Icosapent

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# Overview
Icosapent is an antihyperlipidemic that is FDA approved for the treatment of adult patients with severe (500 mg/dL) hypertriglyceridemia..   Common adverse reactions include arthralgia.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Icosapent ethyl (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (500 mg/dL) hypertriglyceridemia.
- Patients should be placed on an appropriate lipid-lowering diet and exercise regimen before receiving icosapent ethyl and should continue this diet and exercise regimen with icosapent ethyl.
- Attempts should be made to control any medical problems such as diabetes mellitus, hypothyroidism, and alcohol intake that may contribute to 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.
- The effect of icosapent ethyl on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined.
- The effect of icosapent ethyl on cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined.
- Assess lipid levels before initiating therapy. Identify other causes (e.g., diabetes mellitus, hypothyroidism, or medications) of high triglyceride levels and manage as appropriate.
- Patients should engage in appropriate nutritional intake and physical activity before receiving icosapent ethyl, which should continue during treatment with icosapent ethyl.
- The daily dose of icosapent ethyl is 4 grams per day taken as 2 capsules twice daily with food.
- Patients should be advised to swallow icosapent ethyl capsules whole. Do not break open, crush, dissolve, or chew icosapent ethyl.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Icosapent in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Icosapent in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Icosapent in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Icosapent in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Icosapent in pediatric patients.

# Contraindications
- icosapent ethyl is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to icosapent ethyl or any of its components.

# Warnings
- icosapent ethyl contains ethyl esters of the omega-3 fatty acid, eicosapentaenoic acid (EPA), obtained from the oil of fish. It is not known whether patients with allergies to fish and/or shellfish are at increased risk of an allergic reaction to icosapent ethyl. icosapent ethyl should be used with caution in patients with known hypersensitivity to fish and/or shellfish.

# Adverse Reactions

## 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Adverse reactions reported in at least 2% and at a greater rate than placebo for patients treated with icosapent ethyl based on pooled data across two clinical studies are listed in Table 1.
- An additional adverse reaction from clinical studies was
Oropharyngeal pain.
Atrial fibrillation. In the REDUCT-IT trial, atrial fibrillation occurred in 5.3% while occurred in 3.9% of the placebo group. This may be dose related. The REDUCE-IT trial used the highest does of 4 grams per day.
A trend towards increased bleeding.
- Oropharyngeal pain.
- Atrial fibrillation. In the REDUCT-IT trial, atrial fibrillation occurred in 5.3% while occurred in 3.9% of the placebo group. This may be dose related. The REDUCE-IT trial used the highest does of 4 grams per day.
- A trend towards increased bleeding.

## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Icosapent in the drug label.

# Drug Interactions
- Some published studies with omega-3 fatty acids have demonstrated prolongation of bleeding time. The prolongation of bleeding time reported in those studies has not exceeded normal limits and did not produce clinically significant bleeding episodes. Patients receiving treatment with icosapent ethyl and other drugs affecting coagulation (e.g., anti-platelet agents) should be monitored periodically.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
- Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. It is unknown whether icosapent ethyl can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. icosapent ethyl should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus.
- In pregnant rats given oral gavage doses of 0.3, 1 and 2 g/kg/day icosapent ethyl from gestation through organogenesis all drug treated groups had visceral or skeletal abnormalities including: 13threduced ribs, additional liver lobes, testes medially displaced and/or not descended at human systemic exposures following a maximum oral dose of 4 g/day based on body surface comparisons. Variations including incomplete or abnormal ossification of various skeletal bones were observed in the 2 g/kg/day group at 5 times human systemic exposure following an oral dose of 4 g/day based on body surface area comparison.
- In a multigenerational developmental study in pregnant rats given oral gavage doses of 0.3, 1, 3 g/kg/day ethyl-EPA from gestation day 7-17, an increased incidence of absent optic nerves and unilateral testes atrophy were observed at 0.3 g/kg/day at human systemic exposure following an oral dose of 4 g/day based on body surface area comparisons across species. Additional variations consisting of early incisor eruption and increased percent cervical ribs were observed at the same exposures. Pups from high dose treated dams exhibited decreased copulation rates, delayed estrus, decreased implantations and decreased surviving fetuses (F2) suggesting multigenerational effects of ethyl-EPA at 7 times human systemic exposure following 4 g/day dose based on body surface area comparisons across species.
- In pregnant rabbits given oral gavage doses of 0.1, 0.3, and 1 g/kg/day from gestation through organogenesis there were increased dead fetuses at 1 g/kg/day secondary to maternal toxicity (significantly decreased food consumption and body weight loss).
- In pregnant rats given ethyl-EPA from gestation day 17 through lactation day 20 at 0.3, 1, 3 g/kg/day complete litter loss was observed in 2/23 litters at the low dose and 1/23 mid-dose dams by post-natal day 4 at human exposures based on a maximum dose of 4 g/day comparing body surface areas across species.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Icosapent in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Icosapent during labor and delivery.

### 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 icosapent ethyl is administered to a nursing mother. An animal study in lactating rats given oral gavage 14C-ethyl EPA demonstrated that drug levels were 6 to 14 times higher in milk than in plasma.

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

### Geriatic Use
- Of the total number of subjects in clinical studies of icosapent ethyl, 33% were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

### Gender
There is no FDA guidance on the use of Icosapent with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Icosapent with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Icosapent in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Icosapent in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Icosapent in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Icosapent in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Oral

### Monitoring
- In patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored periodically during therapy with icosapent ethyl.

# IV Compatibility
There is limited information regarding IV Compatibility of Icosapent in the drug label.

# Overdosage
There is limited information regarding Icosapent overdosage.  If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

# Pharmacology
There is limited information regarding Icosapent Pharmacology in the drug label.

## Mechanism of Action
- Studies suggest that EPA reduces hepatic very low-density lipoprotein triglycerides (VLDL-TG) synthesis and/or secretion and enhances TG clearance from circulating VLDL particles. Potential mechanisms of action include increased -oxidation; inhibition of acyl-CoA:1,2-diacylglycerol acyltransferase (DGAT); decreased lipogenesis in the liver; and increased plasma lipoprotein lipase activity.

## Structure
- icosapent ethyl, a lipid-regulating agent, is supplied as a 1-gram amber-colored, liquid-filled soft gelatin capsule for oral administration.
- Each icosapent ethyl capsule contains 1 gram of icosapent ethyl. Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). The empirical formula of icosapent ethyl is C22H34O2and the molecular weight is 330.51. The chemical name for icosapent ethyl is ethyl all-cis-5,8,11,14,17-icosapentaenoate with the following chemical structure:
- icosapent ethyl 1-gram capsules also contain the following inactive ingredients: tocopherol, gelatin, glycerin, maltitol, sorbitol, and purified water.

## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Icosapent in the drug label.

## Pharmacokinetics
- absorption: After oral administration, icosapent ethyl is de-esterified during the absorption process and the active metabolite EPA is absorbed in the small intestine and enters the systemic circulation mainly via the thoracic duct lymphatic system. Peak plasma concentrations of EPA were reached approximately 5 hours following oral doses of icosapent ethyl.
- icosapent ethyl was administered with or following a meal in all clinical studies; no food effect studies were performed. Take icosapent ethyl with or following a meal.
- Distribution: The mean volume of distribution at steady-state of EPA is approximately 88 liters. The majority of EPA circulating in plasma is incorporated in phospholipids, triglycerides and cholesteryl esters, and <1% is present as the unesterified fatty acid. Greater than 99% of unesterified EPA is bound to plasma proteins.
- Metabolism and Excretion: EPA is mainly metabolized by the liver via beta-oxidation similar to dietary fatty acids. Beta oxidation splits the long carbon chain of EPA into acetyl Coenzyme A, which is converted into energy via the Krebs cycle. Cytochrome P450-mediated metabolism is a minor pathway of elimination of EPA. The total plasma clearance of EPA at steady state is 684 mL/hr. The plasma elimination half-life (t1/2) of EPA is approximately 89 hours. icosapent ethyl does not undergo renal excretion.
- icosapent ethyl was studied at the 4 g/day dose level with the following medications which are typical substrates of cytochrome P450 enzymes, and no drug-drug interactions were observed:
- Omeprazole: In a drug-drug interaction study with 28 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the steady-state AUC or Cmax of omeprazole when co-administered at 40 mg/day to steady-state.
- Rosiglitazone: In a drug-drug interaction study with 28 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the single dose AUC or Cmax of rosiglitazone at 8 mg.
- Warfarin: In a drug-drug interaction study with 25 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the single dose AUC or Cmax of R- and S-warfarin or the anti-coagulation pharmacodynamics of warfarin when co-administered as racemic warfarin at 25 mg.
- Atorvastatin: In a drug-drug interaction study of 26 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the steady-state AUC or Cmax of atorvastatin, 2-hydroxyatorvastatin, or 4-hydroxyatorvastatin when co-administered with atorvastatin 80 mg/day to steady-state.
- Gender: When administered icosapent ethyl in clinical trials, plasma total EPA concentrations did not differ significantly between men and women.
- Pediatric: The pharmacokinetics of icosapent ethyl has not been studied in pediatric patients.
- Hepatic or Renal Impairment: icosapent ethyl has not been studied in patients with renal or hepatic impairment.

## Nonclinical Toxicology
- In a 2-year rat carcinogenicity study with oral gavage doses of 0.09, 0.27, and 0.91 g/kg/day icosapent ethyl, respectively, males did not exhibit drug-related neoplasms. Hemangiomas and hemangiosarcomas of the mesenteric lymph node, the site of drug absorption, were observed in females at clinically relevant exposures based on body surface area comparisons across species relative to the maximum clinical dose of 4 g/day. Overall incidence of hemangiomas and hemangiosarcomas in all vascular tissues did not increase with treatment.
- In a 6-month carcinogenicity study in Tg.rasH2 transgenic mice with oral gavage doses of 0.5, 1, 2, and 4.6 g/kg/day icosapent ethyl, drug-related incidences of benign squamous cell papilloma in the skin and subcutis of the tail was observed in high dose male mice. The papillomas were considered to develop secondary to chronic irritation of the proximal tail associated with fecal excretion of oil and therefore not clinically relevant. Drug-related neoplasms were not observed in female mice.
- Icosapent ethyl was not mutagenic with or without metabolic activation in the bacterial mutagenesis (Ames) assay or in the in vivo mouse micronucleus assay. A chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells was positive for clastogenicity with and without metabolic activation.
- In an oral gavage rat fertility study, ethyl-EPA, administered at doses of 0.3, 1, and 3 g/kg/day to male rats for 9 weeks before mating and to female rats for 14 days before mating through day 7 of gestation, increased anogenital distance in female pups and increased cervical ribs were observed at 3 g/kg/day (7 times human systemic exposure with 4 g/day clinical dose based on a body surface area comparison).

# Clinical Studies
- The effects of icosapent ethyl 4 grams per day were assessed in a randomized, placebo-controlled, double-blind, parallel-group study of adult patients (76 on icosapent ethyl, 75 on placebo) with severe hypertriglyceridemia. Patients whose baseline TG levels were between 500 and 2,000 mg/dL were enrolled in this study for 12 weeks. The median baseline TG and LDL-C levels in these patients were 684 mg/dL and 86 mg/dL, respectively. Median baseline HDL-C level was 27 mg/dL. The randomized population in this study was mostly Caucasian (88%) and male (76%). The mean age was 53 years and the mean body mass index was 31 kg/m2. Twenty-five percent of patients were on concomitant statin therapy, 28% were diabetics, and 39% of the patients had TG levels >750 mg/dL.
- The changes in the major lipoprotein lipid parameters for the groups receiving icosapent ethyl or placebo are shown in Table 2.
- icosapent ethyl 4 grams per day reduced median TG, VLDL-C, and Apo B levels from baseline relative to placebo. The reduction in TG observed with icosapent ethyl was not associated with elevations in LDL-C levels relative to placebo.
- The effect of icosapent ethyl on the risk of pancreatitis in patients with severe hypertriglyceridemia has not been determined.
- The effect of icosapent ethyl on cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia levels has not been determined.

# How Supplied
- icosapent ethyl (icosapent ethyl) capsules are supplied as 1-gram amber-colored soft-gelatin capsules imprinted with icosapent ethyl.
- Bottles of 120: NDC 52937-001-20.
- Store at 20 to 25 C (68 to 77F); excursions permitted to 15 to 30 C (59 to 86F) . Keep out of reach of children.

## Storage
There is limited information regarding Icosapent Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- icosapent ethyl should be used with caution in patients with known sensitivity or allergy to fish and/or shellfish .
- Patients should be advised that use of lipid-regulating agents does not reduce the importance of appropriate nutritional intake and physical activity .
- Patients should be advised not to alter icosapent ethyl capsules in any way and to ingest intact capsules only.
- Instruct patients to take icosapent ethyl as prescribed. If a dose is missed, patients should take it as soon as they remember. However if they miss one day of icosapent ethyl, they should not double the dose when they take it.

# Precautions with Alcohol
- Alcohol-Icosapent interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names

# Look-Alike Drug Names
There is limited information regarding Icosapent Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price