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    Fibric Acid Derivatives/Fibrates

    DEA CLASS

    Rx

    DESCRIPTION

    Fibrate antilipemic; active metabolite of fenofibrate.
    Lowers serum triglycerides; used primarily for hypertriglyceridemia; also for primary hypercholesterolemia or mixed dyslipidemia.
    No benefit on cardiovascular morbidity and mortality over statin monotherapy has been established; not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus.

    COMMON BRAND NAMES

    Fibricor, Trilipix

    HOW SUPPLIED

    Fenofibric Acid/Fibricor Oral Tab: 35mg, 105mg
    Fenofibric Acid/Trilipix Oral Cap DR Pellets: 45mg, 135mg

    DOSAGE & INDICATIONS

    For use as an adjunct to diet in the treatment of hyperlipoproteinemia or hypertriglyceridemia.
    NOTE: Patients should be placed on an appropriate lipid-lowering diet before and while receiving fenofibric acid. 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 fenofibric acid therapy.
    NOTE: Fenofibric acid is not indicated for patients who have elevated chylomicrons and triglycerides, but who have normal VLDL concentrations.
    NOTE: One delayed-release capsule of fenofibric acid 135 mg produces plasma concentrations equivalent to one 200 mg capsule of micronized fenofibrate administered under fed conditions.
    For the treatment of severe hypertriglyceridemia.
    Oral dosage (fenofibric acid delayed-release capsules, TriLipix)
    Adults

    45—135 mg PO once daily. If needed, dosage may be adjusted at 4—8 week intervals to a maximum dosage of 135 mg PO once daily.

    Geriatric

    Exercise caution in geriatric patients due to a higher frequency of decreased renal function in this population. Dosage selection should be made based on renal function.

    Oral dosage (fenofibric acid tablets, Fibricor)
    Adults

    35—105 mg PO once daily. If needed, dosage may be adjusted at 4—8 week intervals to a maximum dosage of 105 mg PO once daily.

    Geriatric

    Exercise caution in geriatric patients due to a higher frequency of decreased renal function in this population. Dosage selection should be made based on renal function.

    For the treatment of primary hyperlipidemia or mixed dyslipidemia (e.g., to reduce elevated LDL-C, total cholesterol, triglycerides and apolipoprotein B and to increase HDL-C).
    Oral dosage (fenofibric acid delayed-release capsules, TriLipix)
    Adults

    135 mg PO once daily.

    Geriatric

    Exercise caution in geriatric patients due to a higher frequency of decreased renal function in this population. Dosage selection should be made based on renal function.

    Oral dosage (fenofibric acid tablets, Fibricor)
    Adults

    105 PO once daily.

    Geriatric

    Exercise caution in geriatric patients due to a higher frequency of decreased renal function in this population. Dosage selection should be made based on renal function.

    MAXIMUM DOSAGE

    Adults

    135 mg/day PO of fenofibric acid delayed-release capsules (TriLipix); 105 mg/day PO fenofibric acid tablets (Fibricor).

    Elderly

    135 mg/day PO of fenofibric acid delayed-release capsules (TriLipix); 105 mg/day PO fenofibric acid tablets (Fibricor).

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Fenofibric acid is contraindicated in patients with active liver disease, including primary biliary cirrhosis, and in patients with an unexplained persistent liver function abnormality.

    Renal Impairment

    CrCl > 80 mL/min: No dosage adjustment is necessary.
    CrCl 30—80 mL/min: Initially, 35 mg fenofibric acid tablets (Fibricor) or 45 mg fenofibric acid delayed-release capsules (TriLipix) PO once daily. 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
    Fenofibric acid is highly bound to plasma proteins; use is contraindicated.

    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 fenofibric acid. 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 fenofibric acid therapy.

    Oral Administration

    May administer without regard to meals.

    Oral Solid Formulations

    Do not crush, break, or dissolve the capsules; the capsules should be swallowed whole.
    For convenience, fenofibric acid capsules may be administered at the same time as the statin for patients taking these medications concomitantly.

    STORAGE

    Fibricor:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Trilipix:
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Fenofibric acid is contraindicated in patients with hypersensitivity to fenofibric acid, choline fenofibrate, or fenofibrate.

    Dialysis, renal disease, renal failure, renal impairment

    Fenofibric acid is contraindicated in patients with severe renal dysfunction including renal failure or severe renal disease and those on dialysis. Per the manufacturer, fenofibric acid accumulates during chronic therapy in these patients and is not removed by hemodialysis. Fenofibric acid clearance is also reduced in patients with mild to moderate renal impairment. Elevations in serum creatinine have been reported in patients on fenofibrate. These elevations return to baseline upon discontinuation of therapy. The risk of 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.

    Cholelithiasis, gallbladder disease

    Fenofibric acid is contraindicated in patients with pre-existing gallbladder disease because it may exacerbate this condition. Other fibric acid derivatives, clofibrate and gemfibrozil, have been associated with a higher risk of cholecystitis and cholelithiasis in clinical trials. Fenofibric acid is the active metabolite of fenofibrate. 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. However, fenofibric acid may increase the saturation of cholesterol in the bile, and therefore could potentially lead to cholelithiasis. If gallstones develop, discontinue fenofibric acid.

    Biliary cirrhosis, hepatic disease

    Fenofibric acid is contraindicated in patients with active hepatic disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities. Serious drug-induced liver injury (DILI), including liver transplantation and death, have been reported with postmarketing use of fenofibric acid. DILI has been characterized as hepatocellular, chronic active, and cholestatic hepatitis, as well as, cirrhosis in association with chronic active hepatitis. Reports of DILI have occurred within the first few weeks to several months after therapy initiation and was reversible in some cases following discontinuation. In clinical trials, fenofibric acid 135 mg was associated with elevations in AST or ALT. Based on the incidence observed with fenofibrate therapy, increases in transaminases may be dose-related. Monitor liver function, including AST, ALT, and bilirubin, at baseline and periodically throughout fenofibric acid therapy. If a patient experiences persistent LFT elevations (ALT or AST greater than 3 times the upper limit of normal or if accompanied by elevations in bilirubin) or develops signs or symptoms of liver injury, discontinue fenofibric acid. Do no restart fenofibric acid therapy in these patients if there is no alternative explanation for the liver injury.

    Pancreatitis

    Significantly elevated serum triglyceride concentrations (e.g., > 2000 mg/dL) may increase the risk of pancreatitis. The effect of fenofibric acid on this risk has not been adequately studied. Pancreatitis has been reported in patients taking fenofibric acid. Use fenofibric acid with caution in patients at risk for developing pancreatitis.

    Cardiac disease

    Because of clinical and pharmacologic similarities between fenofibric acid and other fibric acid derivatives, findings of important cardiac trials of gemfibrozil and clofibrate may also be applicable to fenofibrate and fenofibric acid. 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 or fenofibric acid, and the benefit/risk ratio for primary or secondary cardiac disease, or other non-cardiovascular mortality has not been established. Fenofibric acid should only be used in the treatment of dyslipidemias where the benefit to the patient would outweigh the potential health risks.

    Anticoagulant therapy, thromboembolic disease

    Caution should be used when fenofibric acid is used in patients with thromboembolic disease. Fenofibric acid is the active metabolite of fenofibrate, and thrombosis has occurred in patients taking fenofibrate. In addition, caution should be used when prescribing fenofibrate or fenofibric acid to patients receiving anticoagulant therapy. Fenofibrate has been shown to potentiate the effects of coumarin-type anticoagulants.

    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, the risk of adverse effects from fenofibric acid is greater in patients with impaired renal function. Since geriatric patients have a higher incidence of renal impairment, dose selection for geriatric patients should be based on renal function.

    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 2 large, randomized controlled trials of patients with type 2 diabetes mellitus.

    Hypothyroidism

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

    Pregnancy

    Use fenofibrate during pregnancy only if the potential benefit justifies the potential risk to the fetus. Limited data with fenofibrate use in human pregnancy are insufficient to determine an associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, no evidence of embryofetal toxicity was observed with oral fenofibrate administration during organogenesis at doses less than or equivalent to the maximum recommended clinical dose (based on body surface area). Adverse reproductive outcomes occurred at higher doses in the presence of maternal toxicity.

    Breast-feeding

    Fenofibrate is contraindicated in breast-feeding women. Advise women to not breast-feed during fenofibrate treatment and for 5 days after the final dose because of the potential for serious adverse reactions in breast-fed infants (e.g., disruption of infant lipid metabolism). There is no available information on the presence of fenofibrate in human milk, effects of the drug on the breast-fed infant, or the effects on milk production. If pharmacotherapy is necessary for the nursing mother, consider a nonabsorbable resin such as cholestyramine, colesevelam, or colestipol. These agents do not enter the bloodstream and therefore 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.

    ADVERSE REACTIONS

    Severe

    cirrhosis / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    agranulocytosis / Delayed / 0-1.0
    pulmonary embolism / Delayed / 1.0-1.0
    thrombosis / Delayed / 1.0-1.0
    cholecystitis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    visual impairment / Early / Incidence not known

    Moderate

    elevated hepatic enzymes / Delayed / 0.2-13.0
    constipation / Delayed / 2.1-2.1
    thrombocytopenia / Delayed / 0-1.0
    hypertension / Early / 3.0
    cholelithiasis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    myasthenia / Delayed / Incidence not known
    myopathy / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    interstitial lung disease / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    decreased HDL cholesterol (HDL-C) concentration / Delayed / Incidence not known
    vitamin B12 deficiency / Delayed / Incidence not known

    Mild

    headache / Early / 3.2-13.1
    back pain / Delayed / 4.1-6.3
    infection / Delayed / 0-5.0
    pharyngitis / Delayed / 3.5-4.7
    abdominal pain / Early / 4.6-4.6
    arthralgia / Delayed / 3.9-4.3
    dizziness / Early / 4.0-4.1
    myalgia / Early / 3.1-3.5
    sinusitis / Delayed / 2.9-3.5
    fatigue / Early / 2.0-3.3
    muscle cramps / Delayed / 1.6-3.1
    insomnia / Early / 0-3.0
    nausea / Early / 2.3-2.3
    rhinitis / Early / 2.3-2.3
    diarrhea / Early / 3.0
    dyspepsia / Early / 3.0
    vomiting / Early / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    weakness / Early / Incidence not known
    libido decrease / Delayed / Incidence not known
    drowsiness / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    maculopapular rash / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    rash / Early / Incidence not known
    photosensitivity / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acarbose: (Moderate) Dose reductions and increased frequency of glucose monitoring may be required when antidiabetic agents are administered with fibric acid derivatives (e.g., clofibrate, fenofibric acid, fenofibrate, gemfibrozil). Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Acetaminophen; Aspirin; Diphenhydramine: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates, such as diphenhydramine, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of diphenhydramine during coadministration with fenofibric acid.
    Acetaminophen; Diphenhydramine: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates, such as diphenhydramine, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of diphenhydramine during coadministration with fenofibric acid.
    Acetohexamide: (Moderate) Monitor blood glucose during concomitant sulfonylurea and fenofibric acid use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Albiglutide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fibric acid derivative use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Aliskiren; Valsartan: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as valsartan, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of valsartan during coadministration with fenofibric acid.
    Alogliptin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Alogliptin; Pioglitazone: (Moderate) Monitor blood glucose during concomitant pioglitazone and fenofibric acid use; a pioglitazone dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Alpha-glucosidase Inhibitors: (Moderate) Dose reductions and increased frequency of glucose monitoring may be required when antidiabetic agents are administered with fibric acid derivatives (e.g., clofibrate, fenofibric acid, fenofibrate, gemfibrozil). Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Amlodipine; Atorvastatin: (Moderate) Use caution and the lowest atorvastatin dose necessary if coadministration with fenofibric acid is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy.
    Amlodipine; Celecoxib: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as celecoxib, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of celecoxib during coadministration with fenofibric acid.
    Amlodipine; Valsartan: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as valsartan, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of valsartan during coadministration with fenofibric acid.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as valsartan, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of valsartan during coadministration with fenofibric acid.
    Amoxicillin; Clarithromycin; Omeprazole: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as omeprazole, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of omeprazole during coadministration with fenofibric acid.
    Amprenavir: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as amprenavir, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of amprenavir during coadministration with fenofibric acid.
    Aspirin, ASA; Carisoprodol: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as carisoprodol, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of carisoprodol during coadministration with fenofibric acid.
    Aspirin, ASA; Carisoprodol; Codeine: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as carisoprodol, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of carisoprodol during coadministration with fenofibric acid.
    Aspirin, ASA; Omeprazole: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as omeprazole, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of omeprazole during coadministration with fenofibric acid.
    Aspirin, ASA; Pravastatin: (Moderate) Monitor for an increase in pravastatin-related adverse reactions if coadministration with fenofibric acid is necessary. Concomitant use increases the risk for rhabdomyolysis and has been shown to increase the overall exposure of pravastatin by 13%.
    Atorvastatin: (Moderate) Use caution and the lowest atorvastatin dose necessary if coadministration with fenofibric acid is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy.
    Atorvastatin; Ezetimibe: (Moderate) Ezetimibe was approved by the FDA for use in combination with fenofibrate as adjunctive therapy to diet for the treatment of hypercholesterolemia in patients with mixed hyperlipidemia in May 2006. However, the safety and effective use of ezetimibe when coadministered with other fibric acid derivatives such as gemfibrozil or clofibrate has not been established. Until further data are available to support efficacy and safety, ezetimibe is not recommended for use with gemfibrozil. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. The incidence rates for cholecystectomy have been reported as 0.6% for fenofibrate monotherapy and 1.7% for combination therapy (ezetimibe plus fenofibrate), respectively. According to the manufacturer, the number of patients exposed to combination therapy versus fenofibrate or ezetimibe monotherapy has been inadequate to assess gallbladder disease risk. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. In a pharmacokinetic study, concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1.5- or 1.7-fold, respectively. However, ezetimibe does not affect the pharmacokinetics of fenofibrate or the bioavailability of gemfibrozil. (Moderate) Use caution and the lowest atorvastatin dose necessary if coadministration with fenofibric acid is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates, such as phenobarbital, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of phenobarbital during coadministration with fenofibric acid.
    Bempedoic Acid; Ezetimibe: (Moderate) Ezetimibe was approved by the FDA for use in combination with fenofibrate as adjunctive therapy to diet for the treatment of hypercholesterolemia in patients with mixed hyperlipidemia in May 2006. However, the safety and effective use of ezetimibe when coadministered with other fibric acid derivatives such as gemfibrozil or clofibrate has not been established. Until further data are available to support efficacy and safety, ezetimibe is not recommended for use with gemfibrozil. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. The incidence rates for cholecystectomy have been reported as 0.6% for fenofibrate monotherapy and 1.7% for combination therapy (ezetimibe plus fenofibrate), respectively. According to the manufacturer, the number of patients exposed to combination therapy versus fenofibrate or ezetimibe monotherapy has been inadequate to assess gallbladder disease risk. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. In a pharmacokinetic study, concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1.5- or 1.7-fold, respectively. However, ezetimibe does not affect the pharmacokinetics of fenofibrate or the bioavailability of gemfibrozil.
    Bortezomib: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as bortezomib, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of bortezomib during coadministration with fenofibric acid.
    Bosentan: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as bosentan, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of bosentan during coadministration with fenofibric acid.
    Bupivacaine; Meloxicam: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as meloxicam, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of meloxicam during coadministration with fenofibric acid.
    Canagliflozin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Canagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Candesartan: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as candesartan, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of candesartan during coadministration with fenofibric acid.
    Candesartan; Hydrochlorothiazide, HCTZ: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as candesartan, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of candesartan during coadministration with fenofibric acid.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates, such as diphenhydramine, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of diphenhydramine during coadministration with fenofibric acid.
    Carisoprodol: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as carisoprodol, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of carisoprodol during coadministration with fenofibric acid.
    Celecoxib: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as celecoxib, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of celecoxib during coadministration with fenofibric acid.
    Celecoxib; Tramadol: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as celecoxib, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of celecoxib during coadministration with fenofibric acid.
    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.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as ibuprofen, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of ibuprofen during coadministration with fenofibric acid.
    Chlorpropamide: (Moderate) Monitor blood glucose during concomitant sulfonylurea and fenofibric acid use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Cholestyramine: (Moderate) Based on reported interactions with gemfibrozil, cholestyramine can potentially reduce the oral bioavailability of fenofibric acid if these agents are administered together. Although the presence of a drug interaction is uncertain, patients should take fenofibric acid at least 1 hour before or 4 to 6 hours after cholestyramine to avoid affecting the bioavailability of fenofibric acid.
    Citalopram: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as citalopram, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. The manufacturer of citalopram recommends 20 mg/day as the maximum daily dose of citalopram in patients receiving CYP2C19 inhibitors, due to the potential risk for QT prolongation. Monitor the therapeutic effect of citalopram during coadministration with fenofibric acid.
    Clomipramine: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as clomipramine, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of clomipramine during coadministration with fenofibric acid.
    Clopidogrel: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as clopidogrel, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of clopidogrel during coadministration with fenofibric acid.
    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 coadministered, 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: (Moderate) Based on reported interactions with gemfibrozil, colestipol can potentially reduce the oral bioavailability of fenofibric acid if these agents are administered together. Although the presence of a drug interaction is uncertain, patients should take fenofibric acid at least 1 hour before or 4 to 6 hours after colestipol to avoid affecting the bioavailability of fenofibric acid.
    Dapagliflozin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Dapagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Dapagliflozin; Saxagliptin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates, such as diphenhydramine, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of diphenhydramine during coadministration with fenofibric acid.
    Diazepam: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as diazepam, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of diazepam during coadministration with fenofibric acid.
    Diclofenac: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as diclofenac, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of diclofenac during coadministration with fenofibric acid.
    Diclofenac; Misoprostol: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as diclofenac, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of diclofenac during coadministration with fenofibric acid.
    Dipeptidyl Peptidase-4 Inhibitors: (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 inhibitor (DPP-4) and fibric acid derivative use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Diphenhydramine: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates, such as diphenhydramine, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of diphenhydramine during coadministration with fenofibric acid.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates, such as diphenhydramine, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of diphenhydramine during coadministration with fenofibric acid.
    Diphenhydramine; Ibuprofen: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as ibuprofen, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of ibuprofen during coadministration with fenofibric acid. (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates, such as diphenhydramine, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of diphenhydramine during coadministration with fenofibric acid.
    Diphenhydramine; Naproxen: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as naproxen, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of naproxen during coadministration with fenofibric acid. (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates, such as diphenhydramine, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of diphenhydramine during coadministration with fenofibric acid.
    Diphenhydramine; Phenylephrine: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates, such as diphenhydramine, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of diphenhydramine during coadministration with fenofibric acid.
    Dronabinol: (Moderate) Use caution if coadministration of dronabinol with fenofibric acid 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; fenofibric acid is a weak-to-moderate inhibitor of CYP2C9. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Dulaglutide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fibric acid derivative use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Empagliflozin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Empagliflozin; Linagliptin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Empagliflozin; Linagliptin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Empagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Ertugliflozin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Ertugliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Ertugliflozin; Sitagliptin: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Escitalopram: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as escitalopram, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of escitalopram during coadministration with fenofibric acid.
    Etravirine: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates, such as etravirine, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of etravirine during coadministration with fenofibric acid.
    Exenatide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fibric acid derivative use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Ezetimibe: (Moderate) Ezetimibe was approved by the FDA for use in combination with fenofibrate as adjunctive therapy to diet for the treatment of hypercholesterolemia in patients with mixed hyperlipidemia in May 2006. However, the safety and effective use of ezetimibe when coadministered with other fibric acid derivatives such as gemfibrozil or clofibrate has not been established. Until further data are available to support efficacy and safety, ezetimibe is not recommended for use with gemfibrozil. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. The incidence rates for cholecystectomy have been reported as 0.6% for fenofibrate monotherapy and 1.7% for combination therapy (ezetimibe plus fenofibrate), respectively. According to the manufacturer, the number of patients exposed to combination therapy versus fenofibrate or ezetimibe monotherapy has been inadequate to assess gallbladder disease risk. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. In a pharmacokinetic study, concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1.5- or 1.7-fold, respectively. However, ezetimibe does not affect the pharmacokinetics of fenofibrate or the bioavailability of gemfibrozil.
    Ezetimibe; Simvastatin: (Moderate) Concomitant use of fenofibric acid and simvastatin may increase the risk of myopathy, rhabdomyolysis, and acute renal failure. This risk of myopathy, rhabdomyolysis, and acute renal failure 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) Ezetimibe was approved by the FDA for use in combination with fenofibrate as adjunctive therapy to diet for the treatment of hypercholesterolemia in patients with mixed hyperlipidemia in May 2006. However, the safety and effective use of ezetimibe when coadministered with other fibric acid derivatives such as gemfibrozil or clofibrate has not been established. Until further data are available to support efficacy and safety, ezetimibe is not recommended for use with gemfibrozil. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. The incidence rates for cholecystectomy have been reported as 0.6% for fenofibrate monotherapy and 1.7% for combination therapy (ezetimibe plus fenofibrate), respectively. According to the manufacturer, the number of patients exposed to combination therapy versus fenofibrate or ezetimibe monotherapy has been inadequate to assess gallbladder disease risk. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. In a pharmacokinetic study, concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1.5- or 1.7-fold, respectively. However, ezetimibe does not affect the pharmacokinetics of fenofibrate or the bioavailability of gemfibrozil.
    Fluoxetine: (Minor) As fenofibric acid is a mild-to-moderate inhibitor of CYP2C9 and CYP2C19; while fluoxetine is a substrate of both. Although not formally studied, co-administration may lead to increased fluoxetine plasma concentrations and toxicity. Monitor the therapeutic effect of fluoxetine during coadministration with fenofibric acid.
    Flurbiprofen: (Minor) As fenofibric acid is a mild-to-moderate inhibitor of CYP2C9; while flurbiprofen is a substrate of CYP2C9. Although not formally studied, co-administration may lead to increased fluriprofen plasma concentrations and toxicity. Monitor the therapeutic effect of flurbiprofen during coadministration with fenofibric acid.
    Fluvastatin: (Major) Use caution when coadministering fluvastatin and fenofibric acid. 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.
    Fosamprenavir: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as fosamprenavir, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of fosamprenavir during coadministration with fenofibric acid.
    Fosphenytoin: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates, such as phenytoin, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of phenytoin during coadministration with fenofibric acid.
    Glimepiride: (Moderate) Monitor blood glucose during concomitant sulfonylurea and fenofibric acid use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Glimepiride; Rosiglitazone: (Moderate) Dose reductions and increased frequency of glucose monitoring may be required when antidiabetic agents are administered with fibric acid derivatives (e.g., clofibrate, fenofibric acid, fenofibrate, gemfibrozil). Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. (Moderate) Monitor blood glucose during concomitant sulfonylurea and fenofibric acid use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Glipizide: (Moderate) Monitor blood glucose during concomitant sulfonylurea and fenofibric acid use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Glipizide; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant sulfonylurea and fenofibric acid use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Glyburide: (Moderate) Monitor blood glucose during concomitant sulfonylurea and fenofibric acid use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Glyburide; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant sulfonylurea and fenofibric acid use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Hydrocodone; Ibuprofen: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as ibuprofen, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of ibuprofen during coadministration with fenofibric acid.
    Ibuprofen: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as ibuprofen, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of ibuprofen during coadministration with fenofibric acid.
    Ibuprofen; Famotidine: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as ibuprofen, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of ibuprofen during coadministration with fenofibric acid.
    Ibuprofen; Oxycodone: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as ibuprofen, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of ibuprofen during coadministration with fenofibric acid.
    Ibuprofen; Pseudoephedrine: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as ibuprofen, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of ibuprofen during coadministration with fenofibric acid.
    Imipramine: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as imipramine, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of imipramine during coadministration with fenofibric acid.
    Incretin Mimetics: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fibric acid derivative use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Indomethacin: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as indomethacin, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of indomethacin during coadministration with fenofibric acid.
    Insulin Degludec; Liraglutide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fibric acid derivative use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulin Glargine; Lixisenatide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fibric acid derivative use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Insulins: (Moderate) Monitor blood glucose during concomitant fibric acid derivatives and insulin use; an insulin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Lacosamide: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as lacosamide, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of lacosamide during coadministration with fenofibric acid.
    Lansoprazole: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as lansoprazole, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of lansoprazole during coadministration with fenofibric acid.
    Lansoprazole; Amoxicillin; Clarithromycin: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as lansoprazole, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of lansoprazole during coadministration with fenofibric acid.
    Lansoprazole; Naproxen: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as naproxen, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of naproxen during coadministration with fenofibric acid. (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as lansoprazole, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of lansoprazole during coadministration with fenofibric acid.
    Linagliptin; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Liraglutide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fibric acid derivative use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Lixisenatide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fibric acid derivative use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Losartan: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as losartan, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of losartan during coadministration with fenofibric acid.
    Losartan; Hydrochlorothiazide, HCTZ: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as losartan, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of losartan during coadministration with fenofibric acid.
    Lovastatin: (Moderate) Concurrent use of fenofibric acid 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 fenofibric acid and lovastatin.
    Lovastatin; Niacin: (Moderate) Concurrent use of fenofibric acid 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 fenofibric acid and lovastatin.
    Meloxicam: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as meloxicam, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of meloxicam during coadministration with fenofibric acid.
    Metformin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Metformin; Repaglinide: (Moderate) Dose reductions and increased frequency of glucose monitoring may be required when antidiabetic agents are administered with fibric acid derivatives (e.g., clofibrate, fenofibric acid, fenofibrate, gemfibrozil). Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Metformin; Rosiglitazone: (Moderate) Dose reductions and increased frequency of glucose monitoring may be required when antidiabetic agents are administered with fibric acid derivatives (e.g., clofibrate, fenofibric acid, fenofibrate, gemfibrozil). Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion. (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Metformin; Saxagliptin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Metformin; Sitagliptin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Methadone: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates, such as methadone, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of methadone during coadministration with fenofibric acid.
    Miglitol: (Moderate) Dose reductions and increased frequency of glucose monitoring may be required when antidiabetic agents are administered with fibric acid derivatives (e.g., clofibrate, fenofibric acid, fenofibrate, gemfibrozil). Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Naproxen: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as naproxen, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of naproxen during coadministration with fenofibric acid.
    Naproxen; Esomeprazole: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as naproxen, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of naproxen during coadministration with fenofibric acid.
    Naproxen; Pseudoephedrine: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as naproxen, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of naproxen during coadministration with fenofibric acid.
    Nateglinide: (Moderate) Dose reductions and increased frequency of glucose monitoring may be required when antidiabetic agents are administered with fibric acid derivatives (e.g., clofibrate, fenofibric acid, fenofibrate, gemfibrozil). Adjust nateglinide dosage if clinically indicated. Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Nebivolol; Valsartan: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as valsartan, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of valsartan during coadministration with fenofibric acid.
    Nelfinavir: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as nelfinavir, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of nelfinavir during coadministration with fenofibric acid.
    Niacin; Simvastatin: (Moderate) Concomitant use of fenofibric acid and simvastatin may increase the risk of myopathy, rhabdomyolysis, and acute renal failure. This risk of myopathy, rhabdomyolysis, and acute renal failure 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.
    Olanzapine: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as olanzapine, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of olanzapine during coadministration with fenofibric acid.
    Olanzapine; Fluoxetine: (Minor) As fenofibric acid is a mild-to-moderate inhibitor of CYP2C9 and CYP2C19; while fluoxetine is a substrate of both. Although not formally studied, co-administration may lead to increased fluoxetine plasma concentrations and toxicity. Monitor the therapeutic effect of fluoxetine during coadministration with fenofibric acid. (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as olanzapine, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of olanzapine during coadministration with fenofibric acid.
    Olanzapine; Samidorphan: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as olanzapine, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of olanzapine during coadministration with fenofibric acid.
    Omeprazole: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as omeprazole, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of omeprazole during coadministration with fenofibric acid.
    Omeprazole; Amoxicillin; Rifabutin: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as omeprazole, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of omeprazole during coadministration with fenofibric acid.
    Omeprazole; Sodium Bicarbonate: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as omeprazole, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of omeprazole during coadministration with fenofibric acid.
    Paclitaxel: (Minor) Paclitaxel is a substrate of CYP2C8, and fenofibric acid is a weak CYP2C8 inhibitor. If coadministration is necessary, use caution and monitor for increased paclitaxel side effects, including myelosuppression and peripheral neuropathy.
    Phenobarbital: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates, such as phenobarbital, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of phenobarbital during coadministration with fenofibric acid.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates, such as phenobarbital, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of phenobarbital during coadministration with fenofibric acid.
    Phenytoin: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates, such as phenytoin, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of phenytoin during coadministration with fenofibric acid.
    Pioglitazone: (Moderate) Monitor blood glucose during concomitant pioglitazone and fenofibric acid use; a pioglitazone dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Pioglitazone; Glimepiride: (Moderate) Monitor blood glucose during concomitant pioglitazone and fenofibric acid use; a pioglitazone dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant sulfonylurea and fenofibric acid use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Pioglitazone; Metformin: (Moderate) Monitor blood glucose during concomitant metformin and fibric acid derivative use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant pioglitazone and fenofibric acid use; a pioglitazone dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Piroxicam: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as piroxicam, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of piroxicam during coadministration with fenofibric acid.
    Pitavastatin: (Moderate) Clinical practice guidelines state the concurrent use of fenofibric acid and pitavastatin is reasonable and preferred over gemfibrozil if statin/fibrate combination therapy is indicated. However, because combination therapy increases the risk of myopathy, caution is advised.
    Pramlintide: (Moderate) Dose reductions and increased frequency of glucose monitoring may be required when antidiabetic agents are administered with fibric acid derivatives (e.g., clofibrate, fenofibric acid, fenofibrate, gemfibrozil). Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Pravastatin: (Moderate) Monitor for an increase in pravastatin-related adverse reactions if coadministration with fenofibric acid is necessary. Concomitant use increases the risk for rhabdomyolysis and has been shown to increase the overall exposure of pravastatin by 13%.
    Primidone: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates, such as primidone, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of primidone during coadministration with fenofibric acid.
    Probenecid; 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 coadministered, 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.
    Propranolol: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as propranolol, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of propranolol during coadministration with fenofibric acid.
    Propranolol; Hydrochlorothiazide, HCTZ: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as propranolol, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of propranolol during coadministration with fenofibric acid.
    Quinine: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates, such as quinine, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of quinine during coadministration with fenofibric acid.
    Rabeprazole: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as rabeprazole, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of rabeprazole during coadministration with fenofibric acid.
    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.
    Ramelteon: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as ramelteon, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of ramelteon during coadministration with fenofibric acid.
    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) Dose reductions and increased frequency of glucose monitoring may be required when antidiabetic agents are administered with fibric acid derivatives (e.g., clofibrate, fenofibric acid, fenofibrate, gemfibrozil). Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Rosiglitazone: (Moderate) Dose reductions and increased frequency of glucose monitoring may be required when antidiabetic agents are administered with fibric acid derivatives (e.g., clofibrate, fenofibric acid, fenofibrate, gemfibrozil). Fibric acid derivatives may enhance the hypoglycemic effects of antidiabetic agents through increased insulin sensitivity and decreased glucagon secretion.
    Rosuvastatin: (Moderate) Clinical practice guidelines state the concurrent use of fenofibric acid and rosuvastatin is reasonable and preferred over gemfibrozil if statin/fibrate combination therapy is indicated. However, because combination therapy increases the risk of myopathy, caution is advised.
    Rosuvastatin; Ezetimibe: (Moderate) Clinical practice guidelines state the concurrent use of fenofibric acid and rosuvastatin is reasonable and preferred over gemfibrozil if statin/fibrate combination therapy is indicated. However, because combination therapy increases the risk of myopathy, caution is advised. (Moderate) Ezetimibe was approved by the FDA for use in combination with fenofibrate as adjunctive therapy to diet for the treatment of hypercholesterolemia in patients with mixed hyperlipidemia in May 2006. However, the safety and effective use of ezetimibe when coadministered with other fibric acid derivatives such as gemfibrozil or clofibrate has not been established. Until further data are available to support efficacy and safety, ezetimibe is not recommended for use with gemfibrozil. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. The incidence rates for cholecystectomy have been reported as 0.6% for fenofibrate monotherapy and 1.7% for combination therapy (ezetimibe plus fenofibrate), respectively. According to the manufacturer, the number of patients exposed to combination therapy versus fenofibrate or ezetimibe monotherapy has been inadequate to assess gallbladder disease risk. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. In a pharmacokinetic study, concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1.5- or 1.7-fold, respectively. However, ezetimibe does not affect the pharmacokinetics of fenofibrate or the bioavailability of gemfibrozil.
    Sacubitril; Valsartan: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as valsartan, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of valsartan during coadministration with fenofibric acid.
    Semaglutide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fibric acid derivative use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Sertraline: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as sertraline, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of sertraline during coadministration with fenofibric acid.
    SGLT2 Inhibitors: (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fibric acid derivative use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Sildenafil: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as sildenafil , has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of sildenafil during coadministration with fenofibric acid.
    Simvastatin: (Moderate) Concomitant use of fenofibric acid and simvastatin may increase the risk of myopathy, rhabdomyolysis, and acute renal failure. This risk of myopathy, rhabdomyolysis, and acute renal failure 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: (Moderate) Concomitant use of fenofibric acid and simvastatin may increase the risk of myopathy, rhabdomyolysis, and acute renal failure. This risk of myopathy, rhabdomyolysis, and acute renal failure 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.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as sulfamethoxazole, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of sulfamethoxazole during coadministration with fenofibric acid.
    Sulfonylureas: (Moderate) Monitor blood glucose during concomitant sulfonylurea and fenofibric acid use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Sumatriptan; Naproxen: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as naproxen, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of naproxen during coadministration with fenofibric acid.
    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.
    Thalidomide: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as thalidomide, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of thalidomide during coadministration with fenofibric acid.
    Tirzepatide: (Moderate) Monitor blood glucose during concomitant incretin mimetic and fibric acid derivative use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Tolazamide: (Moderate) Monitor blood glucose during concomitant sulfonylurea and fenofibric acid use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Tolbutamide: (Moderate) Monitor blood glucose during concomitant sulfonylurea and fenofibric acid use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
    Torsemide: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as torsemide, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of torsemide during coadministration with fenofibric acid.
    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.
    Valsartan: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as valsartan, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of valsartan during coadministration with fenofibric acid.
    Valsartan; Hydrochlorothiazide, HCTZ: (Minor) At therapeutic concentrations, fenofibric acid is a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C9 substrates, such as valsartan, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of valsartan during coadministration with fenofibric acid.
    Voriconazole: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates such as voriconazole, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of voriconazole during coadministration with fenofibric acid.
    Warfarin: (Moderate) Fenofibric acid 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 fenofibric acid displaces warfarin from protein-binding sites as a potential mechanism. Case reports of significant effects on warfarin exist for all fibrate drugs. Fenofibric acid is the active metabolite of fenofibrate. 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 male (47 years) 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. In order to prevent bleeding complications, patients receiving warfarin concomitantly with fenofibric acid should have frequent 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

    Use fenofibrate during pregnancy only if the potential benefit justifies the potential risk to the fetus. Limited data with fenofibrate use in human pregnancy are insufficient to determine an associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, no evidence of embryofetal toxicity was observed with oral fenofibrate administration during organogenesis at doses less than or equivalent to the maximum recommended clinical dose (based on body surface area). Adverse reproductive outcomes occurred at higher doses in the presence of maternal toxicity.

    Fenofibrate is contraindicated in breast-feeding women. Advise women to not breast-feed during fenofibrate treatment and for 5 days after the final dose because of the potential for serious adverse reactions in breast-fed infants (e.g., disruption of infant lipid metabolism). There is no available information on the presence of fenofibrate in human milk, effects of the drug on the breast-fed infant, or the effects on milk production. If pharmacotherapy is necessary for the nursing mother, consider a nonabsorbable resin such as cholestyramine, colesevelam, or colestipol. These agents do not enter the bloodstream and therefore 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

    Fenofibric acid is the active metabolite of fenofibrate. Many of the lipid-modifications of fenofibric acid are thought to be mediated by activation of peroxisome proliferator activated receptors (PPARs). PPARs function to alter the transcription 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.
     
    Fenofibric acid appears to produce favorable changes in LDL, HDL, and total cholesterol. Fenofibric acid 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 fenofibric acid. Net LDL levels are usually reduced or unchanged. The greatest LDL reductions occur in patients with type IIa or IIb dyslipidemias. Fenofibric acid induces lipoprotein lipase and decreases hepatic production of apolipoprotein CIII via PPAR activity, which enhances plasma catabolism and clearance of triglyceride-rich particles. 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.

    PHARMACOKINETICS

    Fenofibric acid is administered orally and is the active metabolite of fenofibrate. Plasma concentrations of fenofibric acid reach steady state after 8 days. In normal and dyslipidemic patients, fenofibric acid is extensively protein bound (99%). It is primarily conjugated with glucuronic acid and is primarily excreted in the urine as fenofibric acid and fenofibric acid glucuronide. The elimination half-life of fenofibric acid is 20 hours.
     
    Affected cytochrome P450 isoenzymes: CYP2C8, CYP2C9, CYP2C19, CYP2A6
    Fenofibric acid is a weak inhibitor of CYP2C8, CYP2C19, and CYP2A6, and a mild-to-moderate inhibitor of CYP2C9 at therapeutic concentrations. It is not metabolized by the cytochrome P450 system.

    Oral Route

    Fenofibric acid delayed-release capsules are well absorbed, with an absolute bioavailability of approximately 81%. The absolute bioavailability of fenofibric acid tablets has not been determined. Peak plasma concentrations of fenofibric acid delayed-release capsules and tablets generally occur within 4—5 hours and 2.5 hours, respectively, after administration under fasted conditions. One fenofibric acid 135 mg delayed-release capsule administered under fed conditions produces plasma concentrations equivalent to one 200 mg capsule of micronized fenofibrate; one fenofibric acid 105 mg tablet administered under fasting conditions produces plasma concentrations equivalent to one 145 mg fenofibrate tablet. There are no significant differences in Cmax and AUC under fed or fasted conditions.