Fenofibric Acid

• 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.

• 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
  
  

  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.

  
  
  

  ]
  
  

  .
  
• Fenofibrate didnot  reduce coronary heart disease morbidity and mortality in two large, randomized controlled trials of patients with type 2 diabetesmellitus 
  
  

  [see
  
  

  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.

  
  
  

   
  
  

  and
  
  

   
  
  

  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.

  
  
  

  ]
  
  

  .
  

• Severe hypertriglyceridemia:
  45 to 135 mg orally once daily; the dosage should be adjusted according to patient response (
  
  
  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.

  
  
  
  ).
  
• Primary hyperlipidemia:
  135 mg orally once daily (
  
  
  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.

  
  
  
  ).
  
• Administer as a single dose, at any time of day, with or without food (
  
  
  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.

  
  
  
  ).
  
• Assess TG when clinically appropriate, as early as 4 to 8 weeks after initiating fenofibric acid delayed-release capsules. Discontinue fenofibric acid delayed-release capsules in patients who do not have an adequate response after 2 months of treatment (
  
  
  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.

  
  
  
  ).
  
• Swallow capsules whole. Do not crush, break, dissolve, or chew (
  
  
  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.

  
  
  
  ).
  
• Renal impairment:
  Initial dosage of 45 mg orally once daily (
  
  
  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/1.73m²), 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/1.73m²), including those with end-stagerenal  disease (ESRD) and those receiving dialysis

    [see Use in Specific Populations (8.6)

    and

    Clinical Pharmacology (12.3)]

    .

  
  
  
  ).
  
• Geriatric patients:
  Select the dosage on the basis of renal function (
  
  
  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)]

  .

  
  
  
  ).
  

• 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 capsules
  135 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.
  

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.

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.