PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. variety of clinical studies have demonstrated that elevated levels of total -C, LDL-C, and apo B, an LDL membrane complex, are risk factors for human atherosclerosis. Similarly, decreased levels of HDL-C and its transport complex, apolipoprotein (apo AI and apo AII) are risk factors for the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C, LDL-C, and TG, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering TG on the risk of cardiovascular morbidity and mortality has not been determined.Fenofibric acid, the active metabolite of fenofibrate, produces reductions in TC, LDL-C, apo B, total triglycerides, and triglyceride-rich lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate results in increases in HDL and apoproteins apo AI and apo AII.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Fenofibrate is pro-drug of the active chemical moiety fenofibric acid. Fenofibrate is converted by ester hydrolysis in the body to fenofibric acid which is the active constituent measurable in the circulation.Plasma concentrations of fenofibric acid after single-dose administration of fenofibrate tablets, 120 mg are equivalent to those of fenofibrate 130 mg capsules under high-fat conditions.A high-fat meal did not affect the fenofibric acid AUC after fenofibrate administration but did increase the mean Cmax by 44% compared to fasting conditions.oAbsorption: The absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, fenofibrate is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of single dose of radiolabelled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid from fenofibrate occur, on average, within to hours after administration. Doses of three fenofibrate tablets, 40 mg are considered to be equivalent to single doses of fenofibrate tablets, 120 mg.oDistribution: In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within week of dosing and did not demonstrate accumulation across time following multiple dose administration. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.oMetabolism: Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate is detected in plasma.Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. small amount of fenofibric acid is reduced at the carbonyl moiety to benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine. In vivo metabolism data indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to significant extent.oElimination: After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabelled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces.Fenofibric acid from fenofibrate is eliminated with half-life of 23 hours, allowing once daily dosing.oGeriatrics: In elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that similar dosage regimen can be used in the elderly, without increasing accumulation of the drug or metabolites [see Dosage and Administration (2.5) and Use in Specific Populations (8.5)].oPediatrics: The pharmacokinetics of fenofibrate has not been studied in pediatric populations.oGender: No pharmacokinetic difference between males and females has been observed for fenofibrate.oRace: The influence of race on the pharmacokinetics of fenofibrate has not been studied; however, fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability.oRenal 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/1.73m2) showed 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 30-80 mL/min or eGFR 30-59 mL/min/1.73m2) had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of fenofibrate should be avoided in patients who have severe renal impairment and dose reduction is required in patients having mild to moderate renal impairment. [See Dosage and Administration (2.4).] oHepatic Impairment: No pharmacokinetic studies have been conducted in patients with hepatic impairment.oDrug-Drug Interactions: In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations. Table describes the effects of co-administered drugs on fenofibric acid systemic exposure. Table describes the effects of co-administered fenofibrate or fenofibric acid on systemic exposure of other drugs.Table 2. Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Fenofibrate AdministrationCo-Administered DrugDosage Regimen of Co-Administered DrugDosage Regimen of FenofibrateChanges in Fenofibric Acid Exposure AUCCmax Lipid-lowering agentsAtorvastatin20 mg once daily for 10 daysFenofibrate 160 mgTriCor (fenofibrate) oral tablet once daily for 10 days2%4%Pravastatin40 mg as single doseFenofibrate x 67 mgTriCor (fenofibrate) oral micronized capsule as single dose1%2%Fluvastatin40 mg as single doseFenofibrate 160 mg as single dose2%10%Anti-diabetic agentsGlimepiride1 mg as single doseFenofibrate 145 mg once daily for 10 days1%1%Metformin850 mg three times daily for 10 daysFenofibrate 54 mg three times daily for 10 days9%6%Rosiglitazone8 mg once daily for daysFenofibrate 145 mg once daily for 14 days10%3%Table 3. Effects of Fenofibrate Co-Administration on Systemic Exposure of Other DrugsDosage Regimen of FenofibrateDosage Regimen of Co-Administered DrugChange in Co-Administered Drug ExposureAnalyteAUCCmax Lipid-lowering agentsFenofibrate 160 mgTriCor (fenofibrate) oral tablet once daily for 10 daysAtorvastatin, 20 mg once daily for 10 daysAtorvastatin17%0%Fenofibrate x 67 mgTriCor (fenofibrate) oral micronized capsule as single-dose Pravastatin, 40 mg as single dosePravastatin13%13%3-Hydroxyl-iso-pravastatin26%29%Fenofibrate 160 mg as single-doseFluvastatin, 40 mg as single dose(+)-3R, 5S-Fluvastatin15%16%Anti-diabetic agentsFenofibrate 145 mg once daily for 10 daysGlimepiride, mg as single doseGlimepiride35%18%Fenofibrate 54 mg three times daily for 10 daysMetformin, 850 mg three times daily for 10 daysMetformin3%6%Fenofibrate 145 mg once daily for 14 days Rosiglitazone, mg once daily for daysRosiglitazone6%1%. oAbsorption: The absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, fenofibrate is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of single dose of radiolabelled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid from fenofibrate occur, on average, within to hours after administration. oDistribution: In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within week of dosing and did not demonstrate accumulation across time following multiple dose administration. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.. oMetabolism: Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate is detected in plasma.Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. small amount of fenofibric acid is reduced at the carbonyl moiety to benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine. In vivo metabolism data indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to significant extent.. oElimination: After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabelled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces.Fenofibric acid from fenofibrate is eliminated with half-life of 23 hours, allowing once daily dosing.. oGeriatrics: In elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that similar dosage regimen can be used in the elderly, without increasing accumulation of the drug or metabolites [see Dosage and Administration (2.5) and Use in Specific Populations (8.5)].. oPediatrics: The pharmacokinetics of fenofibrate has not been studied in pediatric populations.. oGender: No pharmacokinetic difference between males and females has been observed for fenofibrate.. oRace: The influence of race on the pharmacokinetics of fenofibrate has not been studied; however, fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability.. oRenal 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/1.73m2) showed 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 30-80 mL/min or eGFR 30-59 mL/min/1.73m2) had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of fenofibrate should be avoided in patients who have severe renal impairment and dose reduction is required in patients having mild to moderate renal impairment. [See Dosage and Administration (2.4).] oHepatic Impairment: No pharmacokinetic studies have been conducted in patients with hepatic impairment.. oDrug-Drug Interactions: In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.. Table describes the effects of co-administered drugs on fenofibric acid systemic exposure. Table describes the effects of co-administered fenofibrate or fenofibric acid on systemic exposure of other drugs.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are described below and elsewhere in the labeling: oMortality and coronary heart disease morbidity [see Warnings and Precautions (5.1)]oHepatoxicity [see Warnings and Precautions (5.2)]oPancreatitis [see Warnings and Precautions (5.7)]oHypersensitivity Reactions [see Warnings and Precautions (5.9)]oVenothromboembolic Disease [see Warnings and Precautions (5.10)]. oMortality and coronary heart disease morbidity [see Warnings and Precautions (5.1)]. oHepatoxicity [see Warnings and Precautions (5.2)]. oPancreatitis [see Warnings and Precautions (5.7)]. oHypersensitivity Reactions [see Warnings and Precautions (5.9)]. oVenothromboembolic Disease [see Warnings and Precautions (5.10)]. The most common adverse reactions (>2% and at least 1% greater than placebo) are abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis. (6)To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect rates observed in clinical practice.Adverse reactions reported by 2% or more of patients treated with fenofibrate and greater than placebo during double-blind, placebo-controlled trials are listed in Table 1. Adverse reactions led to discontinuation of treatment in 5.0% of patients treated with fenofibrate and in 3.0% 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 TrialsBODY SYSTEM Adverse Reaction FenofibrateDosage equivalent to 130 mg fenofibrate(N=439)Placebo (N=365)BODY AS WHOLE Abdominal Pain4.6%4.4% Back Pain3.4%2.5% Headache3.2%2.7%DIGESTIVE Nausea2.3%1.9% Constipation2.1%1.4%METABOLIC AND NUTRITIONAL DISORDERS Abnormal Liver Tests7.5%1.4% Increased AST3.4%0.5% Increased ALT3.0%1.6% Increased Creatine Phosphokinase3.0%1.4%RESPIRATORY Respiratory Disorder6.2%5.5% Rhinitis2.3%1.1%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 EnzymesIn 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 fenofibrate at doses equivalent to 87 mg to 130 mg fenofibrate daily (at the highest dose, comparable to fenofibrate, 120 mg) versus 1.1% of patients treated with placebo. In an 8-week study, the incidence of ALT or AST elevations >= times the upper limit of normal was 13% in patients receiving dosages equivalent to 87 mg to 130 mg fenofibrate daily and was 0% in those receiving dosages equivalent to 43 mg or less fenofibrate daily or placebo.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post approval use of fenofibrate. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure:myalgia, rhabdomyolysis, pancreatitis, acute renal failure, muscle spasms, hepatitis, cirrhosis, increased total bilirubin, anemia, arthralgia, decreases in hematocrit, white blood cell decreases, asthenia, severely depressed HDL cholesterol levels, and interstitial lung disease. Photosensitivity reactions have occurred days to months after initiation; in some of these cases, patients reported prior photosensitivity reaction to ketoprofen.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 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, 45, and 200 mg/kg/day, approximately 0.3, 1, and times the maximum recommended human dose (MRHD), based on body surface area comparisons (mg/m2). At dose of 200 mg/kg/day (at times the MRHD), the incidence of liver carcinomas was significantly increased in both sexes. statistically significant increase in pancreatic carcinomas was observed in males at and times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed at times the MRHD in males. In second 24-month rat carcinogenicity study in different strain of rats (Sprague-Dawley), doses of 10 and 60 mg/kg/day (0.3 and 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 times the MRHD.A 117-week carcinogenicity study was conducted in rats comparing three drugs: fenofibrate 10 and 60 mg/kg/day (0.3 and times the MRHD), clofibrate (400 mg/kg/day; times the human dose), and gemfibrozil (250 mg/kg/day; times the human dose, based on mg/m2 surface 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 21-month study in CF-1 mice, fenofibrate 10, 45, and 200 mg/kg/day (approximately 0.2, 1, and times the MRHD on the basis of mg/m2 surface area) significantly increased the liver carcinomas in both sexes at times the MRHD. In second 18-month study at 10, 60, and 200 mg/kg/day, fenofibrate significantly increased the liver carcinomas in male mice and liver adenomas in female mice at 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 (~10 times the MRHD, based on mg/m2 surface area comparisons).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The active moiety of fenofibrate tablets is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been extensively studied through oral administration of fenofibrate.The lipid-lowering effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor alpha (PPAR). Through this mechanism, fenofibrate 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). The resulting decrease in TG produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPAR also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol.Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid.. 12.2 Pharmacodynamics. variety of clinical studies have demonstrated that elevated levels of total -C, LDL-C, and apo B, an LDL membrane complex, are risk factors for human atherosclerosis. Similarly, decreased levels of HDL-C and its transport complex, apolipoprotein (apo AI and apo AII) are risk factors for the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C, LDL-C, and TG, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering TG on the risk of cardiovascular morbidity and mortality has not been determined.Fenofibric acid, the active metabolite of fenofibrate, produces reductions in TC, LDL-C, apo B, total triglycerides, and triglyceride-rich lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate results in increases in HDL and apoproteins apo AI and apo AII.. 12.3 Pharmacokinetics. Fenofibrate is pro-drug of the active chemical moiety fenofibric acid. Fenofibrate is converted by ester hydrolysis in the body to fenofibric acid which is the active constituent measurable in the circulation.Plasma concentrations of fenofibric acid after single-dose administration of fenofibrate tablets, 120 mg are equivalent to those of fenofibrate 130 mg capsules under high-fat conditions.A high-fat meal did not affect the fenofibric acid AUC after fenofibrate administration but did increase the mean Cmax by 44% compared to fasting conditions.oAbsorption: The absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, fenofibrate is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of single dose of radiolabelled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid from fenofibrate occur, on average, within to hours after administration. Doses of three fenofibrate tablets, 40 mg are considered to be equivalent to single doses of fenofibrate tablets, 120 mg.oDistribution: In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within week of dosing and did not demonstrate accumulation across time following multiple dose administration. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.oMetabolism: Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate is detected in plasma.Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. small amount of fenofibric acid is reduced at the carbonyl moiety to benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine. In vivo metabolism data indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to significant extent.oElimination: After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabelled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces.Fenofibric acid from fenofibrate is eliminated with half-life of 23 hours, allowing once daily dosing.oGeriatrics: In elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that similar dosage regimen can be used in the elderly, without increasing accumulation of the drug or metabolites [see Dosage and Administration (2.5) and Use in Specific Populations (8.5)].oPediatrics: The pharmacokinetics of fenofibrate has not been studied in pediatric populations.oGender: No pharmacokinetic difference between males and females has been observed for fenofibrate.oRace: The influence of race on the pharmacokinetics of fenofibrate has not been studied; however, fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability.oRenal 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/1.73m2) showed 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 30-80 mL/min or eGFR 30-59 mL/min/1.73m2) had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of fenofibrate should be avoided in patients who have severe renal impairment and dose reduction is required in patients having mild to moderate renal impairment. [See Dosage and Administration (2.4).] oHepatic Impairment: No pharmacokinetic studies have been conducted in patients with hepatic impairment.oDrug-Drug Interactions: In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations. Table describes the effects of co-administered drugs on fenofibric acid systemic exposure. Table describes the effects of co-administered fenofibrate or fenofibric acid on systemic exposure of other drugs.Table 2. Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Fenofibrate AdministrationCo-Administered DrugDosage Regimen of Co-Administered DrugDosage Regimen of FenofibrateChanges in Fenofibric Acid Exposure AUCCmax Lipid-lowering agentsAtorvastatin20 mg once daily for 10 daysFenofibrate 160 mgTriCor (fenofibrate) oral tablet once daily for 10 days2%4%Pravastatin40 mg as single doseFenofibrate x 67 mgTriCor (fenofibrate) oral micronized capsule as single dose1%2%Fluvastatin40 mg as single doseFenofibrate 160 mg as single dose2%10%Anti-diabetic agentsGlimepiride1 mg as single doseFenofibrate 145 mg once daily for 10 days1%1%Metformin850 mg three times daily for 10 daysFenofibrate 54 mg three times daily for 10 days9%6%Rosiglitazone8 mg once daily for daysFenofibrate 145 mg once daily for 14 days10%3%Table 3. Effects of Fenofibrate Co-Administration on Systemic Exposure of Other DrugsDosage Regimen of FenofibrateDosage Regimen of Co-Administered DrugChange in Co-Administered Drug ExposureAnalyteAUCCmax Lipid-lowering agentsFenofibrate 160 mgTriCor (fenofibrate) oral tablet once daily for 10 daysAtorvastatin, 20 mg once daily for 10 daysAtorvastatin17%0%Fenofibrate x 67 mgTriCor (fenofibrate) oral micronized capsule as single-dose Pravastatin, 40 mg as single dosePravastatin13%13%3-Hydroxyl-iso-pravastatin26%29%Fenofibrate 160 mg as single-doseFluvastatin, 40 mg as single dose(+)-3R, 5S-Fluvastatin15%16%Anti-diabetic agentsFenofibrate 145 mg once daily for 10 daysGlimepiride, mg as single doseGlimepiride35%18%Fenofibrate 54 mg three times daily for 10 daysMetformin, 850 mg three times daily for 10 daysMetformin3%6%Fenofibrate 145 mg once daily for 14 days Rosiglitazone, mg once daily for daysRosiglitazone6%1%. oAbsorption: The absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, fenofibrate is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of single dose of radiolabelled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid from fenofibrate occur, on average, within to hours after administration. oDistribution: In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within week of dosing and did not demonstrate accumulation across time following multiple dose administration. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.. oMetabolism: Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate is detected in plasma.Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. small amount of fenofibric acid is reduced at the carbonyl moiety to benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine. In vivo metabolism data indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to significant extent.. oElimination: After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabelled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces.Fenofibric acid from fenofibrate is eliminated with half-life of 23 hours, allowing once daily dosing.. oGeriatrics: In elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that similar dosage regimen can be used in the elderly, without increasing accumulation of the drug or metabolites [see Dosage and Administration (2.5) and Use in Specific Populations (8.5)].. oPediatrics: The pharmacokinetics of fenofibrate has not been studied in pediatric populations.. oGender: No pharmacokinetic difference between males and females has been observed for fenofibrate.. oRace: The influence of race on the pharmacokinetics of fenofibrate has not been studied; however, fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability.. oRenal 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/1.73m2) showed 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 30-80 mL/min or eGFR 30-59 mL/min/1.73m2) had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of fenofibrate should be avoided in patients who have severe renal impairment and dose reduction is required in patients having mild to moderate renal impairment. [See Dosage and Administration (2.4).] oHepatic Impairment: No pharmacokinetic studies have been conducted in patients with hepatic impairment.. oDrug-Drug Interactions: In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.. Table describes the effects of co-administered drugs on fenofibric acid systemic exposure. Table describes the effects of co-administered fenofibrate or fenofibric acid on systemic exposure of other drugs.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. oCoumarin Anticoagulants (7.1)oImmunosuppressants (7.2)oBile-Acid Binding Resins (7.3). oCoumarin Anticoagulants (7.1). oImmunosuppressants (7.2). oBile-Acid Binding Resins (7.3). 7.1 Coumarin Anticoagulants. Caution should be exercised when coumarin anticoagulants are given in conjunction with fenofibrate tablets. 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 prothrombin time/INR has stabilized [see Warnings and Precautions (5.6)].. 7.2 Immunosuppressants. 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 fenofibrate tablets, there is risk that an interaction will lead to deterioration of renal function. The benefits and risks of using fenofibrate tablets with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed and renal function monitored.. 7.3 Bile-Acid Binding Resins. Since bile acid resins may bind other drugs given concurrently, patients should take fenofibrate tablets at least hour before or to hours after bile acid binding resin to avoid impeding its absorption.. 7.4 Colchicine. Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Primary Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia. The effects of fenofibrate at dose equivalent to 120 mg fenofibrate per day were assessed from four randomized, placebo-controlled, double-blind, parallel-group studies including patients with the following mean baseline lipid values: total-C 306.9 mg/dL; LDL-C 213.8 mg/dL; HDL-C 52.3 mg/dL; and triglycerides 191.0 mg/dL. Fenofibrate therapy lowered LDL-C, Total-C, and the LDL-C/HDL-C ratio. Fenofibrate therapy also lowered triglycerides and raised HDL-C (see Table 4).Table 4. Mean Percent Change in Lipid Parameters at End of TreatmentDuration of study treatment was to months. Treatment GroupTotal-CLDL-CHDL-CTGPooled Cohort Mean baseline lipid values (n=646)306.9 mg/dL213.8 mg/dL52.3 mg/dL191.0 mg/dL All FEN (n=361)-18.7%p=<0.05 vs. placebo -20.6% +11.0% -28.9% Placebo (n=285)-0.4%-2.2%+0.7%+7.7%Baseline LDL-C >160 mg/dL and TG <150 mg/dL (Type IIa) Mean baseline lipid values (n=334)307.7 mg/dL227.7 mg/dL58.1 mg/dL101.7 mg/dL All FEN (n=193)-22.4% -31.4% +9.8% -23.5% Placebo (n=141)+0.2%-2.2%+2.6%+11.7%Baseline LDL-C >160 mg/dL and TG >=150 mg/dL (Type IIb) Mean baseline lipid values (n=242)312.8 mg/dL219.8 mg/dL46.7 mg/dL231.9 mg/dL All FEN (n=126)-16.8% -20.1% +14.6% -35.9% Placebo (n=116)-3.0%-6.6%+2.3%+0.9%In subset of the subjects, measurements of apo were conducted. Fenofibrate treatment significantly reduced apo from baseline to endpoint as compared with placebo (-25.1% vs. 2.4%, p<0.0001, n=213 and 143 respectively).. 14.2 Severe Hypertriglyceridemia. The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials of 147 hypertriglyceridemic patients. Patients were treated for eight weeks under protocols that differed only in that one entered patients with baseline TG levels of 500 to 1500 mg/dL, and the other TG levels of 350 to 500 mg/dL. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia, treatment with fenofibrate at dosages equivalent to 120 mg fenofibrate tablets per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol. Treatment of patients with elevated triglycerides often results in an increase of LDL-C (see Table 5).Table 5. Effects of Fenofibrate in Patients With Severe HypertriglyceridemiaStudy 1PlaceboFenofibrateBaseline TG levels 350 to 499 mg/dLNBaseline (Mean)Endpoint (Mean)% Change (Mean)NBaseline (Mean)Endpoint (Mean)% Change (Mean)Triglycerides28449450-0.527432223-46.2p=<0.05 vs. placebo VLDL Triglycerides193673502.719350178-44.1 Total Cholesterol282552612.827252227-9.1 HDL Cholesterol283536427344019.6 LDL Cholesterol28120129122712813714.5VLDL Cholesterol2799995.8279246-44.7 Study 2PlaceboFenofibrateBaseline TG levels 500 to 1500 mg/dLNBaseline (Mean)Endpoint (Mean)% Change (Mean)NBaseline (Mean)Endpoint (Mean)% Change (Mean)Triglycerides447107507.248726308-54.5 VLDL Triglycerides2953757118.733543205-50.6 Total Cholesterol442722710.448261223-13.8 HDL Cholesterol4427285.048303622.9 LDL Cholesterol4210090-4.24510313145.0 VLDL Cholesterol4213714211.04512654-49.4.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Fenofibrate tablets are contraindicated in:opatients with severe renal dysfunction, including those receiving dialysis [see Clinical Pharmacology (12.3)].opatients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities [see Warnings and Precautions (5.2)]. opatients with pre-existing gallbladder disease [see Warnings and Precautions (5.5)].opatients with known hypersensitivity to fenofibrate [see Warnings and Precautions (5.9)]. onursing mothers [see Use in Specific Populations (8.2)].. opatients with severe renal dysfunction, including those receiving dialysis [see Clinical Pharmacology (12.3)].. opatients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities [see Warnings and Precautions (5.2)]. opatients with pre-existing gallbladder disease [see Warnings and Precautions (5.5)].. opatients with known hypersensitivity to fenofibrate [see Warnings and Precautions (5.9)]. onursing mothers [see Use in Specific Populations (8.2)].. oSevere renal dysfunction, including patients receiving dialysis (4, 8.6, 12.3)oActive liver disease (4, 5.3)oGallbladder disease (4, 5.5)oNursing mothers (4, 8.2)oKnown hypersensitivity to fenofibrate (4). oSevere renal dysfunction, including patients receiving dialysis (4, 8.6, 12.3). oActive liver disease (4, 5.3). oGallbladder disease (4, 5.5). oNursing mothers (4, 8.2). oKnown hypersensitivity to fenofibrate (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Fenofibrate tablets are lipid regulating agent available as tablets for oral administration. Each tablet contains 40 mg or 120 mg fenofibrate. The chemical name for fenofibrate is 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester with the following structural formula:The empirical formula is C20H21O4Cl and the molecular weight is 360.83; fenofibrate is insoluble in water. The melting point is 79 to 82C. Fenofibrate is white solid which is stable under ordinary conditions.Inactive ingredients: Each tablet contains lactose monohydrate, NF; Polyethylene Glycol 6000, NF; Poloxamer 188, NF; and magnesium stearate, NF.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oPrimary hypercholesterolemia or mixed dyslipidemia: 120 mg per day (2.2)oSevere hypertriglyceridemia: 40 to 120 mg per day; the dose should be adjusted according to patient response. (2.3)oRenally impaired patients: Initial dose of 40 mg per day; the dose should be increased according to the effect on renal function and lipid levels. (2.4)oGeriatric patients: Select dose on the basis of renal function. (2.5)To increase absorption of fenofibrate tablets, take with food. (2.1) oPrimary hypercholesterolemia or mixed dyslipidemia: 120 mg per day (2.2). oSevere hypertriglyceridemia: 40 to 120 mg per day; the dose should be adjusted according to patient response. (2.3). oRenally impaired patients: Initial dose of 40 mg per day; the dose should be increased according to the effect on renal function and lipid levels. (2.4). oGeriatric patients: Select dose on the basis of renal function. (2.5). 2.1 General Considerations. Fenofibrate tablets should be given with food to optimize the absorption of the medicine. Patients should be advised to swallow fenofibrate tablets whole. Do not crush, dissolve or chew tablets.The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality. Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be an important ancillary measure. Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus should be looked for and adequately treated. Estrogen therapy, thiazide diuretics and beta-blockers, are sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia. Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of fenofibrate tablets if lipid levels fall significantly below the targeted range.Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 120 mg once daily.. 2.2 Primary Hypercholesterolemia or Mixed Dyslipidemia. The initial dose of fenofibrate tablets is 120 mg per day.. 2.3 Severe Hypertriglyceridemia. The initial dose is 40 to 120 mg per day. Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at to week intervals. The maximum dose is 120 mg per day.. 2.4 Impaired Renal Function. Treatment with fenofibrate tablets should be initiated at dose of 40 mg per day in patients with mild to moderately impaired renal function, and increased only after evaluation of the effects on renal function and lipid levels at this dose. The use of fenofibrate tablets should be avoided in patients with severe renal impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].. 2.5 Geriatric Patients. Dose selection for the elderly should be made on the basis of renal function [see Use in Specific Populations (8.5)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. o40 mg: White to off-white oval tablets. Debossed FLO.o120 mg: White to off-white oval tablets. Debossed FHI.. o40 mg: White to off-white oval tablets. Debossed FLO.. o120 mg: White to off-white oval tablets. Debossed FHI.. oOral tablets: 40 mg and 120 mg (3). oOral tablets: 40 mg and 120 mg (3).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Fenofibric acid is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Fenofibric acid exposure is not influenced by age. Since elderly patients have higher incidence of renal impairment, dose selection for the elderly should be made on the basis of renal function [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. Elderly patients with normal renal function should require no dose modifications. Consider monitoring renal function in elderly patients taking fenofibrate tablets.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Fenofibrate tablets 40 mg, are white to off-white oval tablets debossed FLO on one side and blank on the other side.Bottle of 90 tablets, NDC 0115-1522-10Fenofibrate tablets 120 mg, are white to off-white oval tablets debossed FHI on one side and blank on the other side.Bottle of 90 tablets, NDC 0115-1523-10Store at 25C (77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Fenofibrate tablets are peroxisome proliferator receptor alpha (PPAR) activator indicated as an adjunct to diet:oto reduce elevated LDL-C, Total-C, TG, and Apo B, and to increase HDL-C in adult patients with primary hypercholesterolemia or mixed dyslipidemia. (1.1)oto treat adult patients with severe hypertriglyceridemia. (1.2)Important Limitation of Use: Fenofibrate was not shown to reduce coronary heart disease morbidity and mortality in patients with type diabetes mellitus. (5.1). oto reduce elevated LDL-C, Total-C, TG, and Apo B, and to increase HDL-C in adult patients with primary hypercholesterolemia or mixed dyslipidemia. (1.1). oto treat adult patients with severe hypertriglyceridemia. (1.2). 1.1 Primary Hypercholesterolemia and Mixed Dyslipidemia. Fenofibrate tablets are indicated as adjunctive therapy to diet to reduce elevated low-density lipoprotein cholesterol (LDL-C), total cholesterol (Total-C), triglycerides (TG), and apolipoprotein (Apo B), and to increase high-density lipoprotein (HDL-C) in adult patients with primary hypercholesterolemia or mixed dyslipidemia.. 1.2 Severe Hypertriglyceridemia. Fenofibrate tablets are also indicated as adjunctive therapy to diet for treatment of adult patients with severe hypertriglyceridemia. Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually reduce fasting triglycerides and eliminate chylomicronemia thereby obviating the need for pharmacologic intervention.Markedly elevated levels of serum triglycerides (e.g., >2,000 mg/dL) may increase the risk of developing pancreatitis. The effect of fenofibrate therapy on reducing this risk has not been adequately studied.. 1.3 Important Limitations of Use. Fenofibrate was not shown to reduce coronary heart disease morbidity and mortality in patients with type diabetes mellitus [see Warnings and Precautions (5.1)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Patients should be advised:oof the potential benefits and risks of fenofibrate tablets.onot to use fenofibrate tablets if there is known hypersensitivity to fenofibrate or fenofibric acid.othat if they are taking coumarin anticoagulants, fenofibrate tablets may increase their anticoagulant effect, and increased monitoring may be necessary.oof medications that should not be taken in combination with fenofibrate tablets.oto continue to follow an appropriate lipid-modifying diet while taking fenofibrate tablets.oto take fenofibrate tablets once daily, without regard to food, at the prescribed dose, swallowing each tablet whole.oto return to their physicians office for routine monitoring.oto inform their physician of all medications, supplements, and herbal preparations they are taking and any change to their medical condition. Patients should also be advised to inform their physicians prescribing new medication that they are taking fenofibrate tablets.oto inform their physician of symptoms of liver injury (e.g., jaundice, abnormal pain, nausea, malaise, dark urine, abnormal stool, pruritus); any muscle pain, tenderness, or weakness; onset of abdominal pain; or any other new symptoms.onot to breastfeed during treatment with fenofibrate tablets and for days after the final dose.. oof the potential benefits and risks of fenofibrate tablets.. onot to use fenofibrate tablets if there is known hypersensitivity to fenofibrate or fenofibric acid.. othat if they are taking coumarin anticoagulants, fenofibrate tablets may increase their anticoagulant effect, and increased monitoring may be necessary.. oof medications that should not be taken in combination with fenofibrate tablets.. oto continue to follow an appropriate lipid-modifying diet while taking fenofibrate tablets.. oto take fenofibrate tablets once daily, without regard to food, at the prescribed dose, swallowing each tablet whole.. oto return to their physicians office for routine monitoring.. oto inform their physician of all medications, supplements, and herbal preparations they are taking and any change to their medical condition. Patients should also be advised to inform their physicians prescribing new medication that they are taking fenofibrate tablets.. oto inform their physician of symptoms of liver injury (e.g., jaundice, abnormal pain, nausea, malaise, dark urine, abnormal stool, pruritus); any muscle pain, tenderness, or weakness; onset of abdominal pain; or any other new symptoms.. onot to breastfeed during treatment with fenofibrate tablets and for days after the final dose.

LACTATION SECTION.

8.2 Lactation Risk SummaryThere 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 fenofibrate tablets and for days after the final dose [see Contraindications (4)].

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The active moiety of fenofibrate tablets is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been extensively studied through oral administration of fenofibrate.The lipid-lowering effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor alpha (PPAR). Through this mechanism, fenofibrate 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). The resulting decrease in TG produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPAR also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol.Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 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, 45, and 200 mg/kg/day, approximately 0.3, 1, and times the maximum recommended human dose (MRHD), based on body surface area comparisons (mg/m2). At dose of 200 mg/kg/day (at times the MRHD), the incidence of liver carcinomas was significantly increased in both sexes. statistically significant increase in pancreatic carcinomas was observed in males at and times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed at times the MRHD in males. In second 24-month rat carcinogenicity study in different strain of rats (Sprague-Dawley), doses of 10 and 60 mg/kg/day (0.3 and 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 times the MRHD.A 117-week carcinogenicity study was conducted in rats comparing three drugs: fenofibrate 10 and 60 mg/kg/day (0.3 and times the MRHD), clofibrate (400 mg/kg/day; times the human dose), and gemfibrozil (250 mg/kg/day; times the human dose, based on mg/m2 surface 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 21-month study in CF-1 mice, fenofibrate 10, 45, and 200 mg/kg/day (approximately 0.2, 1, and times the MRHD on the basis of mg/m2 surface area) significantly increased the liver carcinomas in both sexes at times the MRHD. In second 18-month study at 10, 60, and 200 mg/kg/day, fenofibrate significantly increased the liver carcinomas in male mice and liver adenomas in female mice at 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 (~10 times the MRHD, based on mg/m2 surface area comparisons).

OVERDOSAGE SECTION.

10 OVERDOSAGE. There is no specific treatment for overdose with fenofibrate tablets. 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 fenofibrate is highly bound to plasma proteins, hemodialysis should not be considered.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 40 mg Tablet Bottle Label. NDC 0115-1522-10FenofibrateTablets40 mgRx only 90 Tablets. 2.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and efficacy have not been established in pediatric patients.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryLimited available data with fenofibrate use in pregnant women are insufficient to determine 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 equivalent to the maximum recommended clinical dose of 120 mg daily, based on body surface area (mg/m2). Adverse reproductive outcomes occurred at higher doses in the presence of maternal toxicity [see Data]. Fenofibrate 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 2-4% and 15-20%, respectively. DataAnimal DataIn pregnant rats given oral dietary doses of 14, 127, and 361 mg/kg/day from gestation day 6-15 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, equivalent to 120 mg fenofibrate tablets 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, 150, and 300 mg/kg/day from gestation day 6-18 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, 75, 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 (>= 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.

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions, Hepatotoxicity (5.2)06/2021. Warnings and Precautions, Hepatotoxicity (5.2)06/2021.

SPL UNCLASSIFIED SECTION.

1.1 Primary Hypercholesterolemia and Mixed Dyslipidemia. Fenofibrate tablets are indicated as adjunctive therapy to diet to reduce elevated low-density lipoprotein cholesterol (LDL-C), total cholesterol (Total-C), triglycerides (TG), and apolipoprotein (Apo B), and to increase high-density lipoprotein (HDL-C) in adult patients with primary hypercholesterolemia or mixed dyslipidemia.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oGeriatric Use: Determine dose selection on the basis of renal function. (8.5)oRenal Impairment: Avoid use in patients with severe renal impairment. Dose reduction is required in patients with mild to moderate renal impairment. (8.6). oGeriatric Use: Determine dose selection on the basis of renal function. (8.5). oRenal Impairment: Avoid use in patients with severe renal impairment. Dose reduction is required in patients with mild to moderate renal impairment. (8.6). 8.1 Pregnancy. Risk SummaryLimited available data with fenofibrate use in pregnant women are insufficient to determine 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 equivalent to the maximum recommended clinical dose of 120 mg daily, based on body surface area (mg/m2). Adverse reproductive outcomes occurred at higher doses in the presence of maternal toxicity [see Data]. Fenofibrate 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 2-4% and 15-20%, respectively. DataAnimal DataIn pregnant rats given oral dietary doses of 14, 127, and 361 mg/kg/day from gestation day 6-15 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, equivalent to 120 mg fenofibrate tablets 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, 150, and 300 mg/kg/day from gestation day 6-18 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, 75, 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 (>= 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 SummaryThere 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 fenofibrate tablets and for days after the final dose [see Contraindications (4)]. 8.4 Pediatric Use. Safety and efficacy have not been established in pediatric patients.. 8.5 Geriatric Use. Fenofibric acid is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Fenofibric acid exposure is not influenced by age. Since elderly patients have higher incidence of renal impairment, dose selection for the elderly should be made on the basis of renal function [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. Elderly patients with normal renal function should require no dose modifications. Consider monitoring renal function in elderly patients taking fenofibrate tablets.. 8.6 Renal Impairment. The use of fenofibrate tablets should be avoided in patients with severe renal impairment [see Contraindications (4)]. Dose reduction is required in patients with mild to moderate renal impairment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. Monitoring renal function in patients with renal impairment is recommended.. 8.7 Hepatic Impairment. The use of fenofibrate tablets has not been evaluated in subjects with hepatic impairment [see Contraindications (4) and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oHepatotoxicity: Serious drug-induced liver injury, including liver transplantation and death, has been reported with fenofibrate. Monitor patients liver function, including serum ALT, AST, and total bilirubin, at baseline and periodically for the duration of therapy. Discontinue if signs or symptoms of liver injury develop or if elevated enzyme levels persist. (5.2)oMyopathy and rhabdomyolysis: Have been reported in patients taking fenofibrate. Risks are increased during co-administration with statin (with significantly higher rate observed for gemfibrozil), particularly in elderly patients and patients with diabetes, renal failure, or hypothyroidism. (5.3)oSerum creatinine: Fenofibrate can reversibly increase serum creatinine levels. (5.4) Monitor renal function periodically in patients with renal impairment. (8.6)oCholelithiasis: Fenofibrate increases cholesterol excretion into the bile, leading to risk of cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. (5.5)oCoumarin anticoagulants: Exercise caution in concomitant treatment with coumarin anticoagulants. Adjust the dosage of coumarin to maintain the prothrombin time/INR at the desired level to prevent bleeding complications. (5.6)oHypersensitivity Reactions: Acute hypersensitivity reactions, including anaphylaxis and angioedema, and delayed hypersensitivity reactions, including severe cutaneous adverse drug reactions have been reported postmarketing. Some cases were life-threatening and required emergency treatment. Discontinue fenofibrate and treat patients appropriately if reactions occur. (5.9). oHepatotoxicity: Serious drug-induced liver injury, including liver transplantation and death, has been reported with fenofibrate. Monitor patients liver function, including serum ALT, AST, and total bilirubin, at baseline and periodically for the duration of therapy. Discontinue if signs or symptoms of liver injury develop or if elevated enzyme levels persist. (5.2). oMyopathy and rhabdomyolysis: Have been reported in patients taking fenofibrate. Risks are increased during co-administration with statin (with significantly higher rate observed for gemfibrozil), particularly in elderly patients and patients with diabetes, renal failure, or hypothyroidism. (5.3). oSerum creatinine: Fenofibrate can reversibly increase serum creatinine levels. (5.4) Monitor renal function periodically in patients with renal impairment. (8.6). oCholelithiasis: Fenofibrate increases cholesterol excretion into the bile, leading to risk of cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. (5.5). oCoumarin anticoagulants: Exercise caution in concomitant treatment with coumarin anticoagulants. Adjust the dosage of coumarin to maintain the prothrombin time/INR at the desired level to prevent bleeding complications. (5.6). oHypersensitivity Reactions: Acute hypersensitivity reactions, including anaphylaxis and angioedema, and delayed hypersensitivity reactions, including severe cutaneous adverse drug reactions have been reported postmarketing. Some cases were life-threatening and required emergency treatment. Discontinue fenofibrate and treat patients appropriately if reactions occur. (5.9). 5.1 Mortality and Coronary Heart Disease Morbidity. The effect of fenofibrate tablets on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established.The Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) trial was randomized placebo-controlled study of 5,518 patients with type diabetes mellitus on background statin therapy treated with fenofibrate. The mean duration of follow-up was 4.7 years. Fenofibrate plus statin combination therapy showed non-significant 8% relative risk reduction in the primary outcome of major adverse cardiovascular events (MACE), composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular disease death (hazard ratio [HR] 0.92, 95% CI 0.79-1.08) (p=0.32) as compared to statin monotherapy. In gender subgroup analysis, the hazard ratio for MACE in men receiving combination therapy versus statin monotherapy was 0.82 (95% CI 0.69-0.99), and the hazard ratio for MACE in women receiving combination therapy versus statin monotherapy was 1.38 (95% CI 0.98-1.94) (interaction p=0.01). The clinical significance of this subgroup finding is unclear.The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was 5-year randomized, placebo-controlled study of 9,795 patients with type diabetes mellitus treated with fenofibrate. Fenofibrate demonstrated non-significant 11% relative reduction in the primary outcome of coronary heart disease events (hazard ratio [HR] 0.89, 95% CI 0.75-1.05, p=0.16) and significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.80-0.99], p=0.04). There was non-significant 11% (HR 1.11 [0.95, 1.29], p=0.18) and 19% (HR 1.19 [0.90, 1.57], p=0.22) increase in total and coronary heart disease mortality, respectively, with fenofibrate as compared to placebo.Because of chemical, pharmacological, and clinical similarities between fenofibrate, clofibrate, and gemfibrozil, the adverse findings in large, randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to fenofibrate tablets.In the Coronary Drug Project, large study of post myocardial infarction of patients treated for years with clofibrate, there was no difference in mortality seen between the clofibrate group and the placebo group. There was however, difference in the rate of cholelithiasis and cholecystitis requiring surgery between the two groups (3.0% vs. 1.8%).In study conducted by the World Health Organization (WHO), 5000 subjects without known coronary artery disease were treated with placebo or clofibrate for years and followed for an additional one year. There was statistically significant, higher age-adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs. 3.96%, p<=0.01). Excess mortality was due to 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis. This appeared to confirm the higher risk of gallbladder disease seen in clofibrate-treated patients studied in the Coronary Drug Project.The Helsinki Heart Study was large (n=4,081) study of middle-aged men without history of coronary artery disease. Subjects received either placebo or gemfibrozil for years, with 3.5 year open extension afterward. Total mortality was numerically higher in the gemfibrozil randomization group but did not achieve statistical significance (p=0.19, 95% confidence interval for relative risk G:P=0.91-1.64). Although cancer deaths trended higher in the gemfibrozil group (p=0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups. Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the year follow-up data from the WHO study (RR=1.29).A secondary prevention component of the Helsinki Heart Study enrolled middle-aged men excluded from the primary prevention study because of known or suspected coronary heart disease. Subjects received gemfibrozil or placebo for years. Although cardiac deaths trended higher in the gemfibrozil group, this was not statistically significant (hazard ratio 2.2, 95% confidence interval: 0.94-5.05).. 5.2 Hepatotoxicity. Serious drug-induced liver injury (DILI), including liver transplantation and death, have been reported postmarketing with fenofibrate. 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 fenofibrate 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, fenofibrate at doses equivalent to 87 mg to 130 mg fenofibrate daily (at the highest dose, comparable to fenofibrate, 120 mg) has been associated with increases in serum AST or ALT. The incidence of increases in transaminases may be dose related [see Adverse Reactions (6.1)]. Fenofibrate is contraindicated in patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities [see Contraindications (4)]. Monitor patients liver function, including serum ALT, AST, and total bilirubin, at baseline and periodically for the duration of therapy with fenofibrate. Discontinue fenofibrate 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 fenofibrate in these patients if there is no alternative explanation for the liver injury.. 5.3 Myopathy and Rhabdomyolysis. Fibrates increase the risk for myopathy and have been associated with rhabdomyolysis. The risk for serious muscle toxicity appears to be increased in elderly patients and in patients with diabetes, renal insufficiency, or hypothyroidism.Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevations of creatine phosphokinase (CPK) levels.Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. CPK levels should be assessed in patients reporting these symptoms, and fenofibrate therapy should be discontinued if markedly elevated CPK levels occur or myopathy/myositis is suspected or diagnosed.Data from observational studies indicate that the risk for rhabdomyolysis is increased when fibrates, in particular gemfibrozil, are co-administered with statin. The combination should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination [see Clinical Pharmacology (12.3)]. Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine [see Drug Interactions (7.4)].. 5.4 Serum Creatinine. Elevations in serum creatinine have been reported in patients on fenofibrate. These elevations tend to return to baseline following discontinuation of fenofibrate. The clinical significance of these observations is unknown. Monitor renal function in patients with renal impairment taking fenofibrate tablets. Renal monitoring should also be considered for patients taking fenofibrate tablets at risk for renal insufficiency such as the elderly and patients with diabetes.. 5.5 Cholelithiasis. Fenofibrate, like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Fenofibrate tablets therapy should be discontinued if gallstones are found.. 5.6 Coumarin Anticoagulants. Caution should be exercised when anticoagulants are given in conjunction with fenofibrate tablets because of the potentiation of coumarin-type anticoagulants in prolonging the prothrombin time/International Normalized Ratio (PT/INR). To prevent bleeding complications, frequent monitoring of PT/INR and dose adjustment of the anticoagulant are recommended until PT/INR has stabilized [see Drug Interactions (7.1)]. 5.7 Pancreatitis. Pancreatitis has been reported in patients taking fenofibrate, gemfibrozil, and clofibrate. This occurrence may represent failure of efficacy in patients with severe hypertriglyceridemia, direct drug effect, or 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 fenofibrate therapy. However, these levels stabilize during long-term administration. Thrombocytopenia and agranulocytosis have been reported in individuals treated with fenofibrate. Periodic monitoring of red and white blood cell counts is recommended during the first 12 months of fenofibrate tablets administration.. 5.9 Hypersensitivity Reactions. Acute HypersensitivityAnaphylaxis and angioedema have been reported postmarketing with fenofibrate. In some cases, reactions were life-threatening and required emergency treatment. If patient develops signs or symptoms of an acute hypersensitivity reaction, advise them to seek immediate medical attention and discontinue fenofibrate.Delayed HypersensitivitySevere cutaneous adverse drug reactions (SCAR), including Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported postmarketing, occurring days to weeks after initiation of fenofibrate. The cases of DRESS were associated with cutaneous reactions (such as rash or exfoliative dermatitis) and combination of eosinophilia, fever, systemic organ involvement (renal, hepatic, or respiratory). Discontinue fenofibrate and treat patients appropriately if SCAR is suspected.. 5.10 Venothromboembolic Disease. In the 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%) in the fenofibrate group (p 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1%) in the fenofibrate group (p 0.022).In the Coronary Drug Project, 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; <0.01).. 5.11 Paradoxical Decreases in HDL Cholesterol Levels. There have been postmarketing and clinical trial reports of severe decreases in HDL cholesterol levels (as low as mg/dL) occurring in diabetic and non-diabetic patients initiated on fibrate therapy. The decrease in HDL-C is mirrored by decrease in apolipoprotein A1. This decrease has been reported to occur within 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. It is recommended that HDL-C levels be checked within the first few months after initiation of fibrate therapy. If severely depressed HDL-C level is detected, fibrate therapy should be withdrawn, and the HDL-C level monitored until it has returned to baseline, and fibrate therapy should not be re-initiated.