LOVAZA

6 ADVERSE REACTIONS The most common adverse reactions (incidence >3% and greater than placebo) were eructation, dyspepsia, and taste perversion. (6) To report SUSPECTED ADVERSE REACTIONS, contact Woodward Pharma Services LLC at 1-844-700-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Table 1. Adverse Reactions Occurring at Incidence ≥3% and Greater than Placebo in Clinical Trials of LOVAZA Adverse Reaction a LOVAZA (n = 655) Placebo (n = 370) n % n % Eructation 29 4 5 1 Dyspepsia 22 3 6 2 Taste perversion 27 4 1 <1 a Trials included subjects with hypertriglyceridemia and severe hypertriglyceridemia. 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 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.

4 CONTRAINDICATIONS LOVAZA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to LOVAZA or any of its components. LOVAZA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to LOVAZA or any of its components. (4)

11 DESCRIPTION LOVAZA, a lipid-regulating agent, is supplied as a liquid-filled gel capsule for oral administration. Each 1 gram capsule of LOVAZA 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 empirical 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 empirical 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: LOVAZA capsules also contain the following inactive ingredients: alpha-tocopherol, gelatin, glycerin and purified water (components of the capsule shell). 400f230c-figure-01 400f230c-figure-02

2 DOSAGE AND ADMINISTRATION Assess TG levels carefully before initiating therapy. Identify other causes (e.g., diabetes mellitus, hypothyroidism, or 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 LOVAZA and should continue this diet during treatment with LOVAZA. In clinical studies, LOVAZA was administered with meals. The daily dose of LOVAZA is 4 grams/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 LOVAZA capsules whole. Do not break open, crush, dissolve, or chew LOVAZA. The daily dose of LOVAZA 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 LOVAZA capsules whole. Do not break open, crush, dissolve, or chew LOVAZA. (2)

1 INDICATIONS AND USAGE LOVAZA (omega-3-acid ethyl esters capsules) is 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 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. LOVAZA 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 LOVAZA on the risk for pancreatitis has not been determined. (1) The effect of LOVAZA on cardiovascular mortality and morbidity has not been determined. (1)

7 DRUG INTERACTIONS Omega-3-acids may prolong bleeding time. Patients taking LOVAZA 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 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.

12 CLINICAL PHARMACOLOGY 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 12.3 Pharmacokinetics Absorption 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 (LOVAZA) 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 LOVAZA was independent of age (younger than 49 years versus 49 years and older). Male and Female Patients : Females tended to have more uptake of EPA into serum phospholipids than males. The clinical significance of this is unknown. Pediatric Patients : Pharmacokinetics of LOVAZA have not been studied. Patients with Renal or Hepatic Impairment: LOVAZA has not been studied in patients with renal or hepatic impairment. Drug Interaction Studies Simvastatin: In a 14-day trial of 24 healthy adult subjects, daily co-administration of simvastatin 80 mg with LOVAZA 4 grams did not affect the extent (AUC) or rate (C max ) 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 co-administration of atorvastatin 80 mg with LOVAZA 4 grams did not affect AUC or C max of exposure to atorvastatin, 2-hydroxyatorvastatin, or 4-hydroxyatorvastatin at steady-state. Rosuvastatin: In a 14-day trial of 48 healthy adult subjects, daily co-administration of rosuvastatin 40 mg with LOVAZA 4 grams did not affect AUC or C max 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.

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3 DOSAGE FORMS AND STRENGTHS LOVAZA (omega-3-acid ethyl esters) capsules, USP are supplied as 1 gram transparent, soft-gelatin capsules filled with light-yellow oil and imprinted with “WP34”. 1 gram transparent soft-gelatin capsules. (3)

LOVAZA Omega-3-Acid Ethyl Esters OMEGA-3-ACID ETHYL ESTERS OMEGA-3 FATTY ACIDS GELATIN GLYCERIN WATER ALPHA-TOCOPHEROL clear WP34

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 ]).

ANDA204940

LOVAZA

Omega-3-Acid Ethyl Esters

69784-420

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Lovaza 120ct label

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information) . 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. Manufactured for: Woodward Pharma Services LLC Wixom, MI 48393 Rev. 02-2021-00

14 CLINICAL STUDIES 14.1 Severe Hypertriglyceridemia The effects of LOVAZA 4 grams/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 mg/dL. The changes in the major lipoprotein lipid parameters for the groups receiving LOVAZA 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 LOVAZA 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 VLDL-C 175 -41.7 175 -0.9 -40.8 HDL-C 22 +9.1 24 0 +9.1 LDL-C 89 +44.5 108 -4.8 +49.3 BL = Baseline (mg/dL); % Change = Median Percent Change from Baseline; Difference = LOVAZA Median % Change – Placebo Median % Change. TC = Total cholesterol. VLDL-C = Very-low-density lipoprotein (VLDL) cholesterol. LOVAZA 4 grams/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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary The available data from published case reports and the pharmacovigilance database on the use of LOVAZA 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). 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 LOVAZA and any potential adverse effects on the breastfed child from LOVAZA or from the underlying maternal condition. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING LOVAZA (omega-3-acid ethyl esters) capsules USP, are supplied as 1 gram, transparent, soft-gelatin capsules filled with light-yellow oil and imprinted with “WP34”. They are available as follows: Bottles of 60: NDC 69784-420-60 Bottles of 120: NDC 69784-420-12 Bottles of 360: NDC 69784-420-36 Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Do not freeze. Dispense in a tight, light-resistant container. Protect from light. Keep out of reach of children.