
Accucaps Industries Limited
Windsor, Ontario
Canada N9C 3R5

Manufactured for:
Apotex Corp.
Weston, Florida
USA 33326
Revision: 4
Revised: May 2014