FENOFIBRIC ACID capsule, delayed release

Fenofibric acid by

Drug Labeling and Warnings

Fenofibric acid by is a Prescription medication manufactured, distributed, or labeled by Micro Labs Limited. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    Fenofibricacid  delayed-release capsules are indicated as adjunctive therapy to diet:

    • toreduce  triglyceride (TG) levels in adults with severe hypertriglyceridemia (TG greater than or equal to 500 mg/dL).
    • toreduce   elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia when use of recommended LDL-C lowering therapy isnot  possible.

    Limitations  of Use

    • Markedlyelevated  levels of serum TG (e.g., > 2,000 mg/dL) may increase the risk of developing pancreatitis. The effect of fenofibrate therapy on reducingthis  risk has not been determined [see Warnings and Precautions (5.7)] .
    • Fenofibrate didnot  reduce coronary heart disease morbidity and mortality in two large, randomized controlled trials of patients with type 2 diabetesmellitus  [see Warnings and Precautions (5.1)  and   Clinical Studies (14.4)] .

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Prior to Initiation of Fenofibric Acid Delayed-Release Capsules

    • Assess lipid levels before initiating therapy. Identify other causes (e.g., diabetes mellitus, hypothyroidism, or medications) of high TG levels and manage as appropriate.
    • Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibric acid delayed-release capsules, and should continue this diet during treatment with fenofibric acid delayed-release capsules.
    • Inpatients  with diabetes and fasting chylomicronemia, improve glycemic control prior to considering starting fenofibric acid delayed-releasecapsules.

    2.2 Recommended Dosage and Administration

    • Severe hypertriglyceridemia:
    • The recommended dosage of fenofibric acid delayed-release capsules are 45 mg or 135 mg orally once daily.
    • Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals.
    • Primary hyperlipidemia:
    • The recommended dosage of fenofibric acid delayed-release capsule is 135 mg orally once daily.
    • Administer fenofibric acid delayed-release capsules as a single dose at any time of day, with or without food.
    • Advise patients to swallow fenofibric acid delayed-release capsules whole. Do not crush, break, dissolve, or chew capsules.
    • Assess TGwhen  clinically appropriate, as early as 4 to 8 weeks after initiating fenofibric acid delayed-release capsules. Discontinue fenofibric acid delayed-releasecapsules  in patients who do not have an adequate response after two months of treatment.
    • If adose  is missed, advise patients not to take an extra dose. Resume treatment with the next dose.
    • Advisepatients  to take fenofibric acid delayed-release capsules at least 1 hour before or 4 hours to 6 hours after a bile acid binding resin to avoidimpeding  its absorption.

    2.3 Recommended Dosage in Patients with Renal Impairment

    • Assessrenal  function prior to initiation of fenofibric acid delayed-release capsules and periodically thereafter [see Warnings and Precautions (5.4)] .
    • Treatment with fenofibric acid delayed-release capsules should be initiated at a dosage of 45 mg orally once daily in patients with mild to moderately impaired renal function (eGFR 30 to <60 mL/min/1.73m 2), and increased only after evaluation of the effects on renal function and TG levels at this dosage.
    • Fenofibricacid  delayed-release capsules are contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73m 2), including those with end-stagerenal  disease (ESRD) and those receiving dialysis [see Use in Specific Populations (8.6)  and   Clinical Pharmacology (12.3)] .

    2.4 Recommended Dosage in Geriatric Patients

    Dosage selection for geriatric patients should be made on the basis of renal function [see Use in Specific Populations (8.6)  and   Clinical Pharmacology (12.3)] .


  • 3 DOSAGE FORMS AND STRENGTHS

    • Fenofibric acid delayed-release capsules 45 mg:  Reddish brown opaque cap imprinted with “CDR” and yellow opaque body imprinted with “45”, size “3”, hard gelatin capsule contains 4 white to off-white, round, biconvex delayed release mini tablets.
    • Fenofibric acid delayed-release capsules135 mg:  Blue opaque cap imprinted with “CDR” and yellow opaque body imprinted with “135”, size “0”, hard gelatin capsule contains 12 white to off-white, round, biconvex delayed release mini tablets.
  • 4 CONTRAINDICATIONS

    Fenofibric acid delayed-release capsules are contraindicated in patients with:


    • Severe renal impairment, including those with end-stage renal disease (ESRD) and those receiving dialysis [see Clinical Pharmacology (12.3)] .
    • Active liver disease, including those with unexplained persistent liver function abnormalities [see Warnings and Precautions (5.2)] .
    • Pre-existing gallbladder disease [see Warnings and Precautions (5.5)] .
    • Hypersensitivity to fenofibric acid, fenofibrate, or any of the excipients in fenofibric acid delayed-release capsules. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with fenofibrate [see Warnings and Precautions (5.9)] .

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Mortality and Coronary Heart Disease Morbidity

    Fenofibrate didnot  reduce cardiovascular disease morbidity or mortality in two large, randomized controlled trials of patients with type 2 diabetesmellitus  [see Clinical Studies (14.4)] .


    Because  of chemical, pharmacological, and clinical similarities between fenofibrates, including fenofibric acid delayed-release capsules; pemafibrate; clofibrate;and  gemfibrozil; the findings in 5 large randomized, placebo-controlled clinical trials with these other fibrate drugs may alsoapply  to fenofibric acid delayed-release capsules.


    Pemafibratedid  not reduce cardiovascular disease morbidity or mortality in a large, randomized, placebo-controlled trial of patients with type 2diabetes  mellitus on background statin therapy [see Clinical Studies (14.4)] .


    In theCoronary  Drug Project, a large trial conducted from 1965 to 1985 in men post myocardial infarction, there was no difference in mortality ornonfatal  myocardial infarction between the clofibrate group and the placebo group after 5 years of treatment (NCT00000482).


    In atrial  conducted by the World Health Organization (WHO) from 1965 to 1976, men without known coronary artery disease were treated withplacebo  or clofibrate for 5 years and followed for an additional 1 year. There was a statistically significant, higher age-adjusted all-cause mortality in the clofibrategroup  compared with the placebo group (5.70% vs. 3.96%, p ≤ 0.01). Excess mortality was due to a 33% increase in non-cardiovascular  causes, including malignancy, post-cholecystectomy complications, and pancreatitis.


    The HelsinkiHeart  Study, conducted from 1982 to 1987, was a large (N = 4,081) trial of middle-aged men without a history of coronary artery disease. Subjectsreceived  either placebo or gemfibrozil for 5 years, with a 3.5-year open extension afterward. Total mortality was numerically but not statisticallyhigher  in the gemfibrozil randomization group versus placebo [95% confidence interval (CI) of the hazard ratio (HR) 0.91 to 1.64].


    Asecondary  prevention component of the Helsinki Heart Study treated middle-aged men with gemfibrozil or placebo for 5 years. The HR for cardiacdeaths  was 2.2, 95% CI, 0.94 to 5.05.


    5.2 Hepatotoxicity

    Serious drug-induced liver injury (DILI), including liver transplantation and death, has been reported with postmarketing use of fenofibrates, including fenofibric acid. DILI has been reported within the first few weeks of treatment or after several months of therapy and in some cases has reversed with discontinuation of fenofibric acid treatment. Patients with DILI have experienced signs and symptoms including dark urine, abnormal stool, jaundice, malaise, abdominal pain, myalgia, weight loss, pruritus, and nausea. Many patients had concurrent elevations of total bilirubin, serum alanine transaminase (ALT), and aspartate transaminase (AST). DILI has been characterized as hepatocellular, chronic active, and cholestatic hepatitis, and cirrhosis has occurred in association with chronic active hepatitis.


    In clinical trials, an intermediate daily dosage or the maximum recommended daily dosage of fenofibrate have been associated with increases in serum AST or ALT. The incidence of increases in transaminases may be dose related [see Adverse Reactions (6.1)] .


    Fenofibric acid is contraindicated in patients with active liver disease, including those with unexplained persistent liver function abnormalities. Monitor patient’s liver function, including serum ALT, AST, and total bilirubin, at baseline and periodically for the duration of therapy with fenofibric acid. Discontinue fenofibric acid if signs or symptoms of liver injury develop or if elevated enzyme levels persist (ALT or AST > 3 times the upper limit of normal, or if accompanied by elevation of bilirubin). Do not restart fenofibric acid in these patients if there is no alternative explanation for the liver injury.


    5.3 Myopathy and Rhabdomyolysis

    Fenofibric acid delayed-release capsules may cause myopathy [muscle pain, tenderness, or weakness associated with elevated creatine kinase (CK)] and rhabdomyolysis.


    Risk Factors for Myopathy


    Risk factors for myopathy include age 65 years or older, uncontrolled hypothyroidism, renal impairment, and concomitant use with certain other drugs [see Drug Interactions (7)  and   Use in Specific Populations (8.6)].


    Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis


    Data from observational studies indicate that the risk for rhabdomyolysis is increased when fibrates, including fenofibrates, are co-administered with a statin. Avoid concomitant use unless the benefit of further alterations in TG levels is likely to outweigh the increased risk of this drug combination [see Drug Interactions (7), Clinical Pharmacology (12.3), and   Clinical Studies (14.4)].


    Cases of myopathy, including rhabdomyolysis, have been reported with fenofibric co-administered with colchicine. Consider whether the benefit of using colchicine concomitantly with fenofibric acid outweighs the increased risk of myopathy [see Drug Interactions (7)] .


    Discontinue fenofibric acid delayed-release capsules if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if fenofibric acid delayed-release capsules are discontinued. Temporarily discontinue fenofibric acid delayed-release capsules in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy).


    Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the fenofibric acid delayed-release capsules dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.


    5.4 Increases in Serum Creatinine

    Increases in serum creatinine have been reported in patients receiving fenofibrates. These increases tend to return to baseline following discontinuation of fenofibric acid delayed-release capsules. The clinical significance of this finding is unknown. Monitor renal function in patients with renal impairment taking fenofibric acid delayed-release capsules. Renal monitoring should also be considered for patients taking fenofibric acid delayed-release capsules at risk for renal insufficiency such as geriatric patients and patients with diabetes. Fenofibric acid delayed-release capsules are contraindicated in patients with severe renal impairment, including those with end-stage renal disease (ESRD) and those receiving dialysis [see Dosage and Administration (2.3), Use in Specific Populations (8.6), and   Clinical Pharmacology (12.3)].


    5.5 Cholelithiasis

    Fenofibrate may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Fenofibric acid delayed-release capsules therapy should be discontinued if gallstones are found. Fenofibric acid delayed-release capsules are contraindicated in patients with pre-existing gallbladder disease.


    5.6 Increased Bleeding Risk with Coumarin Anticoagulants

    Exercise caution when co-administering anticoagulants with fenofibric acid delayed-release capsules because of the potentiation of coumarin-type anticoagulant effects in prolonging the prothrombin time/International Normalized Ratio (PT/INR). To prevent bleeding complications, monitor the PT/INR frequently and adjust the dosage of the anticoagulant until the PT/INR has stabilized [see Drug Interactions (7)] .


    5.7 Pancreatitis

    Pancreatitis has been reported in patients taking fenofibrates. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.


    5.8 Hematologic Changes

    Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of therapy with fenofibrates. However, these levels stabilize during long-term administration. Thrombocytopenia and agranulocytosis have been reported in individuals treated with fenofibric acid delayed-release capsules. Periodic monitoring of red and white blood cell counts is recommended during the first 12 months of fenofibric acid delayed-release capsules administration.


    5.9 Hypersensitivity Reactions

    Acute Hypersensitivity


    Anaphylaxis and angioedema have been reported with postmarketing use of fenofibrates. In some cases, reactions were life-threatening and required emergency treatment. If a patient develops signs or symptoms of an acute hypersensitivity reaction, advise them to seek immediate medical attention and discontinue fenofibric acid delayed-release capsules. Fenofibric acid delayed-release capsules are contraindicated in patients with a hypersensitivity to fenofibrate, fenofibric acid, or any of the ingredients in fenofibric acid delayed-release capsules.


    Delayed Hypersensitivity


    Severe cutaneous adverse drug reactions (SCAR), including Stevens-Johnson syndrome, Toxic Epidermal Necrolysis, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported with postmarketing use of fenofibrates, occurring days to weeks after treatment initiation. The cases of DRESS were associated with cutaneous reactions (such as rash or exfoliative dermatitis) and a combination of eosinophilia, fever, systemic organ involvement (renal, hepatic, or respiratory). Discontinue fenofibric acid delayed-release capsules and treat patients appropriately if SCAR is suspected.


    5.10 Venothromboembolic Disease

    In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, pulmonary embolus (PE) and deep vein thrombosis (DVT) were observed at higher rates in the fenofibrate­-than the placebo-treated group. Of 9,795 patients enrolled in FIELD, there were 4,900 in the placebo group and 4,895 in the fenofibrate group. For DVT, there were 48 events (1%) in the placebo group and 67 (1.4%) in the fenofibrate group (p = 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1.1%) in the fenofibrate group (p = 0.022).


    In the Coronary Drug Project, a higher proportion of the clofibrate group experienced definite or suspected fatal or nonfatal pulmonary embolism or thrombophlebitis than the placebo group (5.2% vs. 3.3% at five years; p < 0.01).


    In the cardiovascular outcome trial with pemafibrate, pulmonary embolism was reported for 37 (0.7%) subjects in the pemafibrate group and 16 (0.3%) subjects in the placebo group. Deep vein thrombosis was reported for 36 (0.7%) subjects in the pemafibrate group and 13 (0.2%) subjects in the placebo group.


    5.11 Paradoxical Decreases in HDL Cholesterol Levels

    There have been postmarketing and clinical trial reports of severe decreases in high-density lipoprotein cholesterol (HDL-C) levels (as low as 2 mg/dL) occurring in patients with and without diabetes initiated on fibrate therapy, including fenofibrate. The decrease in HDL-C is mirrored by a decrease in apolipoprotein A1. This decrease has been reported to occur within 2 weeks to years after initiation of fibrate therapy. The HDL-C levels remain depressed until fibrate therapy has been withdrawn; the response to withdrawal of fibrate therapy is rapid and sustained. The clinical significance of this decrease in HDL-C is unknown. Check HDL-C levels within the first few months after initiation of fenofibric acid delayed-release capsules. If a severely depressed HDL-C level is detected, discontinue fenofibric acid delayed-release capsules and monitor HDL-C until it has returned to baseline. Fenofibric acid delayed-release capsules should not be re-initiated.


  • 6 ADVERSE REACTIONS

    The following serious adverse reactions are described below and elsewhere in the labeling:



    6.1 Clinical Trials Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.


    The safety of fenofibric acid has been established in adults with hypertriglyceridemia or primary hyperlipidemia based on adequate and well-controlled trials of other formulations of fenofibrate, referenced below as “fenofibrate” [see Clinical Studies (14)]. Dosages of fenofibrate used in these trials were comparable to fenofibric acid delayed-release capsule 135 mg per day [see Clinical Pharmacology (12.3)].


    Adverse reactions reported by 2% or more of patients treated with fenofibrate (and greater than placebo) during the double-blind, placebo-controlled trials are listed in Table 1. Adverse reactions led to discontinuation of treatment in 5% of patients treated with fenofibrate and in 3% treated with placebo. Increases in liver function tests were the most frequent events, causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials.


    Table 1. Adverse Reactions Reported by 2% or More of Patients Treated with Fenofibrate and Greater than Placebo During the Double-Blind, Placebo-Controlled Trials

    Adverse Reaction
    		Placebo (N =365)
    		Fenofibrate (N = 439)
    Abnormal Liver Tests
    		1%
    		8%
    Abdominal Pain
    		4%
    		5%
    Increased ALT
    		2%
    		3%
    Increased AST
    		1%
    		3%
    Increased Creatine Phosphokinase
    		1%
    		3%
    Constipation
    		1%
    		2%
    Rhinitis
    		1%
    		2%

    Other Adverse Reactions


    Urticaria


    Urticaria was seen in 1.1% vs. 0%, and rash in 1.4% vs. 0.8% of fenofibrate and placebo patients respectively in controlled trials.


    Increases in Liver Enzymes


    In a pooled analysis of three 12-week, double-blind, controlled studies of fenofibric acid delayed-release capsules, increases in ALT and AST > 3 times the upper limit of normal on two consecutive occasions occurred in 1.9% and 0.2%, respectively, of patients receiving fenofibric acid delayed-release capsules 135 mg daily and placebo, without other lipid-altering drugs.


    In a pooled analysis of 10 placebo-controlled trials, increases to > 3 times the upper limit of normal in ALT occurred in 5.3% of patients taking either an intermediate or maximum recommended daily dosage of fenofibrate versus 1.1% of patients treated with placebo. In an 8-week trial, the incidence of ALT or AST elevations ≥ 3 times the upper limit of normal was 13% in patients receiving an intermediate daily dosage or the maximum recommended daily dosage of fenofibrate and was 0% in those receiving the lowest recommended daily dosage of fenofibrate or placebo [see Warnings and Precautions (5.2)] .


    Clinical trials with fenofibric acid delayed-release capsules did not include a placebo-control arm. However, the adverse reaction profile of fenofibric acid delayed-release capsules was generally consistent with that of fenofibrate. The following adverse reactions not listed above for fenofibrate were reported in ≥ 3% of patients taking fenofibric acid delayed-release capsules:


    Gastrointestinal:Diarrhea, dyspepsia


    General:Pain


    Infections: Nasopharyngitis, sinusitis, upper respiratory tract infection


    Musculoskeletal and Connective Tissue: Arthralgia, myalgia, pain in extremity


    Nervous System: Dizziness

    6.2 Postmarketing Experience

    The following adverse reactions have been identified during post-approval use of fenofibrate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.


    Blood:Anemia


    Gastrointestinal:Pancreatitis

     

    General:Asthenia

     

    Hepatobiliary:Increased total bilirubin, hepatitis, cirrhosis

     

    Immune System:Anaphylaxis, angioedema

     

    Lipid Disorders:Severely depressed HDL-cholesterol levels

     

    Musculoskeletal:Muscle spasms, rhabdomyolysis

     

    Renal and Urinary:Acute renal failure

     

    Respiratory:Interstitial lung disease

     

    Skin and Subcutaneous Tissue:Photosensitivity reactions days to months after initiation. This may occur in patients who report a prior photosensitivity reaction to ketoprofen.


  • 7 DRUG INTERACTIONS

    Table 2 presents clinically important drug interactions with fenofibric acid delayed-release capsules.


    Table 2. Clinically Important Drug Interactions with Fenofibric acid delayed-release capsules

    Statins
    Clinical Impact:
    		Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with statins.
    Intervention:
    		Consider if the benefit of using fenofibric acid delayed-release capsules concomitantly with statin therapy outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dosage titration of statin therapy.
    Colchicine
    Clinical Impact:
    		Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with fenofibrates.
    Intervention:
    		Consider if the benefit of using colchicine concomitantly with fenofibric acid delayed-release capsules outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dosage titration of colchicine.
    Coumarin Anticoagulants
    Clinical Impact:
    		Fibrates may cause potentiation of coumarin-type anticoagulant effects with prolongation of the PT/INR.
    Intervention:
    		Caution should be exercised when coumarin anticoagulants are given in conjunction with fenofibric acid delayed-release capsules. The dosage of the anticoagulants should be reduced to maintain the PT/INR at the desired level to prevent bleeding complications. Frequent PT/INR determinations are advisable until it has been definitely determined that the PT/INR has stabilized
    Immunosuppressants
    Clinical Impact:
    		Immunosuppressants such as cyclosporine and tacrolimus can produce nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine, and because renal excretion is the primary elimination route of fibrate drugs including fenofibric acid delayed-release capsules, there is a risk that an interaction will lead to deterioration of renal function.
    Intervention:
    		The benefits and risks of using fenofibric acid delayed-release capsules with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dosage employed and renal function monitored.
    Bile-Acid Binding Resins
    Clinical Impact:
    		Bile-acid binding resins may bind other drugs given concurrently.
    Intervention:
    		In patients taking a bile acid resin, administer fenofibric acid delayed-release capsules at least 1 hour before or 4 to 6 hours after the bile acid resin to avoid impeding its absorption.

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary


    Limited available data with fenofibrate use in pregnant women are insufficient to determine a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no evidence of embryo-fetal toxicity was observed with oral administration of fenofibrate in rats and rabbits during organogenesis at doses less than or comparable to the maximum recommended clinical dosage of 135 mg of fenofibric acid delayed-release capsules daily, based on body surface area (mg/m 2). Adverse reproductive outcomes occurred at higher doses in the presence of maternal toxicity (see Data). Fenofibric acid delayed-release capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.


    The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.


    Data


    Animal Data


    In pregnant rats given oral dietary doses of 14 mg/kg/day, 127 mg/kg/day, and 361 mg/kg/day from gestation day 6 to 15 during the period of organogenesis, no adverse developmental findings were observed at 14 mg/kg/day (less than the clinical exposure at the maximum recommended human dose [MRHD] of 300 mg fenofibrate daily, comparable to 135 mg fenofibric acid delayed-release capsules daily, based on body surface area comparisons). Increased fetal skeletal malformations were observed at maternally toxic doses (361 mg/kg/day, corresponding to 12 times the clinical exposure at the MRHD) that significantly suppressed maternal body weight gain.


    In pregnant rabbits given oral gavage doses of 15 mg/kg/day, 150 mg/kg/day, and 300 mg/kg/day from gestation day 6 to 18 during the period of organogenesis and allowed to deliver, no adverse developmental findings were observed at 15 mg/kg/day (a dose that approximates the clinical exposure at the MRHD, based on body surface area comparisons). Aborted litters were observed at maternally toxic doses (≥ 150 mg/kg/day, corresponding to ≥ 10 times the clinical exposure at the MRHD) that suppressed maternal body weight gain.


    In pregnant rats given oral dietary doses of 15 mg/kg/day, 75 mg/kg/day, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), no adverse developmental effects were observed at 15 mg/kg/day (less than the clinical exposure at the MRHD, based on body surface area comparisons), despite maternal toxicity (decreased weight gain). Post-implantation loss was observed at ≥ 75 mg/kg/day (≥ 2 times the clinical exposure at the MRHD) in the presence of maternal toxicity (decreased weight gain). Decreased pup survival was noted at 300 mg/kg/day (10 times the clinical exposure at the MRHD), which was associated with decreased maternal body weight gain/maternal neglect.


    8.2 Lactation

    Risk Summary


    There is no available information on the presence of fenofibrate in human milk, effects of the drug on the breastfed infant, or the effects on milk production. Fenofibrate is present in the milk of rats and is therefore likely to be present in human milk. Because of the potential for serious adverse reactions in breastfed infants, such as disruption of infant lipid metabolism, women should not breastfeed during treatment with fenofibric acid delayed-release capsules and for 5 days after the final dose.


    8.4 Pediatric Use

    The safety and effectiveness of fenofibric acid delayed-release capsules have not been established in pediatric patients with severe hypertriglyceridemia or primary hyperlipidemia.


    8.5 Geriatric Use

    Assess renal function in geriatric patients and follow contraindications and dosing recommendations for patients with renal impairment [see Contraindications (4), Warnings and Precautions (5.3, 5.4), and   Use in Specific Populations (8.6)] . While fenofibric acid exposure is not influenced by age, geriatric patients are more likely to have renal impairment, and fenofibric acid is substantially excreted by the kidney [see Clinical Pharmacology (12.3)] . Consider monitoring renal function in geriatric patients taking fenofibric acid delayed-release capsules.


    8.6 Renal Impairment

    Fenofibric acid delayed-release capsules are contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73m 2), including those with end-stage renal disease (ESRD) and those receiving dialysis. Dosage reduction is required in patients with mild to moderate renal impairment [see Dosage and Administration (2.4)  and   Clinical Pharmacology (12.3)] . Patients with severe renal impairment have 2.7-fold higher exposure of fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared with healthy volunteers. Renal impairment is a risk factor for myopathy and rhabdomyolysis [see Warnings and Precautions (5.3, 5.4)  and   Clinical Pharmacology (12.3)].


    8.7 Hepatic Impairment

    The use of fenofibric acid delayed-release capsules has not been evaluated in patients with hepatic impairment. Fenofibric acid delayed-release capsules are contraindicated in patients with active liver disease, including those with unexplained persistent liver function abnormalities [see Clinical Pharmacology (12.3)] .


  • 10 OVERDOSAGE

    In the event of an overdose of fenofibric acid delayed-release capsules, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. There is no specific treatment for overdose with fenofibric acid delayed-release capsules. General supportive care of the patient is indicated, including monitoring of vital signs and observation of clinical status, should an overdose occur. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. Because fenofibric acid is highly bound to plasma proteins, hemodialysis should not be considered.


  • 11 DESCRIPTION

    Fenofibric acid delayed-release capsules (fenofibric acid) are a peroxisome proliferator-activated receptor (PPAR) alpha agonist available as delayed release capsules for oral administration. Each delayed release capsule contains choline fenofibrate, equivalent to 45 mg or 135 mg of fenofibric acid. The chemical name for choline fenofibrate is ethanaminium, 2-hydroxy-N,N,N-trimethyl, 2-{4-(4-chlorobenzoyl)phenoxy] -2-methylpropanoate (1:1) with the following structural formula:

    fenofibricacid-str.jpg  

    The molecular formula is C 22H 28ClNO 5and the molecular weight is 421.91. Choline fenofibrate is freely soluble in methanol, sparingly soluble in ethanol and water, slightly soluble in DMSO and practically insoluble in dichloromethane. The melting point is approximately 210°C. Choline fenofibrate is a white to off white crystalline powder, which is stable under ordinary conditions.


    Each delayed release capsule contains enteric coated mini-tablets comprised of choline fenofibrate and the following inactive ingredients: hypromellose, hydroxypropyl cellulose, methacrylic acid - ethyl acrylate copolymer (1:1) type A , microcrystalline cellulose, povidone K30, silicon dioxide, sodium stearyl fumarate, talc, triethyl citrate.


    The capsule shell of the 45 mg capsule contains the following inactive ingredients: ferrosoferric oxide, ferric oxide red, gelatin and titanium dioxide. The capsule shell of the 135 mg capsule contains the following inactive ingredients: FD&C blue no.1, FD&C red no.3, FD&C red no. 40, gelatin and titanium dioxide.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    The active moiety of fenofibric acid delayed-release capsules is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been studied through oral administration of fenofibrate.


    The lipid-modifying effects of fenofibric acid seen in clinical practice have been explained in vivoin transgenic mice and in vitroin human hepatocyte cultures by the activation of PPAR alpha receptor. Through this mechanism, fenofibric acid increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity).


    12.2 Pharmacodynamics

    Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total cholesterol (Total-C), total triglycerides, and triglyceride rich lipoprotein (VLDL) in treated patients with severe hypertriglyceridemia.


    12.3 Pharmacokinetics

    Fenofibric acid delayed-release capsules contains fenofibric acid, which is the circulating pharmacologically active moiety in plasma after oral administration of fenofibric acid delayed-release capsules. Fenofibric acid is also the circulating pharmacologically active moiety in plasma after oral administration of fenofibrate, the ester of fenofibric acid.


    Absorption


    Fenofibric acid is well absorbed throughout the gastrointestinal tract. The absolute bioavailability of fenofibric acid is approximately 81%.


    Peak plasma levels of fenofibric acid occur within 4 to 5 hours after a single dose administration of fenofibric acid delayed-release capsules capsule under fasting conditions.


    Effect of Food


    Fenofibric acid exposure in plasma, as measured by C maxand AUC, is not significantly different when a single 135 mg dose of fenofibric acid delayed-release capsules are administered under fasting or nonfasting conditions.


    Distribution


    Upon multiple dosing of fenofibric acid delayed-release capsules, fenofibric acid levels reach steady-state within 8 days. Plasma concentrations of fenofibric acid at steady-state are approximately double those following a single dose. Serum protein binding was approximately 99% in normal and dyslipidemic subjects.


    Elimination


    Fenofibric acid is eliminated with a half-life of approximately 20 hours, allowing once daily administration of fenofibric acid delayed-release capsules.


    Metabolism


    Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine.


    In vivometabolism data after fenofibrate administration indicate that fenofibric acid does not undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent.


    Excretion


    After absorption, fenofibric acid delayed-release capsules are primarily excreted in the urine in the form of fenofibric acid and fenofibric acid glucuronide.


    Specific Populations


    Geriatric Patients

     

    In geriatric volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following a single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that a similar dosage regimen can be used in geriatric patients with normal renal function, without increasing accumulation of the drug or metabolites [see Dosage and Administration (2.4)  and   Use in Specific Populations (8.5)] .


    Pediatric Patients


    The pharmacokinetics of fenofibric acid delayed-release capsules has not been studied in pediatric populations.

     

    Male and Female Patients


    No pharmacokinetic difference between males and females has been observed for fenofibric acid.

     

    Racial and Ethnic Groups


    The influence of race on the pharmacokinetics of fenofibric acid has not been studied; however, fenofibric acid is not metabolized by enzymes known for exhibiting inter-ethnic variability.

     

    Patients with Renal Impairment


    The pharmacokinetics of fenofibric acid were examined in patients with mild, moderate, and severe renal impairment. Patients with severe renal impairment (creatinine clearance [CrCl ≤30 mL/min] or estimated glomerular filtration rate [eGFR] <30 mL/min/1.73m 2) showed a 2.7-fold increase in exposure for fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared to that of healthy subjects. Patients with mild to moderate renal impairment (CrCl 30 mL/min to 80 mL/min or eGFR 30 to 59 mL/min/1.73m 2) had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects [see Dosage and Administration (2.3)] .

     

    Patients with Hepatic Impairment


    No pharmacokinetic studies have been conducted in patients with hepatic impairment.


    Drug Interaction Studies

     

    In vitrostudies using human liver microsomes indicate that fenofibric acid is not an inhibitor of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. It is a weak inhibitor of CYP2C8, CYP2C19, and CYP2A6, and mild-to-moderate inhibitor of CYP2C9 at therapeutic concentrations.


    Comparison of atorvastatin exposures when atorvastatin (80 mg once daily for 10 days) is given in combination with fenofibric acid (fenofibric acid delayed-release capsules 135 mg once daily for 10 days) and ezetimibe (10 mg once daily for 10 days) versus when atorvastatin is given in combination with ezetimibe only (ezetimibe 10 mg once daily and atorvastatin, 80 mg once daily for 10 days): The C maxdecreased by 1% for atorvastatin and ortho-hydroxy-atorvastatin and increased by 2% for parahydroxy­-atorvastatin. The AUC decreased 6% and 9% for atorvastatin and orthohydroxy-atorvastatin, respectively, and did not change for para-hydroxy-atorvastatin.


    Comparison of ezetimibe exposures when ezetimibe (10 mg once daily for 10 days) is given in combination with fenofibric acid (fenofibric acid delayed-release capsules 135 mg once daily for 10 days) and atorvastatin (80 mg once daily for 10 days) versus when ezetimibe is given in combination with atorvastatin only (ezetimibe 10 mg once daily and atorvastatin, 80 mg once daily for 10 days): The C maxincreased by 26% and 7% for total and free ezetimibe, respectively. The AUC increased by 27% and 12% for total and free ezetimibe, respectively.


    Table 3 describes the effects of co-administered drugs on fenofibric acid systemic exposure. Table 4 describes the effects of co-administered fenofibric acid on systemic exposure of other drugs.


    Table 3. Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Fenofibric Acid Delayed-Release Capsules or Fenofibrate Administration

    Co-Administered Drug
    		Dosage Regimen of
    Co-Administered Drug
    		Dosage Regimen of
    Fenofibric Acid Delayed-Release Capsules or Fenofibrate
    		Changes in Fenofibric Acid Exposure
     
    		AUC
    		C max
    Lipid-lowering medications
    Rosuvastatin
    		40 mg once daily for 10 days
    		Fenofibric acid delayed-release capsules 135 mg once daily for10 days
    		↓2%
    		↓2%
    Atorvastatin
    		20 mg once daily for 10 days
    		Fenofibrate 160 mg 1once daily for 10 days
    		↓2%
    		↓4%
    Atorvastatin + ezetimibe
    		Atorvastatin, 80 mg once daily and ezetimibe, 10 mg once daily for 10 days
    		Fenofibric acid delayed-release capsules 135 mg once daily for 10 days
    		↑5%
    		↑5%
    Pravastatin
    		40 mg as a single dose
    		Fenofibrate 3 x 67 mg 2as a single dose
    		↓1%
    		↓2%
    Fluvastatin
    		40 mg as a single dose
    		Fenofibrate 160 mg 1as a single dose
    		↓2%
    		↓10%
    Simvastatin
    		80 mg once daily for 7 days
    		Fenofibrate 160 mg 1once daily for 7 days
    		↓5%
    		↓11%
    Anti-diabetic medications
    Glimepiride
    		1 mg as a single dose
    		Fenofibrate 145 mg 1once daily for 10 days
    		↑1%
    		↓1%
    Metformin
    		850 mg three times daily for 10 days
    		Fenofibrate 54 mg 1three times daily for 10 days
    		↓9%
    		↓6%
    Rosiglitazone
    		8 mg once daily for 5 days
    		Fenofibrate 145 mg 1once daily for 14 days
    		↑10%
    		↑3%
    Gastrointestinal medications
    Omeprazole
    		40 mg once daily for 5 days
    		Fenofibric acid delayed-release capsules 135 mg as a single dose fasting
    		↑6%
    		↑17%
    Omeprazole
    		40 mg once daily for 5 days
    		Fenofibric acid delayed-release capsules 135 mg as a single dose with food
    		↑4%
    		↓2%
    1TriCor (fenofibrate) oral tablet
    2TriCor (fenofibrate) oral micronized capsule

    Table 4. Effects of Fenofibric Acid Delayed-Release Capsules or Fenofibrate Co-Administration on Systemic Exposure of Other Drugs

    Dosage Regimen of Fenofibric Acid Delayed-Release Capsules or Fenofibrate
    		Dosage Regimen of Co-Administered Drug
    		Changes in Co-Administered Drug Exposure
     
    		Analyte
    		AUC
    		C max
    Lipid-lowering medications
    Fenofibric acid delayed-release capsules 135 mg once daily for 10 days
    		Rosuvastatin, 40 mg once daily for 10 days
    		Rosuvastatin
    		↑6%
    		↑20%
    Fenofibrate 160 mg 1once daily for 10 days
    		Atorvastatin, 20 mg once daily for 10 days
    		Atorvastatin
    		↓17%
    		0%
    Fenofibrate 3 x 67 mg 2as a single dose
    		Pravastatin, 40 mg as a single dose
     
    		Pravastatin
    		↑13%
    		↑13%
    3α-hydroxyl-iso-pravastatin
    		↑26%
    		↑29%
    Fenofibrate 160 mg 1as a single dose
    		Fluvastatin, 40 mg as a single dose
    		(+)-3R, 5S-Fluvastatin
    		↑15%
    		↑16%
    Fenofibrate 160 mg 1once daily for 7 days
     
    		Simvastatin, 80 mg once daily for 7 days
     
    		Simvastatin acid
    		↓36%
    		↓11%
    Simvastatin
    		↓11%
    		↓17%
    Active HMG-CoA Inhibitors
    		↓12%
    		↓1%
    Total HMG-CoA Inhibitors
    		↓8%
    		↓10%
    Anti-diabetic medications
    Fenofibrate 145 mg 1once daily for 10 days
    		Glimepiride, 1 mg as a single dose
    		Glimepiride
    		↑35%
    		↑18%
    Fenofibrate 54 mg 1three times daily for 10 days
    		Metformin, 850 mg three times daily for 10 days
    		Metformin
    		↑3%
    		↑6%
    Fenofibrate 145 mg 1once daily for 14 days
    		Rosiglitazone, 8 mg once daily for 5 days
    		Rosiglitazone
    		↑6%
    		↓1%
    1TriCor (fenofibrate) oral tablet
    2TriCor (fenofibrate) oral micronized capsule

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

    Fenofibric acid delayed-release capsules (fenofibric acid)


    No carcinogenicity and fertility studies have been conducted with choline fenofibrate or fenofibric acid. However, because fenofibrate is rapidly converted to its active metabolite, fenofibric acid, either during or immediately following absorption both in animals and humans, studies conducted with fenofibrate are relevant for the assessment of the toxicity profile of fenofibric acid. A similar toxicity spectrum is expected after treatment with either fenofibric acid delayed-release capsules or fenofibrate.


    Fenofibrate


    Carcinogenesis


    Two dietary carcinogenicity studies have been conducted in rats with fenofibrate. In the first 24-month study, Wistar rats were dosed with fenofibrate at 10 mg/kg/day, 45 mg/kg/day, and 200 mg/kg/day, approximately 0.3 times, 1 time, and 6 times the maximum recommended human dose (MRHD), based on body surface area comparisons (mg/m 2). At a dose of 200 mg/kg/day (at 6 times the MRHD), the incidence of liver carcinomas was significantly increased in both sexes. A statistically significant increase in pancreatic carcinomas was observed in males at 1 and 6 times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed at 6 times the MRHD in males. In a second 24-month study in a different strain of rats (Sprague-Dawley), doses of 10 mg/kg/day and 60 mg/kg/day (0.3 and 2 times the MRHD) produced significant increases in the incidence of pancreatic acinar adenomas in both sexes and increases in testicular interstitial cell tumors in males at 2 times the MRHD.


    A 117-week carcinogenicity study was conducted in rats comparing three drugs: fenofibrate 10 mg/kg/day and 60 mg/kg/day (0.3 and 2 times the MRHD), clofibrate (400 mg/kg/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the human dose) based on mg/m 2surface area. Fenofibrate increased pancreatic acinar adenomas in both sexes. Clofibrate increased hepatocellular carcinoma and pancreatic acinar adenomas in males and hepatic neoplastic nodules in females. Gemfibrozil increased hepatic neoplastic nodules in males and females, while all three drugs increased testicular interstitial cell tumors in males.


    In a 21-month study in CF-1 mice, fenofibrate 10 mg/kg/day, 45 mg/kg/day, and 200 mg/kg/day (approximately 0.2 times, 1 time, and 3 times the MRHD on the basis of mg/m 2surface area) significantly increased the liver carcinomas in both sexes at 3 times the MRHD. In a second 18-month study at 10 mg/kg/day, 60 mg/kg/day, and 200 mg/kg/day, fenofibrate significantly increased the liver carcinomas in male mice and liver adenomas in female mice at 3 times the MRHD.


    Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual.


    Mutagenesis


    Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and unscheduled DNA synthesis in primary rat hepatocytes.


    Impairment of Fertility


    In fertility studies rats were given oral dietary doses of fenofibrate, males received 61 days prior to mating and females 15 days prior to mating through weaning which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (approximately 10 times the MRHD, based on mg/m 2surface area comparisons).


  • 14 CLINICAL STUDIES

    14.1 Overview of Clinical Trials

    The effectiveness of fenofibric acid delayed-release capsules has been established in adults with hypertriglyceridemia or primary hyperlipidemia based on adequate and well-controlled trials of other formulations of fenofibrate, referenced below as “fenofibrate.” Dosages of fenofibrate used in these trials were comparable to fenofibric acid delayed-release capsule 135 mg per day [see Clinical Pharmacology (12.3)].


    14.2 Clinical Trials in Adults with Hypertriglyceridemia

    The effects of fenofibrate on serum TG were studied in two randomized, double-blind, placebo-controlled clinical trials of 147 patients with hypertriglyceridemia. Patients were treated for 8 weeks under protocols that differed only in that one entered patients with baseline TG levels of 500 to 1,500 mg/dL, and the other TG levels of 350 to 499 mg/dL. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia, treatment with fenofibrate decreased primarily very low-density lipoprotein (VLDL) TG and VLDL cholesterol (VLDL-C). Treatment of patients with elevated TG often results in an increase of LDL-C (see Table 5).


    Table 5. Effects of Fenofibrate in Patients with Hypertriglyceridemia

    Trial 1
    		Placebo
    		Fenofibrate
    Baseline TG levels
    350 to 499 mg/dL
    		N
    		Baseline Mean (mg/dL)
    		Endpoint Mean (mg/dL)
    		Mean % Change
    		N
    		Baseline Mean (mg/dL)
    		Endpoint Mean (mg/dL)
    		Mean % Change
    TG
    		28
    		449
    		450
    		-0.5
    		27
    		432
    		223
    		-46.2*
    VLDL-TG
    		19
    		367
    		350
    		2.7
    		19
    		350
    		178
    		-44.1*
    Total-C
    		28
    		255
    		261
    		2.8
    		27
    		252
    		227
    		-9.1*
    HDL-C
    		28
    		35
    		36
    		4
    		27
    		34
    		40
    		19.6*
    LDL-C
    		28
    		120
    		129
    		12
    		27
    		128
    		137
    		14.5
    VLDL-C
    		27
    		99
    		99
    		5.8
    		27
    		92
    		46
    		-44.7*
    Trial 2
    		Placebo
    		Fenofibrate
    Baseline TG levels
    500 to 1500 mg/dL
    		N
    		Baseline Mean (mg/dL)
    		Endpoint Mean (mg/dL)
    		Mean % Change
    		N
    		Baseline Mean (mg/dL)
    		Endpoint Mean (mg/dL)
    		Mean % Change
    TG
    		44
    		710
    		750
    		7.2
    		48
    		726
    		308
    		-54.5*
    VLDL-TG
    		29
    		537
    		571
    		18.7
    		33
    		543
    		205
    		-50.6*
    Total-C
    		44
    		272
    		271
    		0.4
    		48
    		261
    		223
    		-13.8*
    HDL-C
    		44
    		27
    		28
    		5.0
    		48
    		30
    		36
    		22.9*
    LDL-C
    		42
    		100
    		90
    		-4.2
    		45
    		103
    		131
    		45.0*
    VLDL-C
    		42
    		137
    		142
    		11.0
    		45
    		126
    		54
    		-49.4*
    * = p < 0.05 vs. Placebo

    14.3 Clinical Trials in Adults with Primary Hyperlipidemia

    The effects of fenofibrate were assessed in four randomized, placebo-controlled, double-blind, parallel-group trials in patients with hyperlipidemia and mixed dyslipidemia. Fenofibrate therapy reduced LDL-C, Total-C, and TG, and increased HDL-C (Table 6).


    Table 6. Mean Percent Change in Lipid Parameters at End of Treatment †

    Treatment Group
    		Total-C
    		LDL-C
    		HDL-C
    		TG
    Mean baseline lipid values (n = 646)
    		306.9 mg/dL
    		213.8 mg/dL
    		52.3 mg/dL
    		191.0 mg/dL
    All fenofibrate (n = 361)
    		-18.7%*
    		-20.6%*
    		+11.0%*
    		-28.9%*
    Placebo (n = 285)
    		-0.4%
    		-2.2%
    		+0.7%
    		+7.7%
    † Duration of study treatment was 3 to 6 months
    * p = < 0.05 vs. Placebo

    14.4 Lack of Efficacy in Cardiovascular Outcomes Trials

    Fenofibrate did not reduce cardiovascular disease morbidity or mortality in two large, randomized controlled trials of patients with type 2 diabetes mellitus.


    The Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) (NCT00000620) trial was a randomized placebo-controlled trial of 5,518 patients (2,765 assigned to receive fenofibrate) with type 2 diabetes mellitus on background statin therapy treated with fenofibrate. The mean age at baseline was 62 years and 31% were female. Overall, 68% were White, 15% were Black or African American; 7% identified as Hispanic or Latino ethnicity. The mean duration of follow-up was 4.7 years. The primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular disease death was a HR of 0.92 (95% CI, 0.79 to 1.08) for fenofibrate plus statin combination therapy as compared to statin monotherapy.


    The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial was a 5-year randomized, placebo-controlled trial of 9,795 patients (4,895 assigned to receive fenofibrate) with type 2 diabetes mellitus treated with fenofibrate. The mean age at baseline was 62 years, 37% were female, and 93% were White. The primary outcome of coronary heart disease events was a HR of 0.89 (95% CI, 0.75 to 1.05) with fenofibrate compared to placebo. The HR for total and coronary heart disease mortality, respectively, was 1.11 (95% CI, 0.95 to 1.29) and 1.19 (95% CI, 0.90 to 1.57) with fenofibrate as compared to placebo.


    Because of chemical, pharmacological, and clinical similarities between fenofibrate and pemafibrate, findings in a large randomized, placebo-controlled clinical trial with pemafibrate are relevant for fenofibric acid delayed-release capsules.


    Pemafibrate did not reduce cardiovascular disease morbidity or mortality in a large, randomized, placebo-controlled trial of patients with type 2 diabetes mellitus (TG levels of 200 to 499 mg per deciliter and HDL-C levels of 40 mg per deciliter or lower), on background statin therapy (NCT03071692). The trial was a randomized placebo-controlled trial of 10,497 patients (5,240 assigned to receive pemafibrate) with type 2 diabetes mellitus on background lipid-lowering therapy. The median age at baseline was 64 years and 28% were female. Overall, 86% were White, 5% were Asian, 3% were Black or African American; 19% identified as Hispanic or Latino ethnicity. The median duration of follow-up was 3.4 years. The primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non-fatal ischemic stroke, coronary revascularization, and death from cardiovascular causes, was a HR of 1.03 (95% CI, 0.91 to 1.15) for pemafibrate plus statin combination therapy as compared to statin monotherapy.


  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Fenofibric acid delayed-release capsules 45 mg: Reddish brown opaque cap imprinted with “CDR” and  yellow opaque body imprinted with “45”, size “3”, hard gelatin capsule contains 4 white to off-white, round, biconvex delayed release mini tablets.


    Bottles of 30                                                               NDC: 42571-347-30

    Bottles of 90                                                               NDC: 42571-347-90


    Fenofibric acid delayed-release capsules135 mg: Blue opaque cap imprinted with “CDR” and yellow opaque body imprinted with “135”, size “0”, hard gelatin capsule contains 12 white to off-white, round, biconvex delayed release mini tablets.


    Bottles of 30                                                               NDC: 42571-348-30

    Bottles of 90                                                               NDC: 42571-348-90

    Bottles of 500                                                             NDC: 42571-348-05


    Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP controlled room temperature]. Keep out of the reach of children. Protect from moisture.

  • 17 PATIENT COUNSELING INFORMATION

    Hepatotoxicity


    Inform patients that fenofibric acid delayed-release capsules may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Contraindications (4)  and   Warnings and Precautions (5.2)] .


    Myopathy and Rhabdomyolysis


    Advise patients that fenofibric acid delayed-release capsules may cause myopathy and rhabdomyolysis. Inform patients that the risk is also increased when taking certain types of medication and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to inform other healthcare providers prescribing a new medication or increasing the dosage of an existing medication that they are taking fenofibric acid delayed-release capsules. Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever [see Warnings and Precautions (5.3)  and   Drug Interactions (7)] .


    Increased Bleeding Risk with Coumarin Anticoagulants


    Inform patients that the concomitant use of fenofibric acid delayed-release capsules with coumarin-type anticoagulants may increase the risk of bleeding. Advise patients if they are taking or planning to take coumarin-type anticoagulants to inform their healthcare providers and that increased monitoring may be necessary [see Warnings and Precautions (5.6)  and   Drug Interactions (7)] .


    Hypersensitivity Reactions


    Inform patients that serious hypersensitivity reactions, such as anaphylaxis and angioedema, have been reported with fenofibrates. Advise patients to report immediately any signs or symptoms suggesting allergic reaction, and to discontinue drug until they have consulted prescribing physicians [see Warnings and Precautions (5.9)] .


    Pregnancy


    Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if fenofibric acid delayed-release capsules should be discontinued [see Use in Specific Populations (8.1)] .


    Lactation


    Advise patients that breastfeeding during treatment with fenofibric acid delayed-release capsules are not recommended [see Use in Specific Populations (8.2)].


    Missed Doses


    If a dose is missed, advise patients to not take an extra dose and to resume treatment with the next dose.


    Manufactured by:

    Micro Labs Limited

    Goa-403 722, INDIA.


    Manufactured for:

    Micro Labs USA Inc.

    Somerset, NJ 08873


    Rev. 06/2025


  • PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

    NDC: 42571-347-90
    Fenofibric acid Delayed-Release Capsules
    45 mg*
    Rx Only
    90 Capsules
    MICRO LABS LIMITED

    fenofibricacid-lbla.jpg

    NDC: 42571-348-90
    Fenofibric acid Delayed-Release Capsules
    135 mg*
    Rx Only
    90 Capsules
    MICRO LABS LIMITED

    fenofibricacid-lblb.jpg

  • INGREDIENTS AND APPEARANCE
    FENOFIBRIC ACID 
    fenofibric acid capsule, delayed release
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 42571-347
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    FENOFIBRIC ACID (UNII: BGF9MN2HU1) (FENOFIBRIC ACID - UNII:BGF9MN2HU1) FENOFIBRIC ACID45 mg
    Inactive Ingredients
    Ingredient NameStrength
    HYPROMELLOSE 2208 (15000 MPA.S) (UNII: Z78RG6M2N2)  
    HYDROXYPROPYL CELLULOSE (110000 WAMW) (UNII: 5Y0974F5PW)  
    METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER (1:1) TYPE A (UNII: NX76LV5T8J)  
    MICROCRYSTALLINE CELLULOSE 101 (UNII: 7T9FYH5QMK)  
    POVIDONE K30 (UNII: U725QWY32X)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    SODIUM STEARYL FUMARATE (UNII: 7CV7WJK4UI)  
    TALC (UNII: 7SEV7J4R1U)  
    TRIETHYL CITRATE (UNII: 8Z96QXD6UM)  
    FERROSOFERRIC OXIDE (UNII: XM0M87F357)  
    FERRIC OXIDE RED (UNII: 1K09F3G675)  
    GELATIN (UNII: 2G86QN327L)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    Product Characteristics
    Colorred (Reddish brown opaque cap) , yellow (yellow opaque body) Scoreno score
    ShapeCAPSULESize16mm
    FlavorImprint Code CDR;45
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 42571-347-3030 in 1 BOTTLE; Type 0: Not a Combination Product09/01/2020
    2NDC: 42571-347-9090 in 1 BOTTLE; Type 0: Not a Combination Product09/01/2020
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21345009/01/2020
    FENOFIBRIC ACID 
    fenofibric acid capsule, delayed release
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 42571-348
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    FENOFIBRIC ACID (UNII: BGF9MN2HU1) (FENOFIBRIC ACID - UNII:BGF9MN2HU1) FENOFIBRIC ACID135 mg
    Inactive Ingredients
    Ingredient NameStrength
    HYPROMELLOSE 2208 (15000 MPA.S) (UNII: Z78RG6M2N2)  
    HYDROXYPROPYL CELLULOSE (110000 WAMW) (UNII: 5Y0974F5PW)  
    METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER (1:1) TYPE A (UNII: NX76LV5T8J)  
    MICROCRYSTALLINE CELLULOSE 101 (UNII: 7T9FYH5QMK)  
    POVIDONE K30 (UNII: U725QWY32X)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    SODIUM STEARYL FUMARATE (UNII: 7CV7WJK4UI)  
    TALC (UNII: 7SEV7J4R1U)  
    TRIETHYL CITRATE (UNII: 8Z96QXD6UM)  
    FD&C BLUE NO. 1 (UNII: H3R47K3TBD)  
    FD&C RED NO. 3 (UNII: PN2ZH5LOQY)  
    FD&C RED NO. 40 (UNII: WZB9127XOA)  
    GELATIN (UNII: 2G86QN327L)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    Product Characteristics
    Colorblue (OPAQUE CAP) , yellow (OPAQUE BODY) Scoreno score
    ShapeCAPSULESize21mm
    FlavorImprint Code CDR;135
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 42571-348-3030 in 1 BOTTLE; Type 0: Not a Combination Product09/01/2020
    2NDC: 42571-348-9090 in 1 BOTTLE; Type 0: Not a Combination Product09/01/2020
    3NDC: 42571-348-05500 in 1 BOTTLE; Type 0: Not a Combination Product09/01/2020
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21345009/01/2020
    Labeler - Micro Labs Limited (862174955)
    Establishment
    NameAddressID/FEIBusiness Operations
    Micro Labs Limited915793658analysis(42571-347, 42571-348) , label(42571-347, 42571-348) , manufacture(42571-347, 42571-348) , pack(42571-347, 42571-348)
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