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ICOSAPENT ETHYL

Classification   |    Detailed evidence-based information

Therapeutic Toxic Class

    A) Icosapent ethyl, an ethyl ester of eicosapentaenoic acid, is used as an adjunct to treat severe hypertriglyceridemia along with dietary modifications.

Specific Substances

    1) Eicosapentaenoic acid ethyl ester
    2) Ethyl eicosapentaenoic acid
    3) EPA ethyl ester
    4) Ethyl-EPA
    5) Ethyl all-cis-5,8,11,14,17-icosapentaenoate
    6) 5,8,11,14,17-eicosapentaenoic acid ethyl ester
    7) CAS 86227-47-6
    8) Molecular Formula: C22H34O2

Available Forms Sources

    A) FORMS
    1) Icosapent ethyl is available in 1 gram amber-colored oral capsules (Prod Info VASCEPA(TM) oral capsules, 2012).
    B) USES
    1) Icosapent ethyl is an ethyl ester of eicosapentaenoic acid (EPA) used in conjunction with diet to treat severe (500 mg/dL or greater) hypertriglyceridemia in adults (Prod Info VASCEPA(TM) oral capsules, 2012).

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Icosapent ethyl is an ethyl ester of eicosapentaenoic acid (EPA) used in conjunction with diet to treat severe (500 mg/dL or greater) hypertriglyceridemia in adults.
    B) PHARMACOLOGY: Icosapent ethyl contains ethyl esters of the omega-3 fatty acid, eicosapentaenoic acid (EPA), obtained from fish oil. Studies indicate that EPA, the active metabolite of icosapent ethyl, reduces the synthesis and/or secretion of hepatic very low-density lipoprotein (VLDL) triglycerides, which increases triglyceride clearance from circulating VLDL particles. Potential mechanisms of action include increased beta-oxidation, acyl-CoA:1,2-diacylglycerol acyltransferase (DGAT) inhibition, decreased hepatic lipogenesis, and increased plasma lipoprotein lipase activity.
    C) EPIDEMIOLOGY: Overdose has not been reported.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Arthralgia. Icosapent ethyl may produce a hypersensitivity reaction in individuals with known hypersensitivity to shellfish/fish. Because icosapent ethyl contains ethyl esters of omega-3 fatty acid, patients taking other anticoagulants may be at risk to develop a prolonged bleeding time; the risk of active bleeding is unknown.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Toxicity following overdose has not been reported. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses.
    0.2.20) REPRODUCTIVE
    A) Icosapent ethyl is classified as FDA pregnancy category C. There are no data on the use of icosapent ethyl in pregnant women. The effects, if any, on the developing fetus are unknown. Due to the lack of human safety information, icosapent ethyl should be used in pregnant women only if the potential benefit outweighs the potential risk to the fetus. Omega-3-acid ethyl esters are excreted in human milk; however, the effects of this excretion are not known. Use caution when icosapent ethyl is administered to a nursing mother.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no human data were available to assess the potential carcinogenic activity of icosapent ethyl.

Laboratory Monitoring

    A) Monitor vital signs.
    B) No specific lab work (CBC, electrolytes, urinalysis) is needed unless otherwise clinically indicated.
    C) Toxic levels of icosapent ethyl have not been established; routine drug plasma levels are not likely to be available.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. HYPERSENSITIVITY REACTION: Treat with antihistamines with or without inhaled beta agonists, and corticosteroids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. HYPERSENSITIVITY REACTION: Administer oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids in cases of severe hypersensitivity reaction.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not routinely required following a minor exposure.
    2) HOSPITAL: GI decontamination is generally unnecessary. Consider activated charcoal if a more toxic coingestant is involved.
    D) AIRWAY MANAGEMENT
    1) Airway support is unlikely to be necessary unless severe allergic reaction develops.
    E) ANTIDOTE
    1) None.
    F) BLEEDING
    1) POTENTIAL RISK: Icosapent ethyl contains the ethyl esters of omega-3 fatty acids obtained from fish oil, which theoretically may increase bleeding time, particularly patients taking anticoagulants. The risk of active bleeding with icosapent ethyl exposure is unknown. Coagulation studies should be obtained in a patient showing any evidence of bleeding.
    G) ENHANCED ELIMINATION
    1) Hemodialysis and hemoperfusion are UNLIKELY to be of value because of the high degree of protein binding (99% or greater).
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A minor (a few pills) inadvertent dose in a patient currently being treated with icosapent ethyl can be managed at home. An asymptomatic child with an inadvertent exposure (a few pills) can be monitored at home, if a responsible adult is present.
    2) OBSERVATION CRITERIA: All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.
    3) ADMISSION CRITERIA: Patients demonstrating persistent hypersensitivity or allergic symptoms should be admitted.
    4) CONSULT CRITERIA: Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    I) PITFALLS
    1) Consider the possibility of multidrug involvement when managing a suspected icosapent ethyl overdose.
    J) PHARMACOKINETICS
    1) Less than 1% of icosapent ethyl (unesterified fatty acid) remains in circulation while the active metabolite eicosapentaenoic acid (EPA) is primarily distributed among phospholipids, triglycerides, and cholesteryl esters. Peak plasma concentrations of the active metabolite EPA may be attained in approximately 5 hours. Volume of distribution is approximately 88 L. EPA is extensively metabolized in the liver by beta-oxidation. The elimination half-life of EPA is about 89 hours.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes overdose of other agents that may cause joint pain, a hypersensitivity reaction or may affect coagulation.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULT: The recommended dose is 4 g/day orally in 2 divided doses. PEDIATRIC: Safety and efficacy of icosapent ethyl have not been established for pediatric patients.

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) In pooled data from 2 double-blind clinical trials, arthralgia was reported in 14 of 622 (2.3%) patients administered oral icosapent ethyl compared with 3 of 309 patients (1%) administered placebo (Prod Info VASCEPA(TM) oral capsules, 2012).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) FISH OIL: Icosapent ethyl contains ethyl esters of the omega-3 fatty acid, eicosapentaenoic acid (EPA), obtained from fish oil. At the time of this review, it is unknown if there may be an increased risk of an allergic reaction in individuals with known shellfish/fish hypersensitivity or allergies (Prod Info VASCEPA(TM) oral capsules, 2012).

Reproductive

    3.20.1) SUMMARY
    A) Icosapent ethyl is classified as FDA pregnancy category C. There are no data on the use of icosapent ethyl in pregnant women. The effects, if any, on the developing fetus are unknown. Due to the lack of human safety information, icosapent ethyl should be used in pregnant women only if the potential benefit outweighs the potential risk to the fetus. Omega-3-acid ethyl esters are excreted in human milk; however, the effects of this excretion are not known. Use caution when icosapent ethyl is administered to a nursing mother.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) VISCERAL AND SKELETAL ABNORMALITIES
    a) RATS: Pregnant rats given oral icosapent ethyl at doses equivalent to the maximum oral human dose of 4 g/day through organogenesis resulted in fetal visceral or skeletal abnormalities, including reduced thirteenth ribs, additional liver lobes, and testes that were medially displaced, undescended, or both. Incomplete or abnormal ossification of skeletal bones occurred in doses 5 times the maximum human systemic exposure. In another study, an increased incidence of absent optic nerves and unilateral testes atrophy was reported when pregnant rats were given icosapent ethyl (0.3 g/kg/day or greater at a human systemic exposure of 4 g/day) during gestation day 7 through 17 (Prod Info VASCEPA(R) oral capsules, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified icosapent ethyl as FDA pregnancy category C. There are no data on the use of icosapent ethyl in pregnant women. The effects, if any, on the developing fetus are unknown. Due to the lack of human safety information, icosapent ethyl should be used in pregnant women only if the potential benefit outweighs the potential risk to the fetus (Prod Info VASCEPA(R) oral capsules, 2013).
    B) ANIMAL STUDIES
    1) FETOTOXICITY
    a) RATS: In rats, decreases in implantations and surviving fetuses were observed at doses 7 times the human systemic exposure. In another study, complete litter loss was seen by postnatal day 4 with exposure from gestation day 17 through lactation day 20 in 2 litters with 0.3 g/kg/day doses (n=23) and 1 litter with 1 g/kg/day doses (n=23) at human exposures based on a maximum dose of 4 g/day (Prod Info VASCEPA(R) oral capsules, 2013).
    b) RABBITS: There was an increase in dead fetuses among pregnant rabbits secondary to maternal toxicity following doses of 1 g/kg/day through organogenesis (Prod Info VASCEPA(R) oral capsules, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) BREAST MILK
    a) Omega-3-acid ethyl esters are excreted in human milk; however, the effects of this excretion are not known. Use caution when icosapent ethyl is administered to a nursing mother (Prod Info VASCEPA(R) oral capsules, 2013).
    B) ANIMAL STUDIES
    1) RATS: In lactating rats given oral C-14-ethyl eicosapentaenoic acid (EPA), the drug levels in milk were 6 to 14 times higher than the plasma levels (Prod Info VASCEPA(R) oral capsules, 2013).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: Multigenerational effects (ie, the pups of pregnant rats exposed) included decreased copulation rates, delayed estrus, decreased implantation, and decreased fetal survival following doses in the dams of 7 times the human systemic exposure of 4 g/day from gestation day 7 to 17 (Prod Info VASCEPA(R) oral capsules, 2013).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no human data were available to assess the potential carcinogenic activity of icosapent ethyl.
    3.21.4) ANIMAL STUDIES
    A) HEMANGIOMAS AND HEMANGIOSARCOMAS
    1) RATS: Hemangiomas and hemangiosarcomas of the mesenteric lymph node (the site of drug absorption) were observed in female rats exposed to oral icosapent ethyl at doses relative to the maximum dose of 4 g/day based on body surface area comparisons across species. However, the overall incidence of hemangiomas and hemangiosarcomas in all vascular tissues did not increase with treatment (Prod Info VASCEPA(TM) oral capsules, 2012).
    B) BENIGN SQUAMOUS CELL PAPILLOMA
    1) MICE: In a 6-month carcinogenicity study, the incidence of benign squamous cell papilloma in the skin and subcutis of the tail was increased at the high dose (4.6 g/kg/day) in male mice exposed to oral icosapent ethyl. However, the papillomas were not considered clinically relevant because they developed secondary to chronic irritation of the tail as a result of fecal excretion of oil (Prod Info VASCEPA(TM) oral capsules, 2012).
    C) LACK OF EFFECT
    1) NEOPLASMS
    a) MICE: In a 6-month carcinogenicity study, drug-related neoplasms were not observed in female mice exposed to oral icosapent ethyl (Prod Info VASCEPA(TM) oral capsules, 2012).

Genotoxicity

    A) There was no evidence of mutagenicity with or without metabolic activation in the bacterial mutagenesis (Ames) assay or in vivo mouse micronucleus assay. Evidence of clastogenicity with and without metabolic activation was observed in the chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells (Prod Info VASCEPA(TM) oral capsules, 2012).

Summary Of Exposure

    A) USES: Icosapent ethyl is an ethyl ester of eicosapentaenoic acid (EPA) used in conjunction with diet to treat severe (500 mg/dL or greater) hypertriglyceridemia in adults.
    B) PHARMACOLOGY: Icosapent ethyl contains ethyl esters of the omega-3 fatty acid, eicosapentaenoic acid (EPA), obtained from fish oil. Studies indicate that EPA, the active metabolite of icosapent ethyl, reduces the synthesis and/or secretion of hepatic very low-density lipoprotein (VLDL) triglycerides, which increases triglyceride clearance from circulating VLDL particles. Potential mechanisms of action include increased beta-oxidation, acyl-CoA:1,2-diacylglycerol acyltransferase (DGAT) inhibition, decreased hepatic lipogenesis, and increased plasma lipoprotein lipase activity.
    C) EPIDEMIOLOGY: Overdose has not been reported.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Arthralgia. Icosapent ethyl may produce a hypersensitivity reaction in individuals with known hypersensitivity to shellfish/fish. Because icosapent ethyl contains ethyl esters of omega-3 fatty acid, patients taking other anticoagulants may be at risk to develop a prolonged bleeding time; the risk of active bleeding is unknown.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Toxicity following overdose has not been reported. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses.

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs.
    B) No specific lab work (CBC, electrolytes, urinalysis) is needed unless otherwise clinically indicated.
    C) Toxic levels of icosapent ethyl have not been established; routine drug plasma levels are not likely to be available.
    4.1.2) SERUM/BLOOD
    A) Serum levels of icosapent ethyl are not useful because therapeutic and toxic levels have not been established and are generally not available in a timely fashion.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs.

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients demonstrating persistent hypersensitivity or allergic symptoms should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A minor (a few pills) inadvertent dose in a patient currently being treated with icosapent ethyl can likely be managed at home. An asymptomatic child with an inadvertent exposure (a few pills) can likely be monitored at home, if a responsible adult is present.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with deliberate self-harm ingestions should be evaluated in a healthcare facility and monitored until symptoms resolve. Children with unintentional ingestions who are symptomatic should be observed in a healthcare facility.

Monitoring

    A) Monitor vital signs.
    B) No specific lab work (CBC, electrolytes, urinalysis) is needed unless otherwise clinically indicated.
    C) Toxic levels of icosapent ethyl have not been established; routine drug plasma levels are not likely to be available.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is not routinely required following a minor exposure.
    6.5.2) PREVENTION OF ABSORPTION
    A) GI decontamination is generally not necessary. Consider activated charcoal if a more toxic coingestant is involved.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. HYPERSENSITIVITY REACTION: Treat with antihistamines with or without inhaled beta agonists, and corticosteroids.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. HYPERSENSITIVITY REACTION: Administer oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids in cases of severe hypersensitivity reaction.
    B) MONITORING OF PATIENT
    1) Monitor vital signs.
    2) No specific lab work (CBC, electrolytes, urinalysis) is needed unless otherwise clinically indicated.
    3) Toxic levels of icosapent ethyl have not been established; routine drug plasma levels are not likely to be available.
    C) HYPERSENSITIVITY REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    D) BLEEDING
    1) POTENTIAL RISK: Icosapent ethyl contains ethyl esters of the omega-3 fatty acid, eicosapentaenoic acid (EPA), obtained from fish oil. In some studies, omega 3-fatty acids have produced prolonged bleeding time. However, there were no reports of clinically significant bleeding. Periodic monitoring is recommended in patients receiving icosapent ethyl and other agents affecting coagulation (Prod Info VASCEPA(TM) oral capsules, 2012).
    2) The risk of active bleeding with icosapent ethyl exposure is unknown. Coagulation studies should be obtained in a patient showing any evidence of bleeding.

Enhanced Elimination

    A) LACK OF EFFECT
    1) Hemodialysis and hemoperfusion are UNLIKELY to be of value because of the high degree of protein binding (99% or greater).

Therapeutic Dose

    7.2.1) ADULT
    A) SEVERE HYPERTRIGLYCERIDEMIA: The recommended dose is 4 g/day orally in 2 divided doses with food (Prod Info VASCEPA(TM) oral capsules, 2012).
    7.2.2) PEDIATRIC
    A) Safety and efficacy have not been established for pediatric patients (Prod Info VASCEPA(TM) oral capsules, 2012).

Minimum Lethal Exposure

    A) There have been no reports of icosapent ethyl overdose at the time of this review (Prod Info VASCEPA(TM) oral capsules, 2012).

Maximum Tolerated Exposure

    A) A specific toxic dose for icosapent ethyl has not been established (Prod Info VASCEPA(TM) oral capsules, 2012).

Summary

    A) TOXICITY: A specific toxic dose has not been established.
    B) THERAPEUTIC DOSE: ADULT: The recommended dose is 4 g/day orally in 2 divided doses. PEDIATRIC: Safety and efficacy of icosapent ethyl have not been established for pediatric patients.

Pharmacologic Mechanism

    A) Studies indicate that eicosapentaenoic acid (EPA), the active metabolite of icosapent ethyl, reduces the synthesis and/or secretion of hepatic very low-density lipoprotein (VLDL) triglycerides, which increases triglyceride clearance from circulating VLDL particles. Potential mechanisms of action include increased beta-oxidation, acyl-CoA:1,2-diacylglycerol acyltransferase (DGAT) inhibition, decreased hepatic lipogenesis, and increased plasma lipoprotein lipase activity (Prod Info VASCEPA(TM) oral capsules, 2012).

General Bibliography

    1) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    2) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    3) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    4) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    5) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    6) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
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