Omega 3 - Fatty Acids

Pharmacologic Category

Antilipemic Agent, Omega-3 Fatty Acids

Dosing: Adult

Cardiovascular risk reduction with mild hypertriglyceridemia (Vascepa) (adjunctive agent): Note: Consider in addition to maximally-tolerated statin therapy in patients with triglyceride levels ≥150 mg/dL and either established cardiovascular disease or type 2 diabetes mellitus with ≥2 risk factors for cardiovascular disease.

Oral: 2 g twice daily with meals (Bhatt 2019).

Hypertriglyceridemia: Oral:

Lovaza: 4 g (4 capsules) once daily or 2 g (2 capsules) twice daily.

Vascepa: 2 g (2 [1 g] capsules or 4 [0.5 g] capsules) twice daily with meals.

IgA nephropathy (off-label use): Oral: Lovaza: 4 g (4 capsules) once daily (Donadio 2001).

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). EPA and DHA are not renally eliminated.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Use: Labeled Indications

Cardiovascular risk reduction with mild hypertriglyceridemia (Vascepa): As an adjunct to maximally-tolerated statin therapy to reduce the risk of myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization in adult patients with triglyceride levels ≥150 mg/dL and either established cardiovascular disease or type 2 diabetes mellitus with ≥2 risk factors for cardiovascular disease.

Dietary supplement: As dietary supplements for patients at early risk of coronary artery disease.

Note: Recommendations from the American Heart Association (AHA) state that patients without documented coronary heart disease (CHD) should eat a variety of fish, preferably oily fish (eg, salmon), at least twice a week, or daily in patients with documented CHD (AHA [Kris-Etherton 2002]).

Hypertriglyceridemia (Lovaza and Vascepa): As an adjunct to diet to reduce triglyceride levels in adults with severe (≥500 mg/dL) hypertriglyceridemia.

Note: The Endocrine Society recommends that omega-3 fatty acids may be considered for triglyceride levels >1,000 mg/dL and may be used alone or in combination with HMG-CoA reductase inhibitors (Berglund 2012). A number of OTC formulations containing omega-3 fatty acids are marketed as nutritional supplements; these do not have FDA-approved indications and may not contain the same amounts of the active ingredient.

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

IgA nephropathyLevel of Evidence [B, G]

Data from a randomized, open-label, parallel-group clinical trial support the use of omega-3 fatty acids Ref in the treatment (ie, slowing rate of renal function loss) of IgA nephropathy Ref. A more recent meta-analysis does not confirm the efficacy for this indication, though it may likely be used for this indication Ref. Additional trials may be necessary to further define the role of omega-3 fatty acids in the treatment of patients with IgA nephropathy.

Based on the Caring for Australasians with Renal Impairment guidelines early and prolonged treatment with fish oil may retard the rate of decline in renal function in adults with progressive IgA nephropathy; optimal dosing has yet to be established Ref. Routine use is currently not recommended (Laville 2004).

Level of Evidence Definitions

Level of Evidence Scale

Comparative Efficacy

• OMEGA-3 CARBOXYLIC ACIDS

Clinical Practice Guidelines

Dyslipidemia:

AACE/ACE, “Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease,” April 2017

ACC/AHA, “2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults,” November 2013

AHA/ACC, “Guideline on the Management of Blood Cholesterol,” November 2018

NLA, “National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia” Part 1: April 2015; Part 2: December 2015

The Endocrine Society, “Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline,” September 2012

Prevention:

AHA, “Omega-3 Polyunsaturated Fatty Acid (Fish Oil) Supplementation and the Prevention of Clinical Cardiovascular Disease: A Science Advisory From the American Heart Association,” March 2017

Administration: Oral

Lovaza: Administer with food. Administer whole; do not break, crush, dissolve, or chew.

Vascepa: Administer with meals. Administer whole; do not break, crush, dissolve, or chew.

Bariatric surgery: Capsule, delayed release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Delayed-release capsule should be administered whole. Do not break, crush, dissolve, or chew. If safety and efficacy of fish oil can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, re-evaluation of need for omega-3 therapy after bariatric surgery is advised due to known improvements in cholesterol profile.

Dietary Considerations

Dietary modification is important in the control of severe hypertriglyceridemia. Maintain standard cholesterol-lowering diet during therapy.

Storage/Stability

Lovaza: Store at 25°C (77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F); do not freeze.

Vascepa: Store at 20°C to 25°C (68°F to 77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F).

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

All products:

• It is used to lower triglycerides.

• It may be given to you for other reasons. Talk with the doctor.

Icosapent ethyl:

• It is used with other cholesterol drugs to lower the risk of heart attack, stroke, some heart procedures, and a type of chest pain (unstable angina).

Frequently reported side effects of this drug

• Burping

• Muscle pain

• Constipation

• Throat pain

• Change in taste

• Nausea

• Abdominal pain

• Joint pain

• Diarrhea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Abnormal heartbeat

• Fast heartbeat

• Dizziness

• Passing out

• Shortness of breath

• Chest pain

• Bruising

• Bleeding

• Swelling in the arms or legs

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

International issues:

Other safety concerns:

Contraindications

Hypersensitivity (eg, anaphylactic reaction) to omega-3 fatty acids or any component of formulation.

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: Bleeding, including serious events, has been reported; risk may be increased with concomitant anticoagulant/antiplatelet use. Prolongation of bleeding time not exceeding normal limits has also been observed; use with caution in patients with coagulopathy. Monitor for signs and symptoms of bleeding.

• Fish allergy: Use with caution in patients with known allergy or sensitivity to fish and/or shellfish.

• Hepatic effects: ALT may increase without concurrent AST increase; periodically monitor hepatic transaminases in patients with hepatic impairment.

• Lipid effects: May increase LDL levels; periodically monitor LDL levels.

Disease-related concerns:

• Atrial fibrillation: Atrial fibrillation (AF) or flutter requiring hospitalization may occur; risk increased in patients with a history of AF or flutter and within the first 2 to 3 months of therapy.

• Conditions associated with abnormal lipids: Manage concurrent conditions (eg, diabetes, hypothyroidism, excessive alcohol intake) that may contribute to lipid abnormalities.

Other warnings/precautions:

• Appropriate use: Should be used as an adjunct to diet therapy and exercise. Secondary causes of hyperlipidemia should be ruled out prior to therapy. The effect, if any, of omega-3 fatty acids on the risk of pancreatitis or cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia is not known.

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

Specific information about the safety and efficacy of omega-3-acid ethyl esters is limited. The manufacturer states there were no apparent differences between persons <60 and >60 years of age.

The definition of and, therefore, when to treat hyperlipidemia in the elderly is a controversial issue. According to the ACC/AHA guidelines for adult patients, there are no supporting data for the routine use of nonstatin drugs in combination with a statin to further reduce clinical atherosclerotic cardiovascular disease (ASCVD) events. Evidence for nonstatins in statin-intolerant patients is lacking. Furthermore, there are no data or recommendations on managing patients >75 years of age without clinical ASCVD who have type 1 or 2 diabetes or with a 10-year risk of ASCVD >7.5% (with or without diabetes) (Stone 2013). It is the authors' belief that pharmacologic treatment be reserved for those whom the benefits of treatment are believed to outweigh the potential adverse effects, drug interactions, and cost of treatment.

Pregnancy Considerations

Adequate intake of omega-3 fatty acids is recommended during pregnancy (IOM 2005; Nordgren 2017). Maternal use of supplements or dietary consumption of omega-3 fatty acids (containing eicosapentaenoic acid and docosahexaenoic acid) influences fetal concentrations (Büyükuslu 2017; Coletta 2010; Miles 2011).

Triglyceride concentrations increase during pregnancy as required for normal fetal development. When increases are greater than expected, supervised dietary interventions that include omega-3 fatty acids may be initiated. In women who develop very severe hypertriglyceridemia and are at risk for pancreatitis, use of prescription omega-3 fatty acid products may be considered (Avis 2009; Berglund 2012; Jacobson 2015; Wong 2015).

Breast-Feeding Considerations

Omega-3 fatty acids are present in breast milk and dietary supplementation may influence milk concentrations (IOM 2005).

According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

Briggs' Drugs in Pregnancy & Lactation

• Omega-3 Fatty Acid Supplements

Adverse Reactions

>10%: Hematologic & oncologic: Hemorrhage (12%)

1% to 10%:

Cardiovascular: Atrial fibrillation (≥3%), peripheral edema (≥3%), atrial flutter (≤3%)

Gastrointestinal: Dysgeusia (4%), eructation (4%), constipation (≥3%), gout (≥3%), dyspepsia (3%)

Hematologic & oncologic: Major hemorrhage (3%)

Neuromuscular & skeletal: Musculoskeletal pain (≥3%), arthralgia (≥1%)

Respiratory: Oropharyngeal pain (≥1%)

Frequency not defined:

Dermatologic: Pruritus, skin rash

Endocrine & metabolic: Increased LDL cholesterol

Gastrointestinal: Gastrointestinal disease, vomiting

Hepatic: Increased serum alanine aminotransferase, increased serum aspartate aminotransferase

<1%, postmarketing, and/or case reports: Abdominal distress, anaphylaxis, bleeding tendency disorder, diarrhea, increased serum triglycerides, limb pain, urticaria

* See Cautions in AHFS Essentials for additional information.

Metabolism/Transport Effects

None known.

Drug Interactions Open Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): Omega-3 Fatty Acids may enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Anticoagulants: Omega-3 Fatty Acids may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Ibrutinib: Omega-3 Fatty Acids may enhance the antiplatelet effect of Ibrutinib. Risk C: Monitor therapy

Monitoring Parameters

Triglycerides and other lipids (LDL-C) should be monitored at baseline and periodically. In patients with hepatic impairment, monitor hepatic transaminase levels, particularly ALT, periodically. Signs/symptoms of bleeding.

2013 ACC/AHA Blood Cholesterol Guideline recommendations (Stone 2013): Consider evaluation for GI disturbances and skin changes during therapy.

Advanced Practitioners Physical Assessment/Monitoring

Determine if patient is allergic to fish prior to prescribing. Encourage diet and exercise along with use of this medication. Monitor liver function studies, LDL-C, and TG prior to and as clinically indicated during therapy. Concomitant use with blood thinning medications may increase risk of bleeding. Monitor for signs and symptoms of bleeding.

Nursing Physical Assessment/Monitoring

Do not use if allergic to fish. Encourage diet and exercise along with use of this medication. Discuss fish oils when used with other blood thinning medications (ie. Coumadin ®, Plavix® and aspirin) may increase their effects.

Dosage Forms Considerations

Lovaza: Each 1 g capsule contains the combination of EPA (~465 mg) and DHA (~375 mg) ethyl esters.

Vascepa: Icosapent ethyl contains ethyl esters of an omega-3 fatty acid, EPA, obtained from fish oil. It contains ≥96% EPA and does not contain DHA. Historically, mixtures containing both EPA and DHA have increased LDL cholesterol in patients with severe hypertriglyceridemia. However, studies have suggested that icosapent ethyl has not caused significant increases in LDL cholesterol while significantly decreasing triglyceride levels (Bays 2011; Miller 2011).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral:

Dialyvite Omega-3 Concentrate: 600 mg

Lovaza: 1 g [contains soybean oil, tocopherol, dl-alpha]

Ocean Blue MiniCaps Omega-3: 350 mg [gluten free, lactose free, sugar free; contains fd&c red #40, fd&c yellow #10 (quinoline yellow)]

Omega Power: 1050 mg [gluten free, lactose free, sugar free; contains fd&c red #40, fd&c yellow #10 (quinoline yellow); vanilla flavor]

Omega-3 2100: 1050 mg [odorless; orange flavor]

Triklo: 1 g [DSC]

Vascepa: 0.5 g, 1 g

Generic: 300 mg, 500 mg, 1000 mg, 1 g

Capsule, Oral [preservative free]:

Fish Oil Concentrate: 1000 mg [gluten free, lactose free, milk free, no artificial color(s), no artificial flavor(s), no artificial sweetener, sodium free, starch free, sugar free, wheat free, yeast free]

Maximum Red Krill: 300 mg [gluten free; contains soybean oil]

Omega-3 Fish Oil Ex St: 880 mg [gluten free]

Salmon Oil-1000: 200 mg [corn free, rye free, starch free, sugar free, wheat free]

Sam-E.P.A.: 200-300 MG [dye free]

Sea-Omega: 1000 mg [cholesterol free, corn free, gluten free, milk derivatives/products, no artificial color(s), no artificial flavor(s), sodium free, starch free, sugar free, yeast free; contains soybeans (glycine max)]

Generic: 200 mg, 1000 mg, 1200 mg

Capsule Delayed Release, Oral:

Odorless Coated Fish Oil: 1000 mg [gluten free, lactose free, milk free, no artificial color(s), no artificial flavor(s), no artificial sweetener, starch free, sugar free, wheat free, yeast free]

Pro Nutrients Omega 3: 332.5 mg

Generic: 1000 mg

Tablet Chewable, Oral:

Omega-3 IQ: 240 mg [DSC]

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Vascepa: 1 g

Anatomic Therapeutic Chemical (ATC) Classification

• C10AX06

Generic Available (US)

May be product dependent

Pricing: US

Capsule, delayed release (Pro Nutrients Omega 3 Oral)

332.5 mg (per each): $0.16

Capsules (Dialyvite Omega-3 Concentrate Oral)

600 mg (per each): $0.16

Capsules (Lovaza Oral)

1 g (per each): $2.99

Capsules (Ocean Blue MiniCaps Omega-3 Oral)

350 mg (per each): $0.36

Capsules (Omega Power Oral)

1050 mg (per each): $0.56

Capsules (Omega-3 2100 Oral)

1050 mg (per each): $0.26

Capsules (Omega-3-acid Ethyl Esters Oral)

1 g (per each): $2.07 - $2.69

Capsules (Sea-Omega Oral)

1000 mg (per each): $0.14

Capsules (Vascepa Oral)

0.5 g (per each): $1.94

1 g (per each): $3.31

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

Reduction in the hepatic production of triglyceride-rich very low-density lipoproteins. Possible cellular mechanisms include inhibition of acyl CoA:1,2 diacylglycerol acyltransferase, increased hepatic mitochondrial and peroxisomal beta-oxidation, and a reduction in the hepatic synthesis of triglycerides. The mechanisms contributing to reduction of cardiovascular events are not completely understood but are likely multi-factorial (eg, increased eicosapentaenoic acid [EPA] composition from carotid plaques, increased circulating EPA/arachidonic acid ratio, inhibition of platelet aggregation).

Pharmacodynamics/Kinetics

Absorption:

Omega-3-carboxylic acids: Directly absorbed in the small intestine. Administration with a high-fat meal results in an increased overall exposure of total and free baseline-adjusted EPA by ~140% and 80%, respectively, compared to fasting conditions; a 40% increase in AUC occurred for baseline-adjusted free DHA.

Icosapent ethyl: De-esterified to active metabolite (EPA) which is absorbed in the small intestine

Distribution: Vdss: EPA: ~88 L

Protein binding: EPA: >99%

Metabolism: EPA and DHA are mainly oxidized in the liver similar to fatty acids derived from dietary sources. EPA: minor via CYP-450

Half-life elimination: EPA: ~37 to 89 hours; DHA: ~46 hours

Time to peak, plasma:

Omega-3-carboxylic acids: Following repeat dosing with low-fat meals for ~2 weeks (steady state): EPA: 5 to 8 hours; DHA: 5 to 9 hours

Icosapent ethyl: EPA: ~5 hours

Pharmacodynamics/Kinetics: Additional Considerations

Gender: Females tended to have more uptake of EPA into serum phospholipids than males. The clinical significance of this is unknown.

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

No significant effects or complications reported

Effects on Bleeding

Prolongation of bleeding time has been observed in some clinical studies; however, there is no scientific evidence to warrant discontinuance prior to dental surgery. The clinician should anticipate the potential for slower clotting times.

Related Information

• Multivitamin Product Table
• Oral Medications That Should Not Be Crushed or Altered

Index Terms

AMR101; Docosahexaenoic Acid; Eicosapentaenoic Acid; Ethyl Eicosapentaenoate; Ethyl Esters of Omega-3 Fatty Acids; Ethyl Icosapentate; Ethyl-Eicosapentaenoic Acid; Ethyl-EPA; Fish Oil; Icosapent Ethyl; Omega 3; Omega-3-Acid Ethyl Esters; P-OM3

References

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Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, Braeckman RA, Soni PN. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multi-center, Placebo-controlled, Randomized, Double-blind, 12-week study with an open-label Extension [Marine] trial. Am J Cardiol. 2011;108(5):682-690.[PubMed 21683321]

Berglund L, Brunzell JD, Goldberg AC, et al, "Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline," J Clin Endocrinol Metab, 2012, 97(9):2969-89.[PubMed 22962670]

Bhatt DL, Steg PG, Miller M, et al; REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22. doi: 10.1056/NEJMoa1812792.[PubMed 30415628]

Büyükuslu N, Ovalı S, Altuntaş ŞL, Batırel S, Yiğit P, Garipağaoğlu M. Supplementation of docosahexaenoic acid (DHA) / Eicosapentaenoic acid (EPA) in a ratio of 1/1.3 during the last trimester of pregnancy results in EPA accumulation in cord blood. Prostaglandins Leukot Essent Fatty Acids. 2017;125:32-36. doi: 10.1016/j.plefa.2017.08.005.[PubMed 28987719]

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Brand Names: International

Agemo (PK); Dualtis (GB); Epax (EC); Equiplen (PE); Nebbaro (GB); Omacor (AE, AR, AT, AU, BE, BG, BH, CR, CY, CZ, DE, DO, EE, ES, FI, FR, GB, GR, GT, HN, HR, HU, IE, IL, KR, KW, LK, LT, LU, LV, MT, MY, NI, NL, NO, PA, PL, PT, QA, RO, RU, SA, SI, SK, SV, TH, UA); Omaron (KR); Ysomega (FR)

Last Updated 8/8/20