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  • CLASSES

    Fat Emulsions, Combinations
    Fat Emulsions, Plain

    BOXED WARNING

    Premature neonates

    Deaths have been reported in premature neonates after infusion of intravenous lipid emulsions. Intravascular fat accumulation in the lungs has been observed at autopsy. Treatment of premature or low-birth-weight infants with intravenous lipid emulsion must be done after careful benefit-risk assessment. Strict adherence to the recommended daily dose is mandatory; hourly infusion rate should be as slow as possible and should not exceed 1 g fat/kg in 4 hours. Premature and low-birth-weight infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma concentrations following infusion; therefore, give serious consideration to administration of less than the maximum recommended doses in these patients in order to decrease the chance of intravenous fat overload. Monitor the infant’s ability to eliminate the infused fat from the circulation with assessment of serum triglyceride and/or plasma free fatty acid concentrations. The lipemia must clear between daily infusions. Serum triglyceride concentrations should be maintained at less than 150 to 200 mg/dL in neonates. The US product labeling for SMOFlipid states that the safety and efficacy of SMOFlipid have not been established in pediatric patients, including premature neonates. However, SMOFlipid is approved for use in pediatric patients as young as neonates outside the US.

    DEA CLASS

    Rx

    DESCRIPTION

    Fat emulsions primarily composed of varying ratios of medium-chain and long-chain triglycerides and/or fish oil triglycerides, egg phospholipids, and glycerol
    Used for source of calories and essential fatty acids for parenteral nutrition or when deficiency occurs when oral or enteral nutrition is not possible, insufficient, or contraindicated; Omegaven indicated as lipid source in pediatric patients with parenteral nutrition-associated cholestasis
    Used off-label for lipid resuscitation therapy (LRT) in cases of potentially fatal local anesthetic toxicity or lipophilic agent overdose or poisoning

    COMMON BRAND NAMES

    Intralipid, Nutrilipid, Omegaven, Smoflipid

    HOW SUPPLIED

    Intralipid/Nutrilipid Intravenous Inj Lipid Complex: 20%, 30%
    Omegaven/Smoflipid Intravenous Inj Emulsion: 0.1g, 1mL

    DOSAGE & INDICATIONS

    For the treatment of essential fatty acid deficiency when oral or enteral nutrition is not possible.
    Intravenous dosage (soybean oil-based lipid emulsions [i.e., Intralipid, Nutrilipid])
    Adults

    8% to 10% of the caloric intake should be supplied by intravenous lipid emulsion for correction of fatty acid deficiency.

    Infants, Children, and Adolescents

    8% to 10% of the caloric intake should be supplied by intravenous lipid emulsion for correction of fatty acid deficiency.

    Neonates

    8% to 10% of the caloric intake should be supplied by intravenous lipid emulsion for correction of fatty acid deficiency.

    For nutritional supplementation to provide calories and essential fatty acids as part of parenteral nutrition therapy (essential fatty acid deficiency prophylaxis).
    For nutritional supplementation in patients with parenteral nutrition-associated cholestasis (PNAC).
    Intravenous dosage (fish oil lipid emulsion [i.e., Omegaven])

    NOTE: Omegaven is not indicated for the prevention of PNAC. It has not been demonstrated that Omegaven prevents PNAC in patients on parenteral nutrition.

    Infants, Children, and Adolescents

    1 g/kg/day IV; initial doses may be lower and should be calculated according to individual requirements. Initiate Omegaven dosing as soon as direct or conjugated bilirubin concentrations are 2 mg/dL or greater in patients expected to require parenteral nutrition (PN) for at least 2 weeks. Administer until direct or conjugated bilirubin concentrations are less than 2 mg/dL or until the patient no longer requires PN.

    Neonates

    1 g/kg/day IV; initial doses may be lower and should be calculated according to individual requirements. Initiate Omegaven dosing as soon as direct or conjugated bilirubin concentrations are 2 mg/dL or greater in patients expected to require parenteral nutrition (PN) for at least 2 weeks. Administer until direct or conjugated bilirubin concentrations are less than 2 mg/dL or until the patient no longer requires PN.

    Intravenous dosage (soybean oil/MCT-based lipid emulsions [i.e., Intralipid, Nutrilipid, SMOFlipid])
    Adults

    1 to 2 g/kg/day IV; may advance to a maximum of 2.5 g/kg/day. Fat emulsion should not comprise more than 60% of the patient's total caloric intake. Dosing is highly variable and should be calculated according to individual requirements. For the prevention of fatty acid deficiency, provide at least 2% to 4% of the total caloric intake as linoleic acid and 0.25% to 0.5% as alpha linolenic acid, which for most adults can be supplied as 250 mL of 20% IV lipid emulsion once or twice weekly.

    Children and Adolescents 11 to 17 years

    1 g/kg/day IV; may advance to a maximum dose of 2.5 g/kg/day. Fat emulsion should not comprise more than 60% of the patient's total caloric intake. Dosing is highly variable and should be calculated according to individual requirements. For the prevention of fatty acid deficiency, provide at least 2% to 4% of the total caloric intake as linoleic acid and 0.25% to 0.5% as alpha linolenic acid, or approximately 0.5 to 1 g/kg/day.

    Infants and Children 1 to 10 years

    1 to 2 g/kg/day IV; may advance to a maximum dose of 3 g/kg/day. Fat emulsion should not comprise more than 60% of the patient's total caloric intake. Dosing is highly variable and should be calculated according to individual requirements. For the prevention of fatty acid deficiency, provide at least 2% to 4% of the total caloric intake as linoleic acid and 0.25% to 0.5% as alpha linolenic acid, or approximately 0.5 to 1 g/kg/day.

    Neonates

    0.5 to 1 g/kg/day IV; advance by 0.5 g/kg/day, up to a maximum dose of 3 g/kg/day. Fat emulsion should not comprise more than 60% of the patient's total caloric intake. Dosing is highly variable and should be calculated according to individual requirements. For the prevention of fatty acid deficiency, provide at least 2% to 4% of the total caloric intake as linoleic acid and 0.25% to 0.5% as alpha linolenic acid, or approximately 0.5 to 1 g/kg/day.

    For lipid resuscitation therapy (LRT)† to treat lipophilic agent (i.e., local anesthetics, calcium channel blockers) overdose.
    Intravenous dosage (soybean oil-based lipid emulsions [i.e., Intralipid, Nutrilipid])
    Adults

    1.5 mL/kg (lean body weight) IV bolus followed by 0.25 mL/kg/minute continuous IV infusion. For persistent asystole or pulselessness, may repeat bolus at 5 minute intervals up to a maximum of 3 bolus doses (4.5 mL/kg). After 5 minutes, may increase the infusion rate to 0.5 mL/kg/minute if blood pressure declines or remains low. Continue infusion for at least 10 minutes but no more than 60 minutes after achievement of hemodynamic stability. Max cumulative dose: 12 mL/kg.

    Infants, Children, and Adolescents

    Data are limited to case reports and dosing is not well established; 1 to 1.5 mL/kg IV bolus followed by 0.25 mL/kg/minute continuous IV infusion. May repeat bolus; adult protocols recommend a maximum of 3 bolus doses. Continue infusion for usually no more than 60 minutes.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    2.5 g/kg/day IV for nutritional supplementation (soybean oil-based lipid emulsions); safety and efficacy of Omegaven has not been established; 12 mL/kg IV maximum cumulative dose recommended for lipid resuscitation therapy (off-label).

    Geriatric

    2.5 g/kg/day IV for nutritional supplementation (soybean oil-based lipid emulsions); safety and efficacy of Omegaven has not been established; 12 mL/kg IV maximum cumulative dose recommended for lipid resuscitation therapy (off-label).

    Adolescents

    2.5 g/kg/day IV (soybean oil-based lipid emulsions); 1 g/kg/day IV (Omegaven).

    Children

    11 to 12 years: 2.5 g/kg/day IV (soybean oil-based lipid emulsions); 1 g/kg/day IV (Omegaven).
    1 to 10 years: 3 g/kg/day IV (soybean oil-based lipid emulsions); 1 g/kg/day IV (Omegaven).

    Infants

    3 g/kg/day IV (soybean oil-based lipid emulsions); 1 g/kg/day IV (Omegaven).

    Neonates

    3 g/kg/day IV (soybean oil-based lipid emulsions); 1 g/kg/day IV (Omegaven).

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; the dose should be individualized based on clinical goals. Exercise caution when administering to patients with hepatic impairment as the liver is responsible for converting circulating free fatty acids to low density lipoproteins that enter the bloodstream. Additionally, hepatobiliary disorders are known to occur in patients receiving parenteral nutrition.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; the dose should be individualized based on clinical goals.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Preparation of Total Nutrient Admixture (TNA)
    30% Intralipid should only be administered as part of a 3-in-1 total nutrient admixture (TNA); it is NOT indicated for direct IV infusion. Diluting 30% formulations to a 20% concentration does not produce a solution equivalent to the commercially available 20% emulsions and such a dilution should not be given by direct intravenous administration.
    Pharmacy Bulk Packages are not for direct IV administration.
    Prepare TNA using strict aseptic techniques.
    Do not add intravenous lipid emulsion (ILE) to the parenteral nutrition (PN) container first; destabilization of the lipid may occur. The proper mixing sequence is dextrose, amino acids, and then lipid emulsion. Simultaneous transfer of dextrose, amino acids, and ILE to the PN container is also permitted.
    Use gentle agitation during admixing; shake bags gently after each addition.
    Do not add additives directly to ILE; additives to the TNA solution should be evaluated by a pharmacist for compatibility.
    Storage: Use the Pharmacy Bulk Package within 4 hours after opening. Admixtures should be used promptly with storage under refrigeration not to exceed 24 hours and must be completely infused within 24 hours after removal from refrigeration.
     
    Preparation of Bags for Direct Infusion
    Inspect bag overwrap and primary bag; do not use if damaged. Inspect oxygen indicator and do not use if oxygen indicator is pink or dark pink (Nutrilipid) or black (SMOFlipid). Use only if container and seals are intact.
    Remove infusion bag and discard oxygen indicator, oxygen absorber, and overwrap.
    Discard bag if there is a separation of the lipid emulsion or any signs of discoloration and/or leakage.
    Remove outlet port and attach administration set.
    Additives may only be added to the medication port under strict aseptic techniques and only after evaluation by a pharmacist for compatibility.
    Storage: After removing from the overwrap, ILE should be used immediately. If not used immediately, the product should not be stored longer than 24 hours under refrigeration. After removal from storage, the emulsion should be used within 24 hours.
     
    Intravenous Infusion Administration
    For intravenous infusion only through a peripheral or central line. When administered with dextrose and/or amino acids, solutions with osmolarity of 900 mOsm/L or higher must be infused through a central line.
    Use a 1.2 micron filter. When administering PN as dextrose and amino acids (2-in-1) and the IV lipid emulsion as a separate infusion, 2 filters are necessary. A 0.22 micron in-line filter is used for the dextrose and amino acids solution and a 1.2 micron filter is used for the IV lipid emulsion, which is infused by means of a Y-connector placed closer to the patient than the 0.22 micron filter or via a separate vascular access device. If an occluded filter needs to be removed, replace it with a new filter. Do not allow an unfiltered admixture to continue to infuse.
    Administration tubing and filter should be changed every 24 hours for TNA, dextrose/amino acid solutions (2-in-1), or lipid emulsions. When lipids are infused separately, ILE should hang for no more than 12 hours to minimize microbial growth potential. When administered as part of a 3-in-1 TNA, IV fat emulsions can hang for 24 hours.
    To prevent air embolism, use a non-vented infusion set or close the vent on a vented set, avoid multiple connections, do not connect flexible bags in series, fully evacuate residual gas in the bag prior to administration, do not pressurize the flexible bag to increase flow rates, and if administration is controlled by a pumping device, turn off pump before the bag runs dry.
    Do not use infusion sets and lines that contain di-2-ethyl hexyl phthalate (DEHP); administration sets that contain polyvinyl chloride (PVC) components have DEHP as a plasticizer.
    Soybean oil-based lipid emulsions (i.e., Intralipid, Nutrilipid, SMOFlipid):
    Adult patients: Initial infusion rate is 0.5 mL/minute for first 15 to 30 minutes; gradually increase to the required rate after 30 minutes. Max: 0.5 mL/kg/hour (0.1 g/kg/hour).
    Pediatric patients 11 to 17 years: Initial infusion rate is 0.05 mL/minute for first 10 to 15 minutes; gradually increase to the required rate after 15 minutes. Max: 0.5 mL/kg/hour (0.1 g/kg/hour).
    Pediatric patients 1 to 10 years: Initial infusion rate is 0.05 mL/minute for first 10 to 15 minutes; gradually increase to the required rate after 15 minutes. Max: 0.75 mL/kg/hour (0.15 g/kg/hour).
    Neonates and Infants:
    Initial infusion rate is 0.05 mL/minute for first 10 to 15 minutes; gradually increase to the required rate after 15 minutes. Max: 0.75 mL/kg/hour (0.15 g/kg/hour).
    The use of a dextrose/amino acids PN solution with ILE infused separately is recommended in neonates and infants due to the increased risk of calcium-phosphate precipitation in total nutrient admixtures.
    Additionally, the American Academy of Pediatrics (AAP) recommends that ILE be infused over 24 hours in infants and children to promote lipid tolerance.
    Fish oil triglycerides lipid emulsion (i.e., Omegaven)
    Pediatric patients (all ages): Initial infusion rate is 0.05 mL/minute for first 15 to 30 minutes; gradually increase to the required rate after 30 minutes. Max: 1.5 mL/kg/hour (0.15 g/kg/hour). The recommended duration of infusion is 8 to 24 hours, depending on clinical situation.
     
    Lipid Resuscitation Therapy (LRT) for Lipophilic Agent Overdose
    LRT can be administered through a peripheral intravenous catheter.
    Administer bolus over 1 to 3 minutes
    After the bolus, attach the lipid emulsion bag to an intravenous pump for continuous infusion.
    Continue infusion for at least 10 minutes after achievement of hemodynamic stability but no more than 60 minutes.

    STORAGE

    Intralipid:
    - Avoid use of product if it has been frozen
    - Protect from freezing
    - Store below 77 degrees F
    Liposyn II:
    - Avoid exposure to heat
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Liposyn III:
    - Avoid exposure to heat
    - Protect from freezing
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store below 86 degrees F
    Nutrilipid:
    - Avoid excessive heat (above 104 degrees F)
    - Discard if product has been frozen
    - Do not expose product to temperatures above 77 degrees F
    - Do not freeze
    Omegaven:
    - Avoid excessive heat (above 104 degrees F)
    - Discard if product has been frozen
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - See package insert for detailed storage information
    - Store below 77 degrees F
    Smoflipid:
    - Discard unused portion. Do not store for later use.
    - Discard unused product within 24 hours of opening bottle
    - Do not use if product has been frozen
    - Opened product is stable in refrigerator (36 to 46 degrees F) for 24 hours
    - Protect from freezing
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    30% intravenous lipid emulsion formulations are contraindicated to be given by direct intravenous administration. Diluting 30% formulations to a 10% or 20% concentration does not produce a solution equivalent to the commercially available 10% or 20% emulsions, and such a dilution should not be given by direct intravenous administration.

    Egg hypersensitivity, fish hypersensitivity, peanut hypersensitivity, soya lecithin hypersensitivity

    Intravenous lipid emulsions are contraindicated in patients with fish hypersensitivity, egg hypersensitivity, soybean hypersensitivity (soya lecithin hypersensitivity), or peanut hypersensitivity, or hypersensitivity to any active ingredients or excipients of the products. Signs or symptoms of a hypersensitivity reaction may include tachypnea, dyspnea, hypoxia, bronchospasm, tachycardia, hypotension, cyanosis, vomiting, nausea, headache, sweating, dizziness, altered mentation, flushing, rash, urticaria, erythema, pyrexia, or chills. Discontinue intravenous lipid emulsion infusion immediately if a hypersensitivity reaction occurs, and institute appropriate treatment and supportive measures.

    Diabetes mellitus, hyperlipidemia, hypertriglyceridemia, obesity, pancreatitis

    Intravenous lipid emulsions are contraindicated in patients with severe hyperlipidemia or severe disorders of lipid metabolism if characterized by hypertriglyceridemia (serum triglyceride concentrations more than 1,000 mg/dL). Impaired lipid metabolism may occur in conditions such as inherited lipid disorders, obesity, diabetes mellitus, and metabolic syndrome. Measure serum triglyceride concentrations at baseline, at the time of dosage increase, and routinely during treatment to assess patient’s ability to eliminate and metabolize lipid emulsion. In adult patients with triglyceride concentrations more than 400 mg/dL, reduce the dose of intravenous lipid emulsion and monitor serum triglyceride concentrations to avoid adverse effects associated with hypertriglyceridemia. Serum triglyceride concentrations more than 1,000 mg/dL have been associated with an increased risk of pancreatitis. Clinical practice guidelines recommend the safe use of intravenous fat emulsion in patients with acute pancreatitis as long as serum triglyceride concentrations are closely monitored and remain less than 400 mg/dL.

    Premature neonates

    Deaths have been reported in premature neonates after infusion of intravenous lipid emulsions. Intravascular fat accumulation in the lungs has been observed at autopsy. Treatment of premature or low-birth-weight infants with intravenous lipid emulsion must be done after careful benefit-risk assessment. Strict adherence to the recommended daily dose is mandatory; hourly infusion rate should be as slow as possible and should not exceed 1 g fat/kg in 4 hours. Premature and low-birth-weight infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma concentrations following infusion; therefore, give serious consideration to administration of less than the maximum recommended doses in these patients in order to decrease the chance of intravenous fat overload. Monitor the infant’s ability to eliminate the infused fat from the circulation with assessment of serum triglyceride and/or plasma free fatty acid concentrations. The lipemia must clear between daily infusions. Serum triglyceride concentrations should be maintained at less than 150 to 200 mg/dL in neonates. The US product labeling for SMOFlipid states that the safety and efficacy of SMOFlipid have not been established in pediatric patients, including premature neonates. However, SMOFlipid is approved for use in pediatric patients as young as neonates outside the US.

    Cholelithiasis, cholestasis, hepatic disease, hepatitis

    Use parenteral nutrition with caution in patients with hepatic disease. Hepatobiliary disorders, including cholestasis, hepatic steatosis, steato-hepatitis, gallbladder sludge, fibrosis, and cirrhosis (parenteral nutrition-associated liver disease [PNALD]), potentially leading to hepatic failure, may occur in patients without preexisting hepatic disease who receive parenteral nutrition. Cholecystitis and cholelithiasis have also been observed. Premature neonates may be at particular risk for PNALD due to a decreased ability to clear intravenous lipid emulsions and increased free fatty acid plasma concentrations after administration. Monitor liver function parameters closely in patients receiving parenteral nutrition, particularly premature infants. If liver function test abnormalities develop, consider discontinuation or dose reduction of intravenous lipid emulsion.

    Renal impairment

    Intravenous lipid emulsions contain no more than 25 mcg/L of aluminum. However, aluminum toxicity may occur with prolonged administration in high-risk patients, including those with renal impairment and premature neonates. Premature neonates are at particular risk for aluminum toxicity because of immature renal function, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Patients with renal impairment, who receive parenteral aluminum at rates more than 4 to 5 mcg/kg/day, may develop aluminum toxicity (central nervous system and bone toxicity). Tissue loading may occur at lower administration rates.

    Electrolyte imbalance, malnutrition, refeeding syndrome

    Refeeding syndrome may occur in patients with severe malnutrition or critically ill patients when parenteral nutrition is initiated. Refeeding syndrome is characterized by the intracellular shift of potassium, phosphorus, and magnesium as the patient becomes anabolic. In high-risk patients, feedings should be initiated gradually to minimize the potential for refeeding syndrome. Additionally, monitor electrolytes carefully in patients at risk for refeeding syndrome, and correct electrolyte imbalance prior to initiation of nutrition support.

    Immunosuppression, infection

    Intravenous lipid emulsions may support microbial growth and are an independent risk factor for development of catheter-related bloodstream infections. Patients with malnutrition-associated immunosuppression, long-term use and poor maintenance of intravenous catheters, or concomitant conditions or drugs associated with immunosuppression are at higher risk for infection. To decrease the risk of infection, ensure adherence to aseptic techniques in catheter placement, catheter maintenance, and preparation and administration of intravenous lipid emulsions. Monitor for signs and symptoms of early infections (fever and chills), including laboratory tests that may indicate infection (leukocytosis and hyperglycemia). Frequently assess the parenteral access device and insertion site for edema, redness, and discharge.

    Bone fractures, trauma

    Use intravenous lipid emulsions with caution in trauma patients with bone fractures of the pelvis and long bone as these patients are at high risk for fat embolism.

    Chronic lung disease (CLD), chronic obstructive pulmonary disease (COPD), pulmonary disease, respiratory distress syndrome

    Use soybean oil-based intravenous lipid emulsions with caution in patients with pulmonary disease (i.e., chronic obstructive pulmonary disease (COPD) or chronic lung disease (CLD)) or acute respiratory distress syndrome (ARDS). Alterations in lung function and hemodynamics may occur after administration, due to the proinflammatory properties of soybean oil-based IV lipid emulsions. Clinical practice guidelines recommend withholding or limiting traditional soybean oil-based lipid emulsions in the first week following initiation of parenteral nutrition in critically ill adult patients.

    Pregnancy

    There are no data available on the risks associated with intravenous lipid emulsion during pregnancy. Animal reproduction studies have not been performed with intravenous lipid emulsion, and it is not known if intravenous lipid emulsion can cause fetal harm when administered during pregnancy. Consider the risks and benefits of using intravenous lipid emulsion during pregnancy. Parenteral nutrition should be considered if the pregnant woman’s nutritional requirements cannot be met with oral or enteral intake.

    Breast-feeding

    There are no data available regarding the presence of intravenous lipid emulsion in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother’s clinical need for intravenous lipid emulsion, and any potential adverse effects on the breast-fed infant from intravenous lipid emulsion, or from the underlying maternal condition.

    Bleeding, coagulopathy

    Omegaven (fish oil lipid emulsion) is contraindicated in patients with severe bleeding disorders or coagulopathy due to a potential effect on platelet aggregation. Caution is recommended when using soybean oil-based lipid emulsions in patients with blood coagulation disorders.

    Laboratory test interference

    The lipids contained in the intravenous lipid emulsions may cause laboratory test interference with some laboratory tests such as hemoglobin, lactate dehydrogenase (LDH), bilirubin, and oxygen saturation, if blood is sampled before lipids have cleared from the bloodstream. Lipids are normally cleared 5 to 6 hours after the lipid infusion is stopped. The vitamin K content of intravenous lipid emulsions may counteract anticoagulant activity.

    ADVERSE REACTIONS

    Severe

    cyanosis / Early / 0-1.0
    bradycardia / Rapid / Incidence not known
    apnea / Delayed / Incidence not known
    cholecystitis / Delayed / Incidence not known
    aluminum toxicity / Delayed / Incidence not known

    Moderate

    hypertriglyceridemia / Delayed / 2.0-38.0
    hyperglycemia / Delayed / 2.0-5.0
    hypertension / Early / 3.0-4.0
    chest pain (unspecified) / Early / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    sinus tachycardia / Rapid / 0-1.0
    dyspnea / Early / 0-1.0
    phlebitis / Rapid / 0-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    cholestasis / Delayed / 0-1.0
    neutropenia / Delayed / Incidence not known
    hypertonia / Delayed / Incidence not known
    erythema / Early / Incidence not known
    leukopenia / Delayed / Incidence not known
    hepatomegaly / Delayed / Incidence not known
    splenomegaly / Delayed / Incidence not known
    fat overload syndrome / Delayed / Incidence not known
    parenteral nutrition-associated liver disease / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    cholelithiasis / Delayed / Incidence not known
    steatosis / Delayed / Incidence not known
    bleeding / Early / Incidence not known

    Mild

    nausea / Early / 9.0-11.0
    vomiting / Early / 5.0-7.0
    flatulence / Early / 2.0-4.0
    abdominal pain / Early / 2.0-4.0
    infection / Delayed / 1.0-2.0
    dyspepsia / Early / 2.0-2.0
    leukocytosis / Delayed / 0-1.0
    headache / Early / 0-1.0
    dizziness / Early / 0-1.0
    fever / Early / 0-1.0
    back pain / Delayed / 0-1.0
    rash / Early / 0-1.0
    dysgeusia / Early / 0-1.0
    diaphoresis / Early / 0-1.0
    diarrhea / Early / 0-1.0
    drowsiness / Early / 0-1.0
    flushing / Rapid / 0-1.0
    pruritus / Rapid / 0-1.0
    injection site reaction / Rapid / Incidence not known
    agitation / Early / Incidence not known

    DRUG INTERACTIONS

    Acebutolol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with aspirin. Theoretically, the risk of bleeding may be increased.
    Angiotensin II receptor antagonists: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Angiotensin-converting enzyme inhibitors: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Anticoagulants: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Antithrombin III: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Apixaban: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Argatroban: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Aspirin, ASA: (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with aspirin. Theoretically, the risk of bleeding may be increased.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with aspirin. Theoretically, the risk of bleeding may be increased.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with aspirin. Theoretically, the risk of bleeding may be increased.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with aspirin. Theoretically, the risk of bleeding may be increased.
    Aspirin, ASA; Carisoprodol: (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with aspirin. Theoretically, the risk of bleeding may be increased.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with aspirin. Theoretically, the risk of bleeding may be increased.
    Aspirin, ASA; Dipyridamole: (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with aspirin. Theoretically, the risk of bleeding may be increased.
    Aspirin, ASA; Omeprazole: (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with aspirin. Theoretically, the risk of bleeding may be increased.
    Aspirin, ASA; Oxycodone: (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with aspirin. Theoretically, the risk of bleeding may be increased.
    Aspirin, ASA; Pravastatin: (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with aspirin. Theoretically, the risk of bleeding may be increased.
    Atenolol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Atenolol; Chlorthalidone: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Bendroflumethiazide; Nadolol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Beta-adrenergic blockers: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Betaxolol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Betrixaban: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Bisoprolol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Bivalirudin: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Brimonidine; Timolol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Calcium-channel blockers: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Carteolol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Carvedilol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Central-acting adrenergic agents: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Dabigatran: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Dalteparin: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Danaparoid: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Desirudin: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Dorzolamide; Timolol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Doxazosin: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Edoxaban: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Enoxaparin: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Eplerenone: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Epoprostenol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Esmolol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Fondaparinux: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Heparin: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Labetalol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Lepirudin: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Levobetaxolol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Levobunolol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Loop diuretics: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Metoprolol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Nadolol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Nebivolol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Nebivolol; Valsartan: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Penbutolol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Pentosan: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Phenoxybenzamine: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Phentolamine: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Pindolol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Platelet Inhibitors: (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with other platelet inhibitors. Theoretically, the risk of bleeding may be increased.
    Potassium-sparing diuretics: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Prazosin: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Propranolol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Reserpine: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Rivaroxaban: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Thiazide diuretics: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Thrombolytic Agents: (Moderate) Fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents.
    Timolol: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Tinzaparin: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Vasodilators: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
    Warfarin: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly. (Moderate) Monitor coagulation parameters closely during coadministration. Anticoagulant activity of warfarin may be counteracted by coadministration of intravenous lipid emulsions due to the natural vitamin K content of soybean and olive oils contained in the product.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no data available on the risks associated with intravenous lipid emulsion during pregnancy. Animal reproduction studies have not been performed with intravenous lipid emulsion, and it is not known if intravenous lipid emulsion can cause fetal harm when administered during pregnancy. Consider the risks and benefits of using intravenous lipid emulsion during pregnancy. Parenteral nutrition should be considered if the pregnant woman’s nutritional requirements cannot be met with oral or enteral intake.

    There are no data available regarding the presence of intravenous lipid emulsion in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother’s clinical need for intravenous lipid emulsion, and any potential adverse effects on the breast-fed infant from intravenous lipid emulsion, or from the underlying maternal condition.

    MECHANISM OF ACTION

    Intravenous lipid emulsions (ILEs) are utilized as a source of energy causing an increase in heat production, decrease in respiratory quotient, and increase in oxygen consumption. The most common mechanism of action for energy production derived from fatty acid metabolism is beta oxidation. Fatty acids are important for membrane structure and function, precursors for bioactive molecules (such as prostaglandins), and as regulators for gene expression. ILEs will prevent the biochemical lesions of essential fatty acid deficiency (EFAD) and correct the clinical manifestations of EFAD syndrome. ILEs are oil-in-water emulsions consisting of 1 or more triglyceride-containing oils, a phospholipid emulsifier, and glycerin. Phospholipid emulsifying agents, such as egg phosphatide, produce a barrier to prevent coalescence of oil droplets dispersed in the internal phase of the emulsion. The purpose of the emulsifying agent is to keep the particle size less than 0.5 micrometer. The phospholipid emulsifier provides stability to ILEs by functioning as both a mechanical and electrical barrier. Intravenous lipid emulsions are available as 10% concentration (lipid content of 0.1 g/mL), providing 1.1 kcal/mL, 20% concentration (lipid content of 0.2 g/mL), providing 2 kcal/mL, and 30% concentration (lipid content of 0.3 g/mL), providing 3 kcal/mL.
     
    Lipid Resuscitation Therapy (LRT)
    There are 3 proposed mechanisms for the efficacy of LRT, which include lipid sink sponge: ILEs sequester lipophilic drugs within serum, separating drug molecules from aqueous phase thus removing effects on end-organ tissues; mass action: ILEs provide abundance of free fatty acids as substrate to drive myocyte’s preferred energy pathway, mitochondrial beta-oxidation; and ion channel activation: ILEs activate voltage-gated calcium channels increasing intracellular calcium and cardiac contractility.

    PHARMACOKINETICS

    Lipid emulsions are administered intravenously. The infused fat particles are cleared from the bloodstream in a way thought to be similar to the clearing of naturally produced chylomicrons formed after enteral fat intake. After infusion, there is a transient increase in plasma triglycerides. The triglycerides are hydrolyzed to free fatty acids and glycerol by the enzyme lipoprotein lipase. The free fatty acids either enter the tissues (where they may be oxidized or resynthesized into triglycerides and stored) or circulate in the plasma, bound to albumin. In the liver, circulating free fatty acids are oxidized or converted to very low-density lipoproteins that re-enter the bloodstream. Lipids are normally cleared 5 to 6 hours after the lipid infusion is stopped. Three factors affect the plasma clearance of lipids: phospholipid content (both 20% and 30% intravenous lipid emulsions (ILEs) contain 1.2%), particle size, and infusion rate. Phosphatides are the hydrophobic components of membranes and provide electrically insulated layers. They are involved in the formation of membrane structures. Choline prevents deposition of fat in the liver. Glycerol is metabolized to carbon dioxide and glycogen or is used in the synthesis of body fats. The mean essential fatty acid content of SMOFlipid is 35 mg/mL (range: 28 to 50 mg/mL) of linoleic acid (omega-6) and 4.5 mg/mL (range: 3 to 7 mg/mL) of linolenic acid (omega-3). This represents a linoleic acid content of 14% to 25% and a linolenic content of 1.5% to 3.5%. This compares with 44% to 62% for linoleic acid and 4% to 11% for linolenic acid for soybean oil ILE products. The main fatty acid components of the fish oil in Omegaven are EPA (13% to 26%) and DHA (14% to 27%), which are omega-3 fatty acids. Omegaven also contains 1.5% and 1.1% of linoleic and alpha linolenic acid, respectively. The fish oil component has a total omega-3 fatty acid content of 40% to 54%. The osmolality of Omegaven is 342 mOsm/kg of water which represents an osmolarity of 273 mOsm/L. The osmolality of 20% ILEs is approximately 350 to 390 mOsm/kg of water, which represents an osmolarity of 260 to 280 mOsm/L. The osmolality of 30% ILEs is approximately 310 mOsm/kg of water, representing an osmolarity of 200 mOsm/L. The pH of ILEs ranges from 6 to 9.