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  • CLASSES

    Fibric Acid Derivatives/Fibrates

    DEA CLASS

    Rx

    DESCRIPTION

    Fibrate antilipemic; prodrug hydrolyzed to fenofibroic acid
    Used primarily for hypertriglyceridemia; also for primary hypercholesterolemia or mixed dyslipidemia
    HMG-CoA reductase inhibitors more effective for hypercholesterolemia

    COMMON BRAND NAMES

    Antara, Fenoglide, Lipofen, Lofibra, Tricor, Triglide

    HOW SUPPLIED

    Antara/Fenofibrate/Fenofibrate, Micronized/Lipofen/Lofibra/Tricor Oral Cap: 30mg, 43mg, 50mg, 67mg, 90mg, 130mg, 134mg, 150mg, 200mg
    Fenofibrate/Fenoglide/Lofibra/Tricor/Triglide Oral Tab: 40mg, 48mg, 54mg, 120mg, 145mg, 160mg

    DOSAGE & INDICATIONS

    For use as an adjunct to diet for the treatment of adult patients with severe hypertriglyceridemia.
    NOTE: Fenofibrate tablet and capsule formulations are not bioequivalent.
    NOTE: Fenofibrate was not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus. Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually obviate the need for pharmacologic intervention.
    NOTE: Markedly elevated levels of serum triglycerides (e.g., > 2000 mg/dL) may increase the risk of developing pancreatitis. The effect of fenofibrate therapy on reducing this risk has not been adequately studied.
    Oral dosage (Lipofen capsules- 50 or 150 mg fenofibrate)
    Adults

    Initially, 50—150 mg PO once daily, administered with a meal. Evaluate lipid serum concentrations at 4—8 week intervals. Maximum dosage is 150 mg PO once daily. Consider dosage reduction if serum lipid concentrations fall significantly below target goals.

    Oral dosage (Tricor tablets- 48 or 145 mg fenofibrate)
    Adults

    Initially, 48—145 mg PO once daily, administered without regard to meals. Evaluate lipid serum concentrations at 4—8 week intervals. Maximum dosage is 145 mg/day PO. Consider dosage reduction if serum lipid concentrations fall significantly below target goals.

    Oral dosage (Triglide tablets- 50 or 160 mg fenofibrate)
    Adults

    Initially, 50—160 mg PO once daily, administered without regard to meals. Evaluate lipid serum concentrations at 4—8 week intervals. Maximum dosage is 160 mg/day PO. Consider dosage reduction if serum lipid concentrations fall significantly below target goals.

    Oral dosage (Antara capsules- 30 or 90 mg fenofibrate)
    Adults

    Initially, 30—90 mg PO once daily, administered without regard to meals. Evaluate lipid serum concentrations at 4—8 week intervals. Maximum dosage is 90 mg PO once daily. Consider dosage reduction if serum lipid concentrations fall significantly below target goals.

    Oral dosage (Lofibra capsules or Fenofibrate (micronized) capsules- 67 mg, 134 mg, or 200 mg fenofibrate)
    Adults

    Initially, 67—200 mg PO once daily, administered with a meal. Evaluate lipid serum concentrations at 4—8 week intervals. Maximum dosage is 200 mg PO once daily. Consider dosage reduction if serum lipid concentrations fall significantly below target goals.

    Geriatric

    Initially, 67 mg PO once daily, administered with a meal. If needed, adjust dosage up to 200 mg PO once daily. Evaluate lipid serum concentrations periodically during initial therapy. Consider dosage reduction if serum lipid concentrations fall significantly below target goals. Withdraw therapy in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 200 mg/day.

    Oral dosage (Lofibra tablets or Fenofibrate tablets- 54 or 160 mg fenofibrate)
    Adults

    Initially, 54—160 mg PO once daily, administered with a meal. Evaluate lipid serum concentrations at 4—8 week intervals. Maximum dosage is 160 mg PO once daily. Consider dosage reduction if serum lipid concentrations fall significantly below target goals.

    Geriatric

    Initially, 54 mg PO once daily, administered with a meal. If needed, adjust dosage up to 160 mg PO once daily. Evaluate lipid serum concentrations periodically during initial therapy. Consider dosage reduction if serum lipid concentrations fall significantly below target goals. Withdraw therapy in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 160 mg/day.

    Oral dosage (Fenoglide tablets- 40 or 120 mg fenofibrate)
    Adults

    Initially, 40—120 mg PO once daily, administered with a meal. Evaluate lipid serum concentrations at 4—8 week intervals. Maximum dosage is 120 mg PO once daily. Consider dosage reduction if serum lipid concentrations fall significantly below target goals.

    For use as an adjunct to diet to reduce elevated LDL-cholesterol (LDL-C), total cholesterol (Total-C), triglycerides (TG), and apolipoprotein B (Apo B), and to increase HDL-cholesterol (HDL-C) in adult patients with primary hypercholesterolemia or mixed dyslipidemia.
    NOTE: Fenofibrate tablet and capsule formulations are not bioequivalent.
    NOTE: Fenofibrate was not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus.
    Oral dosage (Lipofen capsules- 50 or 150 mg fenofibrate)
    Adults

    150 mg PO once daily, administered with a meal. Evaluate lipid serum concentrations periodically during initial therapy. Consider dosage reduction if serum lipid concentrations fall significantly below target goals. Withdraw therapy in patients who do not have an adequate response after 2 months of treatment with the maximum recommended dose of 150 mg/day.

    Oral dosage (Tricor tablets- 48 or 145 mg fenofibrate)
    Adults

    145 mg PO once daily, administered without regard to meals. Evaluate lipid serum concentrations periodically during initial therapy. Consider dosage reduction if serum lipid concentrations fall significantly below target goals. Withdraw therapy in patients who do not have an adequate response after 2 months of treatment with the maximum recommended dose of 145 mg/day.

    Oral dosage (Triglide tablets- 50 or 160 mg fenofibrate)
    Adults

    160 mg PO once daily, administered without regard to meals. Evaluate lipid serum concentrations periodically during initial therapy. Consider dosage reduction if serum lipid concentrations fall significantly below target goals. Withdraw therapy in patients who do not have an adequate response after 2 months of treatment with the maximum recommended dose of 160 mg/day.

    Oral dosage (Antara capsules- 30 or 90 mg fenofibrate)
    Adults

    90 mg PO once daily, administered without regard to meals. Evaluate lipid serum concentrations periodically during initial therapy. Consider dosage reduction if serum lipid concentrations fall significantly below target goals. Withdraw therapy in patients who do not have an adequate response after 2 months of treatment with the maximum recommended dose of 90 mg/day.

    Oral dosage (Lofibra capsules or Fenofibrate (micronized) capsules- 67 mg, 134 mg, or 200 mg fenofibrate)
    Adults

    200 mg PO once daily, administered with a meal. Evaluate lipid serum concentrations periodically during initial therapy. Consider dosage reduction if serum lipid concentrations fall significantly below target goals. Withdraw therapy in patients who do not have an adequate response after 2 months of treatment with the maximum recommended dose of 200 mg/day.

    Geriatric

    Initially, 67 mg PO once daily, administered with a meal. If needed, adjust dosage up to 200 mg PO once daily. Evaluate lipid serum concentrations periodically during initial therapy. Consider dosage reduction if serum lipid concentrations fall significantly below target goals. Withdraw therapy in patients who do not have an adequate response after 2 months of treatment with the maximum recommended dose of 200 mg/day.

    Oral dosage (Lofibra tablets or Fenofibrate tablets- 54 or 160 mg fenofibrate)
    Adults

    160 mg PO once daily, administered with a meal. Evaluate lipid serum concentrations periodically during initial therapy. Consider dosage reduction if serum lipid concentrations fall significantly below target goals. Withdraw therapy in patients who do not have an adequate response after 2 months of treatment with the maximum recommended dose of 160 mg/day.

    Geriatric

    Initially, 54 mg PO once daily, administered with a meal. If needed, adjust dosage up to 160 mg PO once daily. Evaluate lipid serum concentrations periodically during initial therapy. Consider dosage reduction if serum lipid concentrations fall significantly below target goals. Withdraw therapy in patients who do not have an adequate response after 2 months of treatment with the maximum recommended dose of 160 mg/day.

    Oral dosage (Fenoglide tablets- 40 or 120 mg fenofibrate)
    Adults

    120 mg PO once daily, administered with a meal. Evaluate lipid serum concentrations periodically during initial therapy. Consider dosage reduction if serum lipid concentrations fall significantly below target goals. Withdraw therapy in patients who do not have an adequate response after 2 months of treatment with the maximum recommended dose of 120 mg/day.

    MAXIMUM DOSAGE

    Adults

    145 mg/day PO for Tricor tablets (new formulation); 160 mg/day PO for Triglide tablets; 200 mg/day for Lofibra capsules; 90 mg/day for Antara capsules; 150 mg/day PO for Lipofen capsules.

    Geriatric

    145 mg/day PO for Tricor tablets (new formulation); 160 mg/day PO for Triglide tablets; 200 mg/day for Lofibra capsules; 90 mg/day for Antara capsules; 150 mg/day PO for Lipofen capsules.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Fenofibrate is contraindicated in patients with hepatic dysfunction, including primary biliary cirrhosis, and in patients with an unexplained persistent liver function abnormality.

    Renal Impairment

    CrCl >= 80 mL/min: No dose adjustment is necessary.
    CrCl 30—80 mL/min: Initially, 48 mg PO once daily for Tricor, 50 mg PO once daily for Triglide or Lipofen formulations, 30 mg PO once daily for Antara capsules, 40 mg once daily for Fenoglide, 54 mg PO once daily for Lofibra tablets, or 67 mg PO once daily for Lofibra capsules. Do not increase dosage until the effects of the initial dosage on renal function and serum lipid concentrations have been fully evaluated.
    CrCl <=30 mL/min: Contraindicated.
     
     
    Intermittent hemodialysis
    Not applicable; fenofibrate is not recommended in patients with severe renal dysfunction. Fenofibrate is not removed during intermittent hemodialysis.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.
     
    NOTE: Patients should be placed on an appropriate lipid-lowering diet before and while receiving fenofibrate. Excess body weight, excess alcohol intake, dietary indiscretion, and poor glycemic control are important factors in conditions of elevated triglycerides and should be addressed prior to instituting fenofibrate therapy.

    Oral Administration
    Oral Solid Formulations

    NOTE: Fenofibrate formulations vary and are not bioequivalent.
    Antara fenofibrate micronized capsules (30 and 90 mg): May administer without regard to meals.
    Generic equivalent to the original Tricor tablet formulation (54 and 160 mg tablets): Administer with meals to optimize bioavailability. NOTE: This original Abbott Tricor brand formulation has been discontinued. A generic equivalent was approved in May 2005; availability is pending.
    Lipofen fenofibrate capsules (50, 100, and 150 mg capsules): Administer with meals to optimize absorption.
    Lofibra fenofibrate micronized capsules (67, 134, and 200 mg): Administer with meals to optimize bioavailability.
    New Tricor formulation of fenofibrate tablets (48 and 145 mg): May administer without regard to meals.
    Triglide tablets, a reformulation of fenofibrate (50 and 160 mg): Instruct patient not to consume chipped or broken tablets. May administer without regard to meals. In a single-dose pharmacokinetics study in healthy volunteers, the Triglide 160 mg tablet was shown to have comparable bioavailability to a single dose of 200 mg fenofibrate capsule, micronized. However, Triglide 160 mg tablet exhibits a 32% higher rate of absorption compared to the 200 mg micronized fenofibrate capsule under low-fat fed conditions. The extent of absorption of Triglide is comparable between fed and fasted conditions; however, food increases the rate of absorption by approximately 55%.

    STORAGE

    Antara:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Fenoglide:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Lipofen:
    - Protect from light
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Lofibra :
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Tricor:
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Triglide:
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Fenofibrate is contraindicated in patients with known hypersensitivity to the drug.
     
    In rodents, one to six times the maximum human dosage of fenofibrate increased the incidence of hepatic and pancreatic cancers. Monkeys have not demonstrated these effects in preclinical studies after 12 months of fenofibrate treatment. In humans, other members of the fibrate class have produced observed peroxisomal morphology changes in liver biopsies. Whether fenofibrate increases the risk of hepatic cancers in humans is unknown, but extensive use of fenofibrate since 1975 has not revealed an association. Fenofibrate has not demonstrated mutagenic potential.

    Cardiac disease

    Findings of important cardiac trials of gemfibrozil and clofibrate may also be applicable to fenofibrate because of the clinical and pharmacologic similarities between fenofibrate and other fibric acid derivatives. In the Helsinki Heart Study, men with known heart disease (secondary prevention group) had a higher trend of cardiac deaths with gemfibrozil versus placebo. Total mortality was found to be elevated in the primary prevention group, despite the effectiveness of gemfibrozil in preventing heart disease. In a study conducted by the WHO, patients without coronary heart disease were treated with clofibrate or placebo for 5 years. There was a significant increase in deaths from non-cardiac causes, including malignancy, post-cholecystectomy complications, and pancreatitis in the clofibrate group. All trials included large numbers of patients treated with fibric acid derivatives for several years. No such trials have been performed for fenofibrate, and the benefit/risk ratio for primary or secondary cardiac disease, or other non-cardiovascular mortality has not been established. Fenofibrate should only be used in the treatment of dyslipidemias where the benefit to the patient would outweigh the potential health risks.

    Biliary cirrhosis, cholelithiasis, gallbladder disease, hepatic disease

    Clofibrate and gemfibrozil have been associated with a higher risk of cholecystitis and cholelithiasis in clinical trials. The association between fenofibrate and gallbladder disease is less defined, but post-marketing studies in Europe suggest that the frequency of gallstones may not be significantly increased with therapy. Fenofibrate does increase the saturation of cholesterol in the bile, and therefore could potentially lead to gallstone formation. Therefore fenofibrate is considered contraindicated in patients with pre-existing gallbladder disease and should not be used in the presence of cholelithiasis, because it may exacerbate these conditions. Fenofibrate is also contraindicated in patients with hepatic disease, including primary biliary cirrhosis and in patients with unexplained persistent liver function abnormalities.

    Dialysis, renal disease, renal failure, renal impairment

    Fenofibrate is contraindicated in severe renal dysfunction including in patients receiving dialysis, with renal failure, or with severe renal disease. Per the manufacturer, fenofibrate accumulates during chronic dosage in these patients and is not removed by hemodialysis. Fenofibrate clearance is also reduced in patients with mild to moderate renal impairment. Rhabdomyolysis and myositis may be increased in patients with impaired renal function who take fibric acid derivatives. Lower doses should be prescribed in patients who have moderate renal dysfunction.

    Anticoagulant therapy

    Caution should be used when prescribing fenofibrate to patients on anticoagulant therapy. Fenofibrate has been demonstrated to potentiate the effects of coumarin-type anticoagulants. (see Drug Interactions).

    Thromboembolic disease

    Caution should be used when fenofibrate is used in patients with thromboembolic disease. Thrombosis has occurred in patients taking fenofibrate.

    Geriatric

    In geriatric volunteers, the oral clearance of fenofibric acid following a single dose was similar to that observed in young adults, suggesting that a similar dosage regimen can be used for geriatric patients. However, some manufacturers recommend a lower initial dosage of fenofibrate in the elderly, which may then be titrated to effect. Because elderly patients are also at increased risk for renal insufficiency, renal monitoring should be considered during fenofibrate therapy. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, fenofibrate requires regular monitoring of liver tests as well as evaluation of the complete blood count (CBC) prior to and after initiation.

    Children, infants, neonates

    The safety and efficacy of fenofibrate have not been established in neonates, infants, children, or adolescents. The NCEP does not recommend pharmaceutical treatment of lipid disorders in children less than 10 years of age.

    Pregnancy

    Fenofibrate is classified as FDA pregnancy category C. Adequate or well-controlled studies have not been done in humans. According to the manufacturer, use of fenofibrate during pregnancy should be avoided unless the potential benefits justify the potential risks to the fetus.

    Breast-feeding

    According to the manufacturer, fenofibrate is contraindicated in breast-feeding women. The importance of continued fenofibrate therapy to the mother should be considered in making the decision whether to discontinue breast-feeding or discontinue the medication. If pharmacotherapy is necessary in the nursing mother, a nonabsorbable resin such as cholestyramine, colesevelam, or colestipol should be considered. These agents do not enter the bloodstream and thusly will not be excreted during lactation. However, resins bind fat-soluble vitamins and prolonged use may result in deficiencies of these vitamins in the mother and her nursing infant.

    Diabetes mellitus

    Patients with diabetes mellitus are at increased risk for serious muscle toxicity, including myopathy and rhabdomyolysis, when treated with fibrate therapy. Additionally, because fenofibrate therapy has been associated with elevations in serum creatinine, renal monitoring should be considered in patients at increased risk for renal impairment including those with diabetes. Of note, fenofibrate was not shown to reduce coronary heart disease morbidity and mortality in a large, randomized controlled trial of patients with type 2 diabetes mellitus.

    Hypothyroidism

    Use fenofibrate cautiously in those patients with hypothyroidism. The risk for fenofibrate-associated serious muscle toxicity, including myopathy and rhabdomyolysis, appears to be increased in patients with hypothyroidism.

    ADVERSE REACTIONS

    Severe

    thrombosis / Delayed / 1.0-1.0
    pulmonary embolism / Delayed / 1.0-1.0
    peptic ulcer / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    cholecystitis / Delayed / Incidence not known
    cirrhosis / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    atrial fibrillation / Early / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known

    Moderate

    elevated hepatic enzymes / Delayed / 3.0-13.0
    constipation / Delayed / 2.1-2.1
    colitis / Delayed / Incidence not known
    esophagitis / Delayed / Incidence not known
    gastritis / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    skin ulcer / Delayed / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    cholelithiasis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    myasthenia / Delayed / Incidence not known
    myopathy / Delayed / Incidence not known
    lymphadenopathy / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    hypertonia / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    migraine / Early / Incidence not known
    palpitations / Early / Incidence not known
    angina / Early / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    hypertension / Early / Incidence not known
    phlebitis / Rapid / Incidence not known
    blurred vision / Early / Incidence not known
    amblyopia / Delayed / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    cataracts / Delayed / Incidence not known
    hyperuricemia / Delayed / Incidence not known
    gout / Delayed / Incidence not known
    candidiasis / Delayed / Incidence not known
    nephrolithiasis / Delayed / Incidence not known
    dysuria / Early / Incidence not known
    cystitis / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    peripheral edema / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    decreased HDL cholesterol (HDL-C) concentration / Delayed / Incidence not known

    Mild

    abdominal pain / Early / 4.6-4.6
    back pain / Delayed / 3.4-3.4
    headache / Early / 3.2-3.2
    diarrhea / Early / 2.3-2.3
    nausea / Early / 2.3-2.3
    rhinitis / Early / 2.3-2.3
    asthenia / Delayed / 2.1-2.1
    rash (unspecified) / Early / 1.4-1.4
    urticaria / Rapid / 1.1-1.1
    dyspepsia / Early / Incidence not known
    appetite stimulation / Delayed / Incidence not known
    flatulence / Early / Incidence not known
    xerostomia / Early / Incidence not known
    vomiting / Early / Incidence not known
    eructation / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    acne vulgaris / Delayed / Incidence not known
    fever / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    diaphoresis / Early / Incidence not known
    photosensitivity / Delayed / Incidence not known
    skin irritation / Early / Incidence not known
    maculopapular rash / Early / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    weakness / Early / Incidence not known
    muscle cramps / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    malaise / Early / Incidence not known
    ecchymosis / Delayed / Incidence not known
    drowsiness / Early / Incidence not known
    libido decrease / Delayed / Incidence not known
    vertigo / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    dizziness / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    insomnia / Early / Incidence not known
    sinusitis / Delayed / Incidence not known
    pharyngitis / Delayed / Incidence not known
    infection / Delayed / Incidence not known
    laryngitis / Delayed / Incidence not known
    cough / Delayed / Incidence not known
    gynecomastia / Delayed / Incidence not known
    increased urinary frequency / Early / Incidence not known
    weight loss / Delayed / Incidence not known
    weight gain / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acarbose: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Albiglutide: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of incretin mimetics through increased insulin sensitivity and decreased glucagon secretion. Patients receiving this combination should be monitored for changes in glycemic control.
    Alogliptin: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Alogliptin; Metformin: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Alogliptin; Pioglitazone: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion; monitor for changes in glycemic control and for needed dose adjustments.
    Alpha-glucosidase Inhibitors: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Amlodipine; Atorvastatin: (Major) Use caution when coadministering atorvastatin and fenofibrate. Using lower starting and maintenance doses of atorvastatin should be considered. The risk of myopathy increases when HMG-CoA reductase inhibitors are administered concurrently with fibric acid derivatives. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Aspirin, ASA; Pravastatin: (Major) The risk of myopathy during treatment with other HMG-CoA reductase inhibitors is generally increased with concurrent therapy with fibric acid derivatives. The use of fibrates alone may occasionally be associated with myopathy. Combination therapy with pravastatin and gemfibrozil is generally not recommended. The combined use of pravastatin and fibrates should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination. Preliminary data suggest that the addition of gemfibrozil to therapy with pravastatin is not associated with greater reduction in LDL-cholesterol than that achieved with pravastatin alone. Pravastatin and gemfibrozil have been administered together in a study of 290 patients, with two patients developing asymptomatic elevations of CPK; severe myopathy was not observed, although muscle biopsies were not performed. In addition, a trial of pravastatin (40 mg/day) coadministration with gemfibrozil (1200 mg/day) has not been shown to be associated with myopathy, although 4 of 75 patients receiving the combination showed marked CPK elevations versus 1 of 73 patients receiving placebo. A trend has been reported toward more frequent CPK elevations and patient withdrawals due to musculoskeletal symptoms in the group receiving combined treatment as compared to the groups receiving placebo, gemfibrozil, or pravastatin monotherapy. In a crossover study in 20 healthy male volunteers given concomitant single doses of pravastatin and gemfibrozil, there was a significant decrease in urinary excretion and protein binding of pravastatin. In addition, there was a significant increase in AUC, Cmax, and Tmax for the pravastatin metabolite SQ 31,906.
    Atorvastatin: (Major) Use caution when coadministering atorvastatin and fenofibrate. Using lower starting and maintenance doses of atorvastatin should be considered. The risk of myopathy increases when HMG-CoA reductase inhibitors are administered concurrently with fibric acid derivatives. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Atorvastatin; Ezetimibe: (Major) Use caution when coadministering atorvastatin and fenofibrate. Using lower starting and maintenance doses of atorvastatin should be considered. The risk of myopathy increases when HMG-CoA reductase inhibitors are administered concurrently with fibric acid derivatives. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. (Moderate) Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis.
    Canagliflozin: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Canagliflozin; Metformin: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Chenodiol: (Major) Fibric acid derivatives (i.e., clofibrate and perhaps other lipid-lowering fibrate drugs) increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of chenodiol.
    Cholestyramine: (Minor) Cholestyramine can potentially reduce the oral bioavailability of fenofibrate if these agents are administered together. Patients should take fenofibrate at least 1 hour before or 4 to 6 hours after a bile acid resin to avoid affecting the bioavailability of fenofibrate.
    Colchicine: (Moderate) Concurrent administration of colchicine and fibric acid derivatives may result in the development of myotoxicity (i.e., muscle pain and weakness, rhabdomyolysis). The pharmacokinetic and/or pharmacodynamic mechanism of this interaction is not clear; however, both colchicine and fibric acid derivatives are associated with the development of myotoxicity and concurrent use may increase the risk of myotoxicity. If such agents are co-administered, advise patients to report signs and symptoms of myotoxicity including muscle tenderness, pain, or weakness; monitoring creatine phosphokinase may not predict the development of severe myopathy.
    Colestipol: (Major) Based on reported interactions with gemfibrozil, colestipol or cholestyramine can potentially reduce the oral bioavailability of fenofibrate if these agents are administered together. Although the presence of a drug interaction is uncertain, patients should take fenofibrate at least 1 hour before or 4 to 6 hours after a bile acid resin to avoid affecting the bioavailability of fenofibrate.
    Cyclosporine: (Moderate) The use of fibric acid derivatives, such as fenofibrate, may potentiate the risk for renal dysfunction with cyclosporine. During the concomitant use of a drug that may exhibit additive or synergistic renal impairment with cyclosporine, close monitoring of renal function (in particular serum creatinine) and cyclosporine levels should be performed. If a significant impairment of renal function occurs, the dosage of the coadministered drug should be reduced or an alternative treatment considered.
    Dapagliflozin: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion; monitor for changes in glycemic control and for needed dose adjustments. Gemfibrozil increases the systemic exposure of pioglitazone or rosiglitazone. Administration of 600 mg of gemfibrozil twice daily with pioglitazone 30 mg/day resulted in a higher pioglitazone exposure of 226%. If coadministered with a strong CYP2C8 inhibitor like gemfibrozil, the maximum recommended dose of pioglitazone is 15 mg daily.
    Dapagliflozin; Metformin: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion; monitor for changes in glycemic control and for needed dose adjustments. Gemfibrozil increases the systemic exposure of pioglitazone or rosiglitazone. Administration of 600 mg of gemfibrozil twice daily with pioglitazone 30 mg/day resulted in a higher pioglitazone exposure of 226%. If coadministered with a strong CYP2C8 inhibitor like gemfibrozil, the maximum recommended dose of pioglitazone is 15 mg daily.
    Dapagliflozin; Saxagliptin: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion; monitor for changes in glycemic control and for needed dose adjustments. Gemfibrozil increases the systemic exposure of pioglitazone or rosiglitazone. Administration of 600 mg of gemfibrozil twice daily with pioglitazone 30 mg/day resulted in a higher pioglitazone exposure of 226%. If coadministered with a strong CYP2C8 inhibitor like gemfibrozil, the maximum recommended dose of pioglitazone is 15 mg daily.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of fenofibrate with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in increased dasabuvir plasma concentrations. Fenofibrate is a mild inhibitor of the hepatic isoenzyme CYP2C8; dasabuvir is metabolized by this enzyme. Monitor for adverse effects if these drugs are administered together.
    Dronabinol, THC: (Major) Use caution if coadministration of dronabinol with fenofibrate is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; fenofibrate is a moderate inhibitor of CYP2C9. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Dulaglutide: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of incretin mimetics through increased insulin sensitivity and decreased glucagon secretion. Patients receiving this combination should be monitored for changes in glycemic control.
    Empagliflozin: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Empagliflozin; Linagliptin: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents, such as linagliptin, should be monitored for changes in glycemic control.
    Empagliflozin; Metformin: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Exenatide: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of incretin mimetics through increased insulin sensitivity and decreased glucagon secretion. Patients receiving this combination should be monitored for changes in glycemic control.
    Ezetimibe: (Moderate) Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis.
    Ezetimibe; Simvastatin: (Major) Fenofibrate and simvastatin should administered concomitantly only with caution. Fenofibrate may increase the risk of myopathy, rhabdomyolysis, and acute renal failure; this risk is increased with higher doses of simvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. (Moderate) Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis.
    Fluvastatin: (Major) Use caution when coadministering fluvastatin and fenofibrate. The risk of myopathy increases when HMG-Co-A reductase inhibitors ('statins'), including fluvastatin, are administered concurrently with fibric acid derivatives. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Glimepiride; Pioglitazone: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion; monitor for changes in glycemic control and for needed dose adjustments.
    Glimepiride; Rosiglitazone: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Additionally, gemfibrozil has been reported to increase the plasma concentrations of rosiglitazone; the mechanism is probably inhibition of CYP2C8-mediated metabolism of rosiglitazone by gemfibrozil. A randomized crossover trial in healthy volunteers studied the effects of gemfibrozil 600 mg or placebo twice daily for 4 days, with a single 4 mg dose of rosiglitazone administered on day 3. Gemfibrozil increased rosiglitazone mean AUC by 2.3-fold and prolonged the elimination half-life from 3.6 to 7.6 hours. The rosiglitazone Cmax was increased 1.2-fold and the concentration measured 24 hours after dosing was increased 9.8-fold. There are no published reports of the potential clinical effects of this interaction. Concomitant administration of the two drugs may enhance rosiglitazone efficacy, but may also increase the risk of adverse effects. If antidiabetic agents are coadministered with gemfibrozil, it would be prudent to carefully monitor glycemic control and for signs and symptoms of adverse effects; dosage adjustment of antidiabetic agents may be necessary.
    Glipizide; Metformin: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Glyburide; Metformin: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Incretin Mimetics: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of incretin mimetics through increased insulin sensitivity and decreased glucagon secretion. Patients receiving this combination should be monitored for changes in glycemic control.
    Insulin Degludec; Liraglutide: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of incretin mimetics through increased insulin sensitivity and decreased glucagon secretion. Patients receiving this combination should be monitored for changes in glycemic control.
    Insulin Glargine; Lixisenatide: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of incretin mimetics through increased insulin sensitivity and decreased glucagon secretion. Patients receiving this combination should be monitored for changes in glycemic control.
    Insulins: (Moderate) Monitor patients receiving fibric acid derivatives concomitantly with insulin for changes in glycemic control. Fibric acid derivatives may enhance the hypoglycemic effects of insulin or other antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Ixabepilone: (Minor) Fenofibrate is an inhibitor of P-glycoprotein (Pgp). Ixabepilone is a Pgp substrate, and concomitant use of ixabepilone with a Pgp inhibitor may cause an increase in ixabepilone concentrations. Caution is recommended if ixabepilone is coadministered with a Pgp inhibitor.
    Lesinurad: (Moderate) Use lesinurad and fenofibrate together with caution; fenofibrate may increase the systemic exposure of lesinurad. Fenofibrate is an inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate.
    Lesinurad; Allopurinol: (Moderate) Use lesinurad and fenofibrate together with caution; fenofibrate may increase the systemic exposure of lesinurad. Fenofibrate is an inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate.
    Linagliptin: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents, such as linagliptin, should be monitored for changes in glycemic control.
    Linagliptin; Metformin: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents, such as linagliptin, should be monitored for changes in glycemic control.
    Liraglutide: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of incretin mimetics through increased insulin sensitivity and decreased glucagon secretion. Patients receiving this combination should be monitored for changes in glycemic control.
    Lixisenatide: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of incretin mimetics through increased insulin sensitivity and decreased glucagon secretion. Patients receiving this combination should be monitored for changes in glycemic control.
    Lovastatin: (Major) Concurrent use of fenofibrate and lovastatin may increase the risk of myopathy, rhabdomyolysis, and acute renal failure. The serious risk of myopathy and rhabdomyolysis should be weighed carefully against the benefit of further alteration in lipid concentrations by the combined use of fenofibrate or fenofibric acid and lovastatin.
    Lovastatin; Niacin: (Major) Concurrent use of fenofibrate and lovastatin may increase the risk of myopathy, rhabdomyolysis, and acute renal failure. The serious risk of myopathy and rhabdomyolysis should be weighed carefully against the benefit of further alteration in lipid concentrations by the combined use of fenofibrate or fenofibric acid and lovastatin.
    Metformin: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Metformin; Pioglitazone: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion; monitor for changes in glycemic control and for needed dose adjustments.
    Metformin; Repaglinide: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Metformin; Rosiglitazone: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Additionally, gemfibrozil has been reported to increase the plasma concentrations of rosiglitazone; the mechanism is probably inhibition of CYP2C8-mediated metabolism of rosiglitazone by gemfibrozil. A randomized crossover trial in healthy volunteers studied the effects of gemfibrozil 600 mg or placebo twice daily for 4 days, with a single 4 mg dose of rosiglitazone administered on day 3. Gemfibrozil increased rosiglitazone mean AUC by 2.3-fold and prolonged the elimination half-life from 3.6 to 7.6 hours. The rosiglitazone Cmax was increased 1.2-fold and the concentration measured 24 hours after dosing was increased 9.8-fold. There are no published reports of the potential clinical effects of this interaction. Concomitant administration of the two drugs may enhance rosiglitazone efficacy, but may also increase the risk of adverse effects. If antidiabetic agents are coadministered with gemfibrozil, it would be prudent to carefully monitor glycemic control and for signs and symptoms of adverse effects; dosage adjustment of antidiabetic agents may be necessary.
    Metformin; Saxagliptin: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Metformin; Sitagliptin: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Miglitol: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Nateglinide: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Niacin; Simvastatin: (Major) Fenofibrate and simvastatin should administered concomitantly only with caution. Fenofibrate may increase the risk of myopathy, rhabdomyolysis, and acute renal failure; this risk is increased with higher doses of simvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Paclitaxel: (Minor) Paclitaxel is a substrate of CYP2C8, and fenofibrate is a CYP2C8 inhibitor. If coadministration is necessary, use caution and monitor for increased paclitaxel side effects, including myelosuppression and peripheral neuropathy.
    Pioglitazone: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion; monitor for changes in glycemic control and for needed dose adjustments.
    Pitavastatin: (Major) The use of fibrates alone, including fenofibrate, may occasionally be associated with myositis, myopathy, or rhabdomyolysis. Concurrent use of fenofibrate and HMG-CoA reductase inhibitors (Statins) has been associated with increases in creatine kinase (CK), an increased risk of rhabdomyolysis, and myoglobinuria leading to acute renal failure. In a single-dose drug interaction study in 23 healthy adults, concomitant administration of fenofibrate (201 mg) with pravastatin (40 mg) resulted in an increase in the mean Cmax and AUC values for pravastatin by 13%. The mean Cmax and AUC for 3-alpha-hydroxy-iso-pravastatin increased by 29% and 26%, respectively. In another drug interaction study, the coadministration of fenofibrate and pravastatin (40 mg) for 10 days resulted in an increase in the mean Cmax and AUC values for pravastatin by 36% and 28%, respectively, and for the metabolite, 3-alpha-hydroxy-iso-pravastatin, by 55% and 39%, respectively. The coadministration of a single dose of fenofibrate and a single dose of fluvastatin resulted in a small increase (approximately 15% to 16%) in exposure to (+)3R,5S-fluvastatin, the active enantiomer of fluvastatin. A single dose of either pravastatin or fluvastatin had no clinically important effect on the pharmacokinetics of fenofibric acid. Concomitant administration of fenofibrate with atorvastatin 20 mg once daily for 10 days resulted in a 17% decrease in atorvastatin AUC values in 22 healthy males. The atorvastatin Cmax values were not significantly affected by fenofibrate. The pharmacokinetics of fenofibric acid were not significantly affected by atorvastatin. Based on studies in other fibrate treated patients, myopathy can occur from 3 weeks to several months after initiating the combined therapy. The combined use of fenofibrate and HMG-CoA reductase inhibitors should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination. It is unknown whether any potential benefit in blood lipids derived from concomitant use would outweigh the potential risks. If fenofibrate and HMG-CoA reductase inhibitors are prescribed together, serum CK levels should be monitored closely during the initial weeks of therapy, but there is no assurance that periodic CK levels will prevent the occurrence of myopathy or renal dysfunction. Patients on fenofibrate should be instructed to report any complaints of muscle pain, tenderness, or weakness to their health care professional immediately. Patients complaining of muscle pain, tenderness, or weakness should have prompt medical evaluation for myopathy, including CK level determination. If myopathy or myositis is suspected or diagnosed, fenofibrate should be stopped.
    Pramlintide: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Pravastatin: (Major) The risk of myopathy during treatment with other HMG-CoA reductase inhibitors is generally increased with concurrent therapy with fibric acid derivatives. The use of fibrates alone may occasionally be associated with myopathy. Combination therapy with pravastatin and gemfibrozil is generally not recommended. The combined use of pravastatin and fibrates should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination. Preliminary data suggest that the addition of gemfibrozil to therapy with pravastatin is not associated with greater reduction in LDL-cholesterol than that achieved with pravastatin alone. Pravastatin and gemfibrozil have been administered together in a study of 290 patients, with two patients developing asymptomatic elevations of CPK; severe myopathy was not observed, although muscle biopsies were not performed. In addition, a trial of pravastatin (40 mg/day) coadministration with gemfibrozil (1200 mg/day) has not been shown to be associated with myopathy, although 4 of 75 patients receiving the combination showed marked CPK elevations versus 1 of 73 patients receiving placebo. A trend has been reported toward more frequent CPK elevations and patient withdrawals due to musculoskeletal symptoms in the group receiving combined treatment as compared to the groups receiving placebo, gemfibrozil, or pravastatin monotherapy. In a crossover study in 20 healthy male volunteers given concomitant single doses of pravastatin and gemfibrozil, there was a significant decrease in urinary excretion and protein binding of pravastatin. In addition, there was a significant increase in AUC, Cmax, and Tmax for the pravastatin metabolite SQ 31,906.
    Raltegravir: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as fibric acid derivatives.
    Red Yeast Rice: (Major) Since compounds in red yeast rice are chemically similar to and possess actions similar to lovastatin, patients should avoid this dietary supplement if they currently take drugs known to increase the risk of myopathy (e.g., fibric acid derivatives (gemfibrozil, fenofibrate, clofibrate)) when coadministered with HMG-CoA reductase inhibitors.
    Repaglinide: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Rosiglitazone: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Additionally, gemfibrozil has been reported to increase the plasma concentrations of rosiglitazone; the mechanism is probably inhibition of CYP2C8-mediated metabolism of rosiglitazone by gemfibrozil. A randomized crossover trial in healthy volunteers studied the effects of gemfibrozil 600 mg or placebo twice daily for 4 days, with a single 4 mg dose of rosiglitazone administered on day 3. Gemfibrozil increased rosiglitazone mean AUC by 2.3-fold and prolonged the elimination half-life from 3.6 to 7.6 hours. The rosiglitazone Cmax was increased 1.2-fold and the concentration measured 24 hours after dosing was increased 9.8-fold. There are no published reports of the potential clinical effects of this interaction. Concomitant administration of the two drugs may enhance rosiglitazone efficacy, but may also increase the risk of adverse effects. If antidiabetic agents are coadministered with gemfibrozil, it would be prudent to carefully monitor glycemic control and for signs and symptoms of adverse effects; dosage adjustment of antidiabetic agents may be necessary.
    Rosuvastatin: (Major) HMG-CoA reductase inhibitors have been administered safely with fibric acid derivatives in some patients; however the risk of potential myopathy is considerably higher during concurrent therapy. Combination therapy with HMG-CoA reductase inhibitors, such as rosuvastatin and gemfibrozil has been associated with a significantly enhanced risk of myopathy and rhabdomyolysis. When possible, avoid concurrent use of HMG-reductase inhibitors with fibrates. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. If rosuvastatin must be used concurrently with gemfibrozil, limit the rosuvastatin dose to 10 mg/day.
    Saxagliptin: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Simvastatin: (Major) Fenofibrate and simvastatin should administered concomitantly only with caution. Fenofibrate may increase the risk of myopathy, rhabdomyolysis, and acute renal failure; this risk is increased with higher doses of simvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Simvastatin; Sitagliptin: (Major) Fenofibrate and simvastatin should administered concomitantly only with caution. Fenofibrate may increase the risk of myopathy, rhabdomyolysis, and acute renal failure; this risk is increased with higher doses of simvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined 'statin' and fibrate therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Sitagliptin: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control.
    Sulfonylureas: (Moderate) Fibric acid derivatives may enhance the hypoglycemic effects antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. Patients receiving these drugs concomitantly with antidiabetic agents should be monitored for changes in glycemic control. In addition, fenofibrate may displace glyburide from protein binding sites which may lead to enhanced hypoglycemic action.
    Tacrolimus: (Moderate) Coadministration of fenofibrate and tacrolimus may result in deterioration of renal function. Tacrolimus can produce nephrotoxicity with decreases in creatinine clearance and increaess in serum creatinine. Because the primary elimination route of fenofibrate is renal excretion, the benefits and risks of using fenofibrate with tacrolimus should be carefully considered, and the lowest effective dose employed with monitoring of renal function.
    Tamoxifen: (Moderate) Fenofibrate is a moderate CYP2C9 and mild CYP2C19 inhibitor. Tamoxifen is metabolized by CYP3A4 and CYP2D6, and to a smaller extent by CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Theoretically, concomitant use of fenofibrate and tamoxifen may result in decreased concentrations of the active metabolites of tamoxifen; the clinical significance of this interaction is not known.
    Telbivudine: (Moderate) The risk of myopathy may be increased if a fibric acid derivative is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Ursodeoxycholic Acid, Ursodiol: (Major) Fibric acid derivatives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of ursodeoxycholic acid, ursodiol.
    Warfarin: (Moderate) Fenofibrate potentiates the effects of warfarin and other oral anticoagulants, resulting in increased prothrombin times. Fibrates have been shown to decrease vitamin K dependent coagulation factor synthesis. Since these drugs are also highly protein-bound, it is possible that fenofibrate displaces warfarin from protein-binding sites as a potential mechanism. Case reports of significant effects on warfarin exist for all fibrate drugs. Three clinical case reports of fenofibrate and warfarin interactions have been reported in post-marketing surveillance of fenofibrate in the US and Europe. In one case, a 47 year old male who had been stable over a course of 20 weeks on his prescribed warfarin dose was admitted to the hospital one week after beginning treatment for hypertriglyceridemia with fenofibrate 201 mg/day. He presented with epigastric discomfort and hematuria. His INR on admission was > 8.5 (previously stabilized at 2 to 2.5 prior to fenofibrate). The patient received treatment with phytonadione and discontinuation of the medications. He was discharged 2 days later, but agreed to be rechallenged under a controlled protocol to confirm the interaction of the fenofibrate with his warfarin. After stabilization of his warfarin dose for 3 weeks, fenofibrate was restarted, and the patient was rechallenged on 2 occasions. Both times, an increase in INR above the therapeutic range occurred. Patients receiving warfarin in conjunction with fenofibrate should have frequent prothrombin time and INR determinations until it has been determined that the INR has been stabilized. A reduction in warfarin dose may be necessary.

    PREGNANCY AND LACTATION

    Pregnancy

    Fenofibrate is classified as FDA pregnancy category C. Adequate or well-controlled studies have not been done in humans. According to the manufacturer, use of fenofibrate during pregnancy should be avoided unless the potential benefits justify the potential risks to the fetus.

    According to the manufacturer, fenofibrate is contraindicated in breast-feeding women. The importance of continued fenofibrate therapy to the mother should be considered in making the decision whether to discontinue breast-feeding or discontinue the medication. If pharmacotherapy is necessary in the nursing mother, a nonabsorbable resin such as cholestyramine, colesevelam, or colestipol should be considered. These agents do not enter the bloodstream and thusly will not be excreted during lactation. However, resins bind fat-soluble vitamins and prolonged use may result in deficiencies of these vitamins in the mother and her nursing infant.

    MECHANISM OF ACTION

    Many of the lipid-modifications of fenofibrate are thought to be mediated by activation of peroxisome proliferator activated receptors (PPARs). PPARs function to alter the transciption of genes involved in lipoprotein metabolism, especially those for apolipoproteins. Modulation of apolipoproteins alters the binding of lipoproteins to cellular receptors and the interaction of lipoproteins with enzymes. The pharmacologic results are complex.
     
    Fenofibrate induces lipoprotein lipase and decreases hepatic production of apolipoprotein CIII via PPAR activity, which enhances plasma catabolism and clearance of triglyceride-rich particles. Fatty acid oxidation is enhanced by fenofibrate activation of acyl CoA synthetase and other enzymes. Inhibition of acetyl-CoA carboxylase and fatty acid synthetase activity by fenofibrate further decreases synthesis of triglycerides. The result is a marked reduction in plasma triglyceride and VLDL levels.
     
    Fenofibrate appears to produce favorable changes in LDL, HDL, and total cholesterol. Fenofibrate appears to favorably affect LDL subfraction ratios. Fenofibrate increases the production of larger and less dense LDL fractions, which appears to promote LDL metabolism via the nonatherogenic receptor pathways. Small, dense LDL particles, which have been associated with atherosclerosis, are reduced in comparison. Lipoprotein a (LPa), a variant form of LDL, is also reduced by fenofibrate. Net LDL levels are usually reduced or unchanged. The greatest LDL reductions occur in patients with type IIa or IIb dyslipidemias. Fenofibrate appears to increase HDL cholesterol via increased transcription of genes for apolipoproteins AI and AII by PPAR, and via decreased activity of cholesteryl ester transfer protein. Fenofibrate may also decrease cholesterol synthesis and may increase the mobilization of cholesterol from arterial and peripheral tissues. Xanthomas and xanthelasmas have regressed during treatment with fenofibrate. There is some preliminary evidence of regression of atherosclerosis. Like other fibrates, fenofibrate causes a relative rise in the proportion of cholesterol to bile acids in the bile.
     
    Fenofibrate has other pharmacologic effects that may have positive benefits in patients with hyperlipoproteinemia. Fenofibrate reduces serum fibrinogen, an independent risk factor for thrombosis. Fenofibrate also increases the urinary excretion of uric acid, which is debated as a cardiac risk factor in patients with type IV hyperlipoproteinemia.

    PHARMACOKINETICS

    Fenofibrate is administered orally. It is a prodrug that is rapidly and completely hydrolyzed by plasma esterases to fenofibric acid following oral administration. Fenofibrate is highly (> 99%) protein-bound, primarily to albumin. Fenofibric acid is primarily conjugated with glucuronic acid. Approximately 60% of a dose is excreted in the urine, and 25% excreted in the feces. The elimination half-life of fenofibrate is 20 hours in patients with normal renal function.
     
    Affected cytochrome P450 isoenzymes: CYP2C8, CYP2C9, CYP2C19, CYP2A6
    Fenofibrate and fenofibric acid are weak inhibitors of CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations. Fenofibrate is not metabolized by CYP isoenzymes.
     

    Oral Route

    Peak concentrations of fenofibric acid generally occur within 4—6 hours of oral fenofibrate administration.
    Fenofibrate micronized capsules (Lofibra  formulation): Absorption is increased by approximately 35% under fed as compared to fasting conditions. This formulation is 30% more bioavailable than a non-micronized preparation that was never marketed in the US; based on blood levels, 67 mg of micronized fenofibrate is equivalent to 100 mg of the non-micronized formulation. Administer this formulation with a meal.
    Fenofibrate micronized capsules (Antara  formulation): Peak plasma concentrations of fenofibric acid from Antara 90 mg capsules occur within 2—6 hours after administration. In the presence of a high-fat meal, there is a 26.7% increase in AUC and 15.35%% increase in Cmax relative to fasting state. This formulation can be taken without regard to meals.
    Fenofibrate 54 and 160 mg tablets (original Tricor  tablet formulation): This formulation has increased bioavailability relative to the capsule formulation. Plasma concentrations following administration of the 54 and 160 mg tablets are equivalent under fed conditions to the 67 and 200 mg capsules, respectively. Bioavailability of the 54 and 160 mg tablets is further enhanced by administration with food. NOTE: Tricor 54 and 160 mg tablets are not currently available. In May 2005, generic equivalents were approved by the FDA. 
    Fenofibrate 48 and 145 mg tablets (new Tricor tablet formulation): The AUC and Cmax of fenofibrate 145 mg are not significantly different when administered under fasting versus nonfasting conditions. Plasma concentrations after administration of three 48 mg or one 145 mg tablets are equivalent under fed conditions to one 200 mg capsule. This formulation (approved November 2004) can be administered without regard to meals.
    Fenofibrate 50 and 160 mg tablets (Triglide tablet formulation): In a single-dose pharmacokinetics study in healthy volunteers, the 160 mg tablet has been shown to have comparable bioavailability to a single dose of 200 mg fenofibrate micronized capsule. However, the 160 mg tablet exhibits a 32% higher rate of absorption compared to the 200 mg micronized capsule under low-fat fed conditions. The extent of absorption of Triglide is comparable between fed and fasted conditions; however, food increases the rate of absorption by approximately 55%. According to the manufacturer, this dosage formulation may be taken without regard to meals.
    Fenofibrate 50 and 150 mg capsules (Lipofen formulation): The extent and rate of absorption after administration of 150 mg Lipofen capsules are equivalent under low-fat and high-fat fed conditions to 160 mg Tricor tablets. Administer this formulation with a meal.