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    Omega-3 Dyslipidemic Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Mixtures of ethyl esters or free fatty acids derived from fish oil primarily composed of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)
    Used as an adjunct to diet to reduce triglyceride levels in adult patients with severe (>= 500 mg/dL) hypertriglyceridemia
    Unknown effect on the risk for pancreatitis or cardiovascular morbidity and mortality

    COMMON BRAND NAMES

    Lovaza, Omacor

    HOW SUPPLIED

    Lovaza/Omacor/Omega-3-Acid Ethyl Esters, Eicosapentaenoic Acid (EPA), Docosahexaenoic Acid (DHA) Oral Cap: 465-375mg

    DOSAGE & INDICATIONS

    For use as an adjunct to diet to reduce hypertriglyceridemia (i.e., defined as triglyceride blood concentrations >= 500 mg/dL).
    NOTE: Patients should be placed on an appropriate lipid-lowering diet and should continue this diet during treatment.
    For use as an adjunct to simvastatin therapy† for the treatment of hypertriglyceridemia.
    Oral dosage (Lovaza)
    Adults

    A dosage of 4 g/day PO as a single dose plus simvastatin 40 mg/day PO has been used in one study evaluating 254 adults with hypertriglyceridemia. At the end of the 8-week treatment regimen, the median percent change in non-HDL-C was significantly greater with Lovaza plus simvastatin compared with placebo plus simvastatin (-9.0% vs. -2.2%, respectively; p < 0.0001). Compared to simvastatin monotherapy, Lovaza plus simvastatin resulted in significant reductions in triglycerides (29.5% vs. 6.3%, p < 0.0001) and very low-density lipoprotein cholesterol (27.5% vs. 7.2%, p < 0.05), and a significant increase in high-density lipoprotein cholesterol (+3.4% vs. -1.2%, p < 0.05).

    Oral dosage (Lovaza and Omtryg)
    Adults

    4 capsules/day PO, either as a single dose PO once per day or as 2 capsules PO twice daily. The effect of treatment on the risk for pancreatitis and cardiovascular morbidity/mortality in patients with severe hypertriglyceridemia has not been determined.

    Oral dosage (Epanova)
    Adults

    2 or 4 g (2 or 4 capsules) PO once daily. Individualize dosage according to response and tolerability. The effect of treatment on the risk for pancreatitis and cardiovascular morbidity/mortality in patients with severe hypertriglyceridemia has not been determined.

    MAXIMUM DOSAGE

    Adults

    4 capsules/day PO.

    Geriatric

    4 capsules/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Lovaza:
    Take with or without food. In clinical trials, Lovaza capsules were administered with meals.
    Capsules should be swallowed whole. Advise patients not to break open, crush, dissolve or chew.
    Omtryg:
    Take with meals.
    Capsules should be swallowed whole. Advise patients not to break open, crush, dissolve or chew.
    Epanova:
    Take with or without food. In clinical trials, Epanova capsules were administered without regard to meals.
    Capsules should be swallowed whole. Advise patients not to break open, crush, dissolve or chew.

    STORAGE

    Lovaza:
    - Do not freeze
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Omacor:
    - Do not freeze
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Fish hypersensitivity

    Fish oil, omega-3-fatty acids are contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to fish oil, omega-3-fatty acids or any of its components. Use with caution in patients with known fish hypersensitivity. These products are derived from fish oils. It is not known whether patients with allergies to fish and/or shellfish are at increased risk of an allergic reaction.

    Hypercholesterolemia

    Because fish oil, omega-3 fatty acids may increase LDL or total serum cholesterol, they should be used cautiously in patients with hypercholesterolemia or mixed dyslipidemias. As with any lipid-regulating product, LDL-C levels should be monitored periodically.

    Anticoagulant therapy, thrombolytic therapy

    Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulant therapy, thrombolytic therapy, or anti-platelet therapy. Theoretically, the risk of bleeding may be increased, but some studies have not shown clinically significant bleeding events with concurrent use. Periodically monitor patients receiving concurrent therapy with fish oils and drugs affecting coagulation for bleeding.

    Atrial fibrillation

    A possible association exists between omega-3-acid ethyl esters and more frequent recurrences of symptomatic atrial fibrillation (AF) or atrial flutter in patients with paroxysmal or persistent AF, particularly within the first 2—3 months of initiating therapy. The clinical significance is uncertain.

    Pregnancy

    There are no adequate and well-controlled studies during pregnancy and data are insufficient to inform a drug-associated risk for major birth defects or miscarriages. Late fetal deaths and a higher incidence of maternal death at parturition were observed in pregnant rats administered doses 5 times the recommended human dose of 4 grams/day based on a body surface area comparison. Minor fetal malformations and abortion were reported when pregnant rats were administered doses 2 times and 4 times the human exposure, respectively, based on a body surface area comparison.

    Breast-feeding

     There is no information regarding the presence of fish oil, omega-3 fatty acids in human milk, the effects on the breastfed infant, or the effects on milk production. Limited data suggest that omega-3 fatty acids derived for fish oil are present in milk at concentrations higher than that in plasma. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for fish oil, omega-3 fatty acids and any potential adverse effects on the breastfed child for fish oil, omega-3 fatty acids. During breast-feeding, fish oil, omega-3 fatty acids do not appear to be harmful to the infant at levels approximating normal maternal dietary intakes (i.e., via fish in the maternal diet). Docosahexaenoic acid (DHA) is present in breast milk under normal physiologic circumstances, and is an important nutritional component.

    ADVERSE REACTIONS

    Severe

    coagulopathy / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    atrial flutter / Early / Incidence not known
    atrial fibrillation / Early / Incidence not known

    Moderate

    constipation / Delayed / Incidence not known
    prolonged bleeding time / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known

    Mild

    diarrhea / Early / 7.0-15.0
    nausea / Early / 4.0-6.0
    abdominal pain / Early / 3.0-5.0
    dysgeusia / Early / 4.0-4.0
    eructation / Early / 3.0-4.0
    dyspepsia / Early / 3.0-3.0
    rash (unspecified) / Early / 1.8-1.8
    vomiting / Early / Incidence not known
    ecchymosis / Delayed / Incidence not known
    epistaxis / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    fatigue / Early / Incidence not known
    pharyngitis / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known

    DRUG INTERACTIONS

    There are no drug interactions associated with Fish Oil, Omega-3 Fatty Acids (FDA-approved) products.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate and well-controlled studies during pregnancy and data are insufficient to inform a drug-associated risk for major birth defects or miscarriages. Late fetal deaths and a higher incidence of maternal death at parturition were observed in pregnant rats administered doses 5 times the recommended human dose of 4 grams/day based on a body surface area comparison. Minor fetal malformations and abortion were reported when pregnant rats were administered doses 2 times and 4 times the human exposure, respectively, based on a body surface area comparison.

     There is no information regarding the presence of fish oil, omega-3 fatty acids in human milk, the effects on the breastfed infant, or the effects on milk production. Limited data suggest that omega-3 fatty acids derived for fish oil are present in milk at concentrations higher than that in plasma. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for fish oil, omega-3 fatty acids and any potential adverse effects on the breastfed child for fish oil, omega-3 fatty acids. During breast-feeding, fish oil, omega-3 fatty acids do not appear to be harmful to the infant at levels approximating normal maternal dietary intakes (i.e., via fish in the maternal diet). Docosahexaenoic acid (DHA) is present in breast milk under normal physiologic circumstances, and is an important nutritional component.

    MECHANISM OF ACTION

    The mechanism of action of fish oil, omega-3 fatty acids for the treatment of hypertriglyceridemia is not completely understood. Inhibition of acyl-CoA:1,2-diacylglycerol acyltransferase, increased mitochondrial and hepatic peroxisomal beta-oxidation, decreased hepatic lipogenesis, and increased plasma lipoprotein lipase activity are potential mechanisms of action. Because eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are poor substrates for the enzymes responsible for triglyceride synthesis and because EPA and DHA inhibit esterification of other fatty acids, fish oil, omega-3 fatty acids may reduce the hepatic synthesis of triglycerides.

    PHARMACOKINETICS

    Fish oil, omega-3 fatty acids is administered orally. When administered as ethyl esters, omega-3 fatty acids induce significant, dose dependent increases in serum phospholipid eicosapentaenoic acid (EPA) content. Increases in docosahexaenoic acid (DHA) content were less marked and not dose-dependent when administered as ethyl esters. Following repeat dosing of omega-3 carboxylic acids under low-fat meal conditions for approximately 2 weeks, maximum plasma concentrations are achieved 5—8 hours after dosing for total EPA and between 5—9 hours after dosing for total DHA. Steady-state concentrations of EPA and DHA in plasma are achieved within 2 weeks of repeat daily dosing with omega-3 carboxylic acids. EPA and DHA from omega-3 carboxylic acids are mainly oxidized in the liver similar to fatty acids derived from dietary sources.
     
    Affected cytochrome P450 isoenzymes: none
    While omega-3-fatty acid containing products have shown increased hepatic concentrations of CYP450 and activities of certain CYP450 isoenzymes in rats, the potential to induce CYP450 activities in humans has not been studied. However, the free forms of the EPA and DHA are typically undetectable in the human circulation. Clinically significant interactions of fish oil, omega-3 fatty acids with other drugs due to inhibition or induction of CYP450 mediated metabolism are not expected.[43902]

    Oral Route

    Lovaza: Lovaza was administered with meals in clinical trials.
     
    Omtryg: Administration of Omtryg under fasted condition in clinical trials resulted in decreases in the peak (Cmax) and total (AUC0-72h) exposure by up to 20 to 80-fold, respectively, for total plasma EPA and by up to 2 to 4-fold, respectively, for total plasma DHA, in comparison to those observed under fed condition (high-fat high-calorie meal).
     
    Epanova: Epanova was administered without regard to meals in clinical trials. Administration of a single dose of Epanova with a high-fat meal increased the overall exposure of total and free baseline-adjusted EPA by approximately 140% and 80%, respectively, compared to fasting conditions. There was no change in overall exposure of baseline-adjusted total DHA; however, there was a 40% increase in AUC for baseline-adjusted free DHA. Overall exposures of unadjusted total and free EPA increased by 80% and 50%, respectively, although there was no change in overall exposure for unadjusted total and free DHA.