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Icosapent Ethyl - Warnings, Precautions, Side Effects, and Dosage

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Icosapent Ethyl - Warnings, Precautions, Side Effects, and Dosage

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Icosapent ethyl is a lipid-regulating agent indicated for hypertriglyceridemia and dyslipidemia. Read this article for more particulars on Icosapent ethyl.

Medically reviewed by

Dr. J. N. Naidu

Published At July 6, 2022
Reviewed AtMarch 27, 2023

Overview:

Icosapent ethyl is a purified preparation of eicosapentaenoic acid (EPA), which is an omega-3 fatty acid. The initial and primary manufacturer and marketer were Amarin Pharma, an Ireland-based pharmaceutical company.

The drug is indicated in the following situations:

  • As adjunctive therapy to statin therapy for the reduction of stroke risk, myocardial infarction, coronary revascularization, and unstable angina that necessitates hospitalization in adults who also display increased triglyceride levels (≥ 150 mg/dL), and any of the following:

  • Dietary adjunct for the reduction of triglyceride levels in adults with severe hypertriglyceridemia (≥ 500 mg/dL).

Icosapent ethyl works by reducing the amount of triglycerides and fats produced by the liver.

The drug was approved by the United States Food and Drug Administration (FDA) in July 2012 for treating severe hypertriglyceridemia (≥ 500 mg/dL). In December 2019, it was approved as an adjunct to statin therapy to reduce the risk of cardiovascular events in cases where serum triglyceride levels were over 150 mg/dL, and with established cardiovascular disease or diabetes, in addition to two or more risk factors for cardiovascular disease.

Icosapent ethyl is marketed under the brand name Vascepa®, but a generic version is also available from Hikma Pharmaceuticals USA, Incorporated.

How Does Icosapent Ethyl Work?

Icosapent ethyl is an ethyl ester of eicosapentaenoic acid (EPA). Its action is facilitated by the actions of EPA. EPA reduces the synthesis or secretion of triglycerides made in the liver, specifically the very low-density lipoprotein triglycerides (VLDL-TG). It also increases the clearance or removal of triglycerides from very low-density lipoprotein particles that circulate in the blood.

[Ethyl Ester:An ethyl ester is produced by reacting ethanol and industrial alcohol with crude fish oil (in free fatty acid form) to produce a synthetic substrate that is heat distilled under a vacuum. The resulting solution is a concentrated omega-3 ethyl ester solution].

[Eicosapentaenoic acid (EPA):An omega-3 fatty acid found in fatty fish like salmon and in fish-oil supplements along with docosahexaenoic acid (DHA)].

Uses of Icosapent Ethyl

Icosapent ethyl is indicated in the following situations:

  • Supplementary to statin therapy to reduce stroke risks, myocardial infarction, coronary revascularization, and unstable angina that necessitates hospitalization in adults with increased triglyceride levels (≥ 150 mg/dL), and any of the following:

  • Dietary adjunct for the reduction of triglyceride levels in adults with severe hypertriglyceridemia (≥ 500 mg/dL).

Dosage Restrictions:

Route of Administration: Oral.

Dosage Form: Amber-colored, liquid-filled soft gelatin capsules.

Available Strengths:

  • 0.5 gm capsules.

  • 1 gm capsules.

The recommended dose of Icosapent ethyl is 4 gms per day (taken with food) to be administered in either of the following ways:

  • Four 0.5 gm capsules twice daily.

  • Two 1 gm capsules twice daily.

Special Considerations:

  • Pancreatitis Risk: The risk of pancreatitis in patients with severe triglyceridemia who consume Icosapent ethyl is unknown, and therefore a matter of concern.

  • Bleeding: Patients on Icosapent ethyl and concomitant anticoagulants and antiplatelets should be closely monitored for prolonged bleeding time.

Warnings and Contraindications:

Contraindications: Icosapent ethyl is contraindicated in patients who display hypersensitivity to the drug itself, or to any of the components in the formulation.

Warnings and Precautions:

  • Allergic Reactions: Patients with a known allergy to fish or shellfish may develop allergies on consumption of Icosapent ethyl, as it contains ethyl esters of the eicosapentaenoic acid (EPA) derived from fish oil.

  • Atrial Fibrillation or Flutter: Icosapent ethyl has been linked with an increased risk of atrial fibrillation or flutter, particularly in patients with a previous history of either condition. There may be a need for hospitalization in these patients.

  • Bleeding: An increased risk of bleeding has been noted with the administration of Icosapent ethyl, especially in patients taking antithrombotic medicines like Aspirin, Warfarin, and Clopidogrel.

For Patients:

What Are Triglycerides?

Triglycerides are a kind of fat found in the blood. The body converts calories you do not immediately need from the food you eat into triglycerides, making them the main constituents of fat in the body.

What Is Hypertriglyceridemia?

An excessively high level of triglycerides in the blood is referred to as hypertriglyceridemia.

What Does a High Triglyceride Level Indicate?

High triglyceride levels usually occur due to obesity, unhealthy dietary patterns, substance abuse, disorders like uncontrolled diabetes, kidney disease and hypothyroidism, and genetics. They usually point to an increased risk of heart conditions and stroke.

Why Is Icosapent Ethyl Prescribed for Increased Triglyceride Levels or Hypertriglyceridemia?

Icosapent ethyl lowers triglyceride levels in two ways:

  • It reduces the production of triglycerides in the liver.

  • It increases the removal of triglycerides from the blood.

Icosapent ethyl may be used as a dietary adjunct in patients with hypertriglyceridemia.

Facts You Should Know About Icosapent Ethyl:

Icosapent ethyl is available in capsular form, and should be taken twice daily, with the total dosage adding up to 4 gms. Always take the drug with food.

How Should You Take Icosapent Ethyl?

  • Take Icosapent ethyl twice daily as prescribed by the doctor.

  • Never attempt to change the dose or stop taking the drug without your doctor’s consent. If you are facing any difficulties or experiencing side effects, let the doctor know about it.

  • Swallow the capsules whole. Do not chew, break open, crush, or dissolve them.

  • If you miss a dose, take it when you do remember. However, never attempt to double dose if you miss a day of taking the drug.

  • If your doctor prescribes dietary changes before starting the drug, make sure to follow the instructions correctly.

What Should You Discuss With Your Doctor Before Beginning Treatment With Icosapent Ethyl?

  • Medical History: Inform your doctor of any medical conditions you may be suffering from, particularly the following:

  • Diabetes mellitus.

  • Liver disease.

  • Pancreatitis or other pancreatic issues.

  • Hypothyroidism.

  • Allergies to fish or shellfish.

  • Drug History: Your doctor will need to determine the risk of drug interactions that may lead to adverse reactions or reduced effectiveness of Icosapent ethyl, so ensure you tell them about all the drugs you may be taking, including prescription medications (especially anticoagulants or blood thinners), dietary supplements, herbal products, and vitamins.

  • Pregnancy: The risks of using Icosapent ethyl during pregnancy are unknown. Inform your doctor if you are pregnant, get pregnant, or plan to get pregnant before or during taking Icosapent ethyl.

  • Lactation: Let your doctor know if you are currently breastfeeding or plan to do so. The baby may be affected by Icosapent ethyl that passes into the breast milk.

Is Icosapent Ethyl Safe?

Icosapent ethyl is relatively safe but may cause severe side effects in some people. Patients experiencing side effects must contact their doctor immediately, who will decide on alternative treatment options or other solutions.

Is Icosapent Ethyl Effective?

4 gms of Icosapent ethyl per day has been known to effectively reduce the median triglyceride, very low density lipoprotein-cholesterol (VLDL-C), and apolipoprotein B (Apo B) levels in comparison to a placebo.

What Are the Side Effects of Icosapent Ethyl?

The side effects you are most likely to include are the following:

  • Muscle pain.

  • Joint pain.

  • Gout.

  • Constipation.

  • Swelling of the hands, legs, and feet.

  • Excessive bleeding, especially if you are already taking blood thinners.

  • Problems with the heart rhythm (atrial fibrillation or flutter).

  • Allergic Reactions: If you are allergic to fish or shellfish, you may develop allergic reactions to Icosapent ethyl.

Can You Stop Taking Icosapent Ethyl Without Your Doctor's Say-So?

Do not stop taking Icosapent ethyl without your doctor’s approval. The only time you may stop taking the drug with immediate effect is if you experience severe side effects such as allergies or excessive bleeding. Make sure to contact your physician or emergency services for any side effects, or in case of emergency.

Are There Any Dietary Restrictions to Consider When Taking Icosapent Ethyl?

Your doctor may ask you to modify your diet in the following ways before starting Icosapent ethyl:

  • Less saturated fat content.

  • Less cholesterol content.

  • Fewer carbohydrates.

  • Reduced intake of added sugars.

Also remember to always take the drug with food.

Should You Undergo Any Tests or Laboratory Investigations Before Starting Icosapent Ethyl?

You may have to undergo blood tests to check the levels of triglycerides and other lipids in your body before beginning Icosapent ethyl treatment.

How Should You Store and Dispose Icosapent Ethyl?

  • Icosapent ethyl should be stored at room temperature between 68° to 77° Fahrenheit (20° to 25° Celsius).

  • Store the capsules in the same container that they are sold in, and keep the lid tightly closed.

  • Keep the drug out of the reach of children and pets.

  • Throw the medication away if it is expired or no longer required. You may dispose of it using your local medicine take-back program, or contact your local pharmacy for alternative information on disposal.

What Can You Do in Case of Overdose?

High doses of Icosapent ethyl may cause serious side effects like irregular heartbeats and severe bleeding. If an overdose occurs, immediately consult the local poison helpline, or visit the emergency room or the physician. Immediate medical attention is a must.

For Doctors:

Indications:

Icosapent ethyl is prescribed in the following situations:

  • Adjunctive to statin therapy for the reduction of stroke risk, myocardial infarction, coronary revascularization, unstable angina that necessitates hospitalization in adults who also have increased triglyceride levels (≥ 150 mg/dL), and any of the following:

  • Cardiovascular disease.

  • Diabetes mellitus, and at least two further risk factors for cardiovascular disease.

  • Dietary adjunct for reducing triglyceride levels in adults with severe hypertriglyceridemia (≥ 500 mg/dL).

Pharmacology:

Description: Icosapent ethyl is an ethyl ester of eicosapentaenoic acid (EPA), an omega-3 fatty acid. It has the empirical formula C22H34O2, and a molecular weight of 330.51.

Components:

  • Active Components:

  • 0.5 gm Capsule:

0.5 gms Icosapent ethyl.

  • 1.0 gm Capsule:

1 gm Icosapent ethyl.

  • Inactive Components:

  • Tocopherol.

  • Gelatin.

  • Glycerin.

  • Maltitol.

  • Sorbitol.

  • Purified water.

Clinical Pharmacology:

Mechanism of Action:

Icosapent ethyl is an ethyl ester of eicosapentaenoic acid (EPA), an omega-3 fatty acid. EPA is known to perform the following actions:

  • Reduces the synthesis or secretion of very low-density lipoprotein triglycerides (VLDL-TG) in the liver.

  • Enhances the clearance of triglycerides from circulating VLDL particles.

The ways in which these actions are performed may include the following:

  • Increased β-oxidation.

  • Inhibition of acyl-CoA:1,2-diacylglycerol acyltransferase (DGAT).

  • Reduced lipogenesis in the liver.

  • Increased activity of plasma lipoprotein lipase.

EPA may also inhibit platelet aggregation in ex vivo (outside the living body) conditions.

Pharmacodynamics:

Patients with severe hypertriglyceridemia who were on Icosapent ethyl 4 gms per day in a dose-ranging study for 12 weeks displayed reduced median TG from baseline relative to placebo.

Pharmacokinetics:

  • Absorption:

  • Icosapent ethyl is de-esterified following oral administration.

  • EPA, which forms the active metabolite, gets absorbed into the small intestine.

  • EPA then enters systemic circulation through the thoracic duct lymphatic system.

  • Peak Plasma Concentration Time: 5 hours after oral administration.

  • Effect of Food: Unknown, but it is advised to take Icosapent ethyl only with or immediately after a meal.

  • Distribution:

  • Mean Volume of Distribution (Steady State of EPA): 88 liters.

  • Circulating EPA: Present mainly in phospholipids, triglycerides, and cholesterol esters.

  • <1 % Circulating EPA: Present as an unesterified fatty acid.

  • >99 % Unesterified EPA: Bound to plasma proteins.

  • Elimination

  • Metabolism:

  • The metabolization of EPA takes place primarily in the liver via beta-oxidation in the same way as dietary fatty acids.

  • The long carbon chain of EPA is split into acetyl Coenzyme A due to beta oxidation.

  • Acetyl Coenzyme A is converted into energy through the Krebs cycle.

  • EPA may be eliminated via cytochrome P450-mediated metabolism (minor elimination pathway).

  • Excretion:

  • Total Steady State Plasma Clearance of EPA: 684 mL/hr.

  • Plasma Elimination Half-Life (t1/2): 89 hours.

  • Renal Excretion: Nil.

Special Considerations:

  • Gender: No significant variations have been noted in the total plasma EPA concentrations between men and women.

  • Hepatic Impairment: No data exist on the pharmacological effects in patients with hepatic impairment.

  • Renal Impairment: No data exist on the pharmacological effects in patients with renal impairment.

  • Pediatric Population: No data exist on the pharmacokinetic effects of Icosapent ethyl in children.

Drug Interactions:

No significant drug interactions or changes in the steady-state area under the curve of dosing interval (AUCτ) or Cmax have occurred with the concurrent administration of Icosapent ethyl and the following drugs:

  • Warfarin.

  • Omeprazole.

  • Rosiglitazone.

  • Atorvastatin.

[Cmax: Maximum serum concentration achieved by a drug after administration, and before second dose administration].

Clinical Trials:

  • Study Description: The REDUCE-IT trial evaluated the safety and benefit of Icosapent ethyl in reducing cardiovascular events among patients with high triglyceride levels compared to a placebo.

  • Study Design:

  • Type of Study: Multinational, double-blinded, randomized, placebo-controlled, event-driven trial.

  • Methods: Eligible patients (n = 8179) were randomized 1:1 into the following groups:

  • Icosapent ethyl 2 gm orally twice daily with food (n = 4089).

  • Placebo group (n = 4090).

  • Primary Composite Endpoint: Time to the first occurrence of any of the following events:

  • Cardiovascular death.

  • Myocardial infarction.

  • Stroke.

  • Coronary revascularization.

  • Hospitalization for unstable angina.

  • Secondary Outcome Measures: Time to the first occurrence of any of the following events:

  • Cardiovascular death.

  • Myocardial infarction.

  • Stroke.

  • Results:

  • Primary Composite Endpoint [Hazard Ratio 0.75, Confidence Interval (CI) 0.68 - 0.83]:

The incidence rate for the Icosapent ethyl group (per 100 patient years) was 4.3, and for the placebo group (per 100 patient years) was 5.7.

  • Secondary Composite Endpoint [Hazard Ratio 0.74, Confidence Interval (CI) 0.65 - 0.83]:

The incidence rate for the Icosapent ethyl group (per 100 patient years) was 2.7, and for the placebo group (per 100 patient years) was 3.7.

  • Adverse Events Profile: None provided.

Patient Counseling Information:

Administration Instructions:

  • Take Icosapent ethyl only as prescribed by the doctor.

  • This drug is to be taken with or immediately after a meal.

  • The capsules must be swallowed whole, not broken, chewed, crushed, or dissolved.

  • Advise patients to use Icosapent ethyl only for the condition prescribed, and to never share the drug with anyone else for any illness, unless prescribed by the doctor.

Complications or Side Effects:

  • Hypersensitivity: Inform patients with known hypersensitivity to the components of the drug, or with allergies to fish or shellfish of the possibility of developing allergic reactions.

  • Bleeding: Severe bleeding may develop, especially in patients taking antithrombotic drugs. They must therefore be made aware of this side effect.

  • Atrial Fibrillation/Flutter: Patients may develop issues with their heart rhythm (atrial fibrillation or flutter) and must be warned of the same.

  • Pregnancy: The effects of the drug on pregnancy are unknown, so patients should be advised to report pregnancy or plans for pregnancy if they take Icosapent ethyl.

  • Lactation: Icosapent ethyl may be present in breast milk and harm babies, so patients should inform their doctors if they are breastfeeding or planning to breastfeed.

Frequently Asked Questions

1.

What Is Icosapent Ethyl Prescribed For?

Icosapent ethyl is a preparation containing omega-3-fatty acids. They are prescribed in addition to statins (cholesterol tablets) to reduce the level of triglyceride and fat levels in the body, thereby decreasing the risk of cardiovascular diseases like stroke, myocardial infarction, and unstable angina.

2.

Is Icosapent Ethyl the Same as Fish Oil?

The major difference is that the Icosapent ethyl is an ethyl ester of eicosapentaenoic acid (EPA), while fish oil supplements contain both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Studies have shown that intake of Icosapent ethyl alone will reduce the triglycerides without an increase in the level of bad cholesterol (LDL - low-density lipoprotein).

3.

What Is the Difference Between Vascepa and Icosapent Ethyl?

Vascepa is a brand name given to Icosapent ethyl formulation. Vascepa is a lipid regulatory drug containing Icospent ethyl as an active ingredient. The drug is approved by the Food and Drug Administration (FDA), which continuously monitors them for quality and safety.

4.

What Is the Mechanism of Action Icosapent Ethyl?

Icosapent ethyl is known to increase beta-oxidation (a process in which the fatty acids are broken down for energy), enhance the activity of lipoprotein lipase (an enzyme that degrades triglycerides in the blood) and decrease lipogenesis (synthesis of fatty acids) in the liver. By the above mechanisms, Icosapent ethyl rapidly clears the triglycerides from the circulating blood.

5.

Is Icosapent Ethyl the Same as Omega-3?

Omega-3-fatty acids are a group of polyunsaturated fatty acids containing alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). But Icosapent ethyl contains only eicosapentaenoic acid (EPA). They are prescribed as adjuvant therapy to reduce the triglycerides in the body.

6.

What Is Icosapent Ethyl Generic For?

Icosapent ethyl is a generic name for the ethyl ester form of eicosapentaenoic acid (EPA). Amarin Corporation (a biopharmaceutical company) got approval for the formulation of Icosapent ethyl from the FDA (Food and drug administration), and Vascepa is the brand name given to them.

7.

What Does Icosapent Ethyl 1 Gram Capsule Contain?

Icosapent ethyl is commercially available as Vascepa in a 1 gram capsule, and each gram contains 1 gram weight of ethyl ester form of eicosapentaenoic acid (EPA). They are found in transparent gelatin capsules that have to be swallowed as a whole without breaking, crushing, or dissolving them.

8.

Does Icosapent Ethyl Make You Gain Weight?

There is no evidence documented in studies on the weight changes related to the intake of Icosapent ethyl. There are few speculations of weight loss with Icosapent ethyl, but that tends to correlate with the side effects like diarrhea and gastrointestinal problems in a few people who are intolerable to Icosapent ethyl.
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Dr. J. N. Naidu
Dr. J. N. Naidu

General Practitioner

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