Usage Considerations: Patients should be placed on an appropriate lipid-lowering diet before receiving LOVAZA and should continue this diet during treatment with LOVAZA.

Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal before instituting therapy with LOVAZA. 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 LOVAZA on the risk for pancreatitis has not been determined. The effect of LOVAZA on cardiovascular mortality and morbidity has not been determined.

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 LOVAZA. In some patients, increases in ALT levels without a concurrent increase in AST levels were observed. In some patients, LOVAZA increases low-density lipoprotein cholesterol (LDL-C) levels. LDL-C levels should be monitored periodically during therapy with LOVAZA.

Laboratory studies should be performed periodically to measure the patient's TG levels during therapy with LOVAZA.

5.2 Fish Allergy

LOVAZA contains 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 LOVAZA. LOVAZA 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 LOVAZA 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 LOVAZA (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 LOVAZA (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 LOVAZA 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. LOVAZA is 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% of subjects treated with LOVAZA and at a greater rate than placebo based on pooled data across 23 clinical trials are listed in Table 1.

Additional adverse reactions from clinical trials are listed below:

6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the events described below have been identified during post-approval use of LOVAZA. Because these events are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or to always establish a causal relationship to drug exposure. The following events have been reported: anaphylactic reaction, hemorrhagic diathesis, urticaria.

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 LOVAZA and concomitant anticoagulants. Patients receiving treatment with LOVAZA and an anticoagulant or other drug affecting coagulation (e.g., anti-platelet agents) should be monitored periodically.

8.1 Pregnancy

8.2 Lactation

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 LOVAZA. Safety and efficacy findings in subjects older than 60 years did not appear to differ from those of subjects younger than 60 years.

12.1 Mechanism of Action

The mechanism of action of LOVAZA 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. LOVAZA 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.

12.3 Pharmacokinetics

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/m2]).

14.1 Severe Hypertriglyceridemia

The effects of LOVAZA 4 grams per day were assessed in 2 randomized, placebo-controlled, double-blind, parallel-group trials of 84 adult subjects (42 on LOVAZA, 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 LOVAZA or placebo are shown in Table 2.

LOVAZA 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 LOVAZA 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 LOVAZA on the risk of pancreatitis has not been determined. The effect of LOVAZA on cardiovascular mortality and morbidity has not been determined.

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

Information for Patients

• LOVAZA 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 LOVAZA capsules in any way and to ingest intact capsules only [see Dosage and Administration (2)].
• Instruct patients to take LOVAZA as prescribed. If a dose is missed, advise patients to take it as soon as they remember. However, if they miss one day of LOVAZA, they should not double the dose when they take it.