Fenofibric Acid

6 ADVERSE REACTIONS The most common adverse events reported during clinical trials with fenofibrate (≥ 2% and at least 1% greater than placebo) were abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis (6.1). To report SUSPECTED ADVERSE REACTIONS, contact 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 a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Fenofibric acid is the active metabolite of fenofibrate. Adverse events 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 events led to discontinuation of treatment in 5% of patients treated with fenofibrate and in 3% treated with placebo. Increases in liver tests were the most frequent events, causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials. Table 1. Adverse Events Reported by 2% or More of Patients Treated with Fenofibrate and Greater than Placebo During the Double-Blind, Placebo-Controlled Trials BODY SYSTEM Adverse Event Fenofibrate* (N = 439) Placebo (N = 365) BODY AS A WHOLE Abdominal Pain 4.6% 4.4% Back Pain 3.4% 2.5% Headache 3.2% 2.7% DIGESTIVE Nausea 2.3% 1.9% Constipation 2.1% 1.4% INVESTIGATIONS Abnormal Liver Tests 7.5% 1.4% Increased AST 3.4% 0.5% Increased ALT 3% 1.6% Increased Creatine Phosphokinase 3% 1.4% RESPIRATORY Respiratory Disorder 6.2% 5.5% Rhinitis 2.3% 1.1% * Dosage equivalent to 135 mg fenofibric acid delayed-release capsules Clinical trials with fenofibric acid delayed-release capsules did not include a placebo-control arm. However, the adverse event profile of fenofibric acid delayed-release capsules was generally consistent with that of fenofibrate. The following adverse events not listed above were reported in ≥ 3% of patients taking fenofibric acid delayed-release capsules alone: Gastrointestinal Disorders : Diarrhea, dyspepsia General Disorders and Administration Site Conditions: Pain Infections and Infestations: Nasopharyngitis, sinusitis, upper respiratory tract infection Musculoskeletal and Connective Tissue Disorders: Arthralgia, myalgia, pain in extremity Nervous System Disorders: Dizzinesss 6.2 Postmarketing Experience The following adverse events have been identified during postapproval use of fenofibrate: rhabdomyolysis, pancreatitis, renal failure, muscle spasms, acute renal failure, hepatitis, cirrhosis, anemia, asthenia, and severely depressed HDL-cholesterol levels. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

4 CONTRAINDICATIONS Fenofibric acid delayed-release capsules are contraindicated in: · patients with severe renal impairment, including those receiving dialysis [see Clinical Pharmacology (12.3)] . · patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities [see Warnings and Precautions (5.3)] . · patients with preexisting gallbladder disease [see Warnings and Precautions (5.5)] . · nursing mothers [see Use in Specific Populations (8.3)] . · patients with hypersensitivity to fenofibric acid or fenofibrate [see Warnings and Precautions (5.9)] . •Severe renal dysfunction, including patients receiving dialysis (4, 12 3). •Active liver disease (4, 5.3). •Gallbladder disease (4, 5.5). •Nursing mothers (4, 8.3). •Known hypersensitivity to fenofibric acid or fenofibrate (4, 5.9)

11 DESCRIPTION Fenofibric acid delayed-release capsules are a lipid regulating agent available as delayed release capsules for oral administration. Each delayed release capsule contains choline fenofibrate, equivalent to 45 mg or 135 mg of fenofibric acid. The chemical name for choline fenofibrate is ethanaminium, 2-hydroxy-N,N,N-trimethyl, 2-{4-(4-chlorobenzoyl)phenoxy] -2-methylpropanoate (1:1) with the following structural formula: The empirical formula is C 22 H 28 ClNO 5 and the molecular weight is 421.91. Choline fenofibrate is freely soluble in water and methanol. The melting point is approximately 210°C. Choline fenofibrate is a white to off-white crystalline powder, which is stable under ordinary conditions. Each delayed release capsule contains enteric coated mini-tablets comprised of choline fenofibrate and the following inactive ingredients: hypromellose, povidone, water, hydroxylpropyl cellulose, colloidal silicon dioxide, sodium stearyl fumarate, methacrylic acid copolymer, talc, triethyl citrate. The capsule shell of the 45 mg capsule contains the following inactive ingredients: gelatin, titanium dioxide, iron oxide yellow, and iron oxide red. The capsule shell of the 135 mg capsule contains the following inactive ingredients: gelatin, titanium dioxide, iron oxide yellow, and FD&C Blue #2. The capsule shells are printed with edible white ink and black ink. The edible white ink contains shellac, propylene glycol, potassium hydroxide, and titanium dioxide and the edible black ink contains shellac, propylene glycol, iron oxide black and, potassium hydroxide. Structure

2 DOSAGE AND ADMINISTRATION •Hypertriglyceridemia: 45 to 135 mg once daily (2.2). •Primary hypercholesterolemia or mixed dyslipidemia: 135 mg once daily (2.3). •Renally impaired patients: 45 mg once daily (2.4). •Maximum dose: 135 mg once daily (2.1). •May be taken without regard to food (2.1). 2.1 General Considerations Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibric acid delayed-release capsules , and should continue this diet during treatment. Fenofibric acid delayed-release capsules can be taken without regard to meals. Patients should be advised to swallow fenofibric acid delayed-release capsules whole. Do not open, crush, dissolve, or chew capsules. Serum lipids should be monitored periodically. 2.2 Severe Hypertriglyceridemia The initial dose of fenofibric acid delayed-release capsules is 45 to 135 mg 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. The maximum dose is 135 mg once daily. 2.3 Primary Hypercholesterolemia or Mixed Dyslipidemia The dose of fenofibric acid delayed-release capsule is 135 mg once daily. 2.4 Impaired Renal Function Treatment with fenofibric acid delayed-release capsules should be initiated at a dose of 45 mg once daily in patients with mild to moderate renal impairment and should only be increased after evaluation of the effects on renal function and lipid levels at this dose. The use of fenofibric acid delayed-release capsules should be avoided in patients with severely impaired renal function [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)] .

1 INDICATIONS AND USAGE Fenofibric acid delayed-release capsules are a peroxisome proliferator-activated receptor (PPAR) alpha agonist indicated as adjunctive therapy to diet to: · Reduce TG in patients with severe hypertriglyceridemia (1.1). · Reduce elevated LDL-C, Total-C, TG and Apo B, and to increase HDLC in patients with primary hypercholesterolemia or mixed dyslipidemia (1.2). Limitations of Use: Fenofibrate at a dose equivalent to 135 mg of fenofibric acid delayed-release capsules did not reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus (5.1) 1.1 Treatment of Severe Hypertriglyceridemia Fenofibric acid delayed-release capsules are indicated as adjunctive therapy to diet to reduce triglycerides (TG) in patients with severe hypertriglyceridemia. Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually obviate the need for pharmacological intervention. Markedly elevated levels of serum triglycerides (e.g. > 2,000 mg/dL) may increase the risk of developing pancreatitis. The effect of fenofibric acid delayed-release capsules therapy on reducing this risk has not been adequately studied. 1.2 Treatment of Primary Hypercholesterolemia or Mixed Dyslipidemia Fenofibric acid delayed-release capsules are indicated as adjunctive therapy to diet to reduce elevated low-density lipoprotein cholesterol (LDL-C), total cholesterol (Total-C), triglycerides (TG), and apolipoprotein B (Apo B), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia or mixed dyslipidemia. 1.3 Limitations of Use Fenofibrate at a dose equivalent to 135 mg of fenofibric acid delayed-release capsules did not reduce coronary heart disease morbidity and mortality in 2 large, randomized controlled trials of patients with type 2 diabetes mellitus [see Warnings and Precautions (5.1)] . 1.4 General Considerations for Treatment Laboratory studies should be performed to establish that lipid levels are abnormal before instituting fenofibric acid delayed-release capsules therapy. Every reasonable attempt should be made to control serum lipids with non-drug methods including appropriate diet, exercise, weight loss in obese patients, and control of any medical problems such as diabetes mellitus and hypothyroidism that may be contributing to the lipid abnormalities. Medications known to exacerbate hypertriglyceridemia (beta-blockers, thiazides, estrogens) should be discontinued or changed if possible, and excessive alcohol intake should be addressed before triglyceride-lowering drug therapy is considered. If the decision is made to use lipid-altering drugs, the patient should be instructed that this does not reduce the importance of adhering to diet. Drug therapy is not indicated for patients who have elevations of chylomicrons and plasma triglycerides, but who have normal levels of VLDL.

10 OVERDOSAGE There is no specific treatment for overdose with fenofibric acid delayed-release capsules. General supportive care of the patient is indicated, including monitoring of vital signs and observation of clinical status, should an overdose occur. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. Because fenofibric acid delayed-release capsules are highly bound to plasma proteins, hemodialysis should not be considered.

7 DRUG INTERACTIONS •Coumarin Anticoagulants: (7.1). •Bile Acid Binding Resins: (7.2). •Immunosuppressants: (7.3). 7.1 Coumarin Anticoagulants Potentiation of coumarin-type anticoagulant effect has been observed with prolongation of the PT/INR. Caution should be exercised when oral coumarin anticoagulants are given in conjunction with fenofibric acid delayed-release capsules. The dosage of the anticoagulant should be reduced to maintain the PT/INR at the desired level to prevent bleeding complications. Frequent PT/INR determinations are advisable until it has been definitely determined that the PT/INR has stabilized [see Warnings and Precautions (5.6)] . 7.2 Bile Acid Binding Resins Since bile acid binding resins may bind other drugs given concurrently, patients should take fenofibric acid delayed-release capsules at least 1 hour before or 4 to 6 hours after a bile acid resin to avoid impeding its absorption. 7.3 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 drugs of the fibrate class including fenofibric acid delayed-release capsules, there is a risk that an interaction will lead to deterioration of renal function. The benefits and risks of using fenofibric acid delayed-release capsules with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed. 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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The active moiety of fenofibric acid delayed-release capsule 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-modifying 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 α (PPARα). Through this mechanism, fenofibric acid increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of Apo CIII (an inhibitor of lipoprotein lipase activity). Activation of PPARα also induces an increase in the synthesis of HDL-C and Apo AI and AII. 12.3 Pharmacokinetics Fenofibric acid delayed-release capsules contain fenofibric acid, which is the only circulating pharmacologically active moiety in plasma after oral administration of fenofibric acid delayed-release capsules. Fenofibric acid is also the circulating pharmacologically active moiety in plasma after oral administration of fenofibrate, the ester of fenofibric acid. Plasma concentrations of fenofibric acid after administration of one 135 mg fenofibric acid delayed release capsule are equivalent to those after one 200 mg capsule of micronized fenofibrate administered under fed conditions. Absorption Fenofibric acid is well absorbed throughout the gastrointestinal tract. The absolute bioavailability of fenofibric acid is approximately 81%. Peak plasma levels of fenofibric acid occur within 4 to 5 hours after a single dose administration of fenofibric acid delayed-release capsule under fasting conditions. Fenofibric acid exposure in plasma, as measured by C max and AUC, is not significantly different when a single 135 mg dose of fenofibric acid delayed-release capsule is administered under fasting or nonfasting conditions. Distribution Upon multiple dosing of fenofibric acid delayed-release capsules, fenofibric acid levels reach steady state within 8 days. Plasma concentrations of fenofibric acid at steady state are approximately slightly more than double those following a single dose. Serum protein binding is approximately 99% in normal and dyslipidemic subjects. Metabolism Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine. In vivo metabolism data after fenofibrate administration indicate that fenofibric acid does not undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent. Elimination After absorption, fenofibric acid delayed-release capsules are primarily excreted in the urine in the form of fenofibric acid and fenofibric acid glucuronide. Fenofibric acid is eliminated with a half-life of approximately 20 hours, allowing once daily administration of fenofibric acid delayed-release capsules. Specific Populations Geriatrics In five elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following a single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that an equivalent dose of fenofibric acid delayed-release capsules can be used in elderly subjects with normal renal function, without increasing accumulation of the drug or metabolites [see Use in Specific Populations (8.5)] . Pediatrics The pharmacokinetics of fenofibric acid delayed-release capsules has not been studied in pediatric populations. Gender No pharmacokinetic difference between males and females has been observed for fenofibric acid delayed-release capsules. Race The influence of race on the pharmacokinetics of fenofibric acid delayed-release capsules has not been studied; however, fenofibric acid is not metabolized by enzymes known for exhibiting inter-ethnic variability. Renal Impairment The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate, and severe renal impairment. Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73m 2 ) showed a 2.7-fold increase in exposure for fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared to that of healthy subjects. Patients with mild to moderate renal impairment (eGFR 30 to 59 mL/min/1.73m 2 ) had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of fenofibric acid delayed-release capsules 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)] . Hepatic Impairment No pharmacokinetic studies have been conducted in patients with hepatic impairment. Drug-drug Interactions In vitro studies using human liver microsomes indicate that fenofibric acid is not an inhibitor of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. It is a weak inhibitor of CYP2C8, CYP2C19, and CYP2A6, and mild-to-moderate inhibitor of CYP2C9 at therapeutic concentrations. Comparison of atorvastatin exposures when atorvastatin (80 mg once daily for 10 days) is given in combination with fenofibric acid (fenofibric acid delayed-release capsule 135 mg once daily for 10 days) and ezetimibe (10 mg once daily for 10 days) versus when atorvastatin is given in combination with ezetimibe only (ezetimibe 10 mg once daily and atorvastatin, 80 mg once daily for 10 days): The C max decreased by 1% for atorvastatin and ortho-hydroxy-atorvastatin and increased by 2% for para-hydroxy-atorvastatin. The AUC decreased 6% and 9% for atorvastatin and ortho-hydroxy-atorvastatin, respectively, and did not change for para-hydroxy-atorvastatin. Comparison of ezetimibe exposures when ezetimibe (10 mg once daily for 10 days) is given in combination with fenofibric acid (fenofibric acid delayed-release capsule 135 mg once daily for 10 days) and atorvastatin (80 mg once daily for 10 days) versus when ezetimibe is given in combination with atorvastatin only (ezetimibe 10 mg once daily and atorvastatin, 80 mg once daily for 10 days): The C max increased by 26% and 7% for total and free ezetimibe, respectively. The AUC increased by 27% and 12% for total and free ezetimibe, respectively. Table 2 describes the effects of co-administered drugs on fenofibric acid systemic exposure. Table 3 describes the effects of co-administered fenofibric acid on other drugs. Table 2. Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Fenofibric Acid Delayed-Release Capsules or Fenofibrate Administration Co-Administered Drug Dosage Regimen of Co-Administered Drug Dosage Regimen of Fenofibric Acid Delayed-Release Capsules or Fenofibrate Changes in Fenofibric Acid Exposure AUC C max Lipid-lowering agents Rosuvastatin 40 mg once daily for 10 days Fenofibric acid delayed-release capsule 135 mg once daily for 10 days ↓2% ↓2% Atorvastatin 20 mg once daily for 10 days Fenofibrate 160 mg 1 once daily for 10 days ↓2% ↓4% Atorvastatin + ezetimibe Atorvastatin, 80 mg once daily and ezetimibe, 10 mg once daily for 10 days Fenofibric acid delayed-release capsule 135 mg once daily for 10 days ↑5% ↑5% Pravastatin 40 mg as a single dose Fenofibrate 3 x 67 mg 2 as a single dose ↓1% ↓2% Fluvastatin 40 mg as a single dose Fenofibrate 160 mg 1 as a single dose ↓2% ↓10% Simvastatin 80 mg once daily for 7 days Fenofibrate 160 mg 1 once daily for 7 days ↓5% ↓11% Anti-diabetic agents Glimepiride 1 mg as a single dose Fenofibrate 145 mg 1 once daily for 10 days ↑1% ↓1% Metformin 850 mg 3 times daily for 10 days Fenofibrate 54 mg 1 3 times daily for 10 days ↓9% ↓6% Rosiglitazone 8 mg once daily for 5 days Fenofibrate 145 mg 1 once daily for 14 days ↑10% ↑3% Gastrointestinal agents Omeprazole 40 mg once daily for 5 days Fenofibric acid delayed-release capsule 135 mg as a single dose fasting ↑6% ↑17% Omeprazole 40 mg once daily for 5 days Fenofibric acid delayed-release capsule 135 mg as a single dose with food ↑4% ↓2% 1 TriCor (fenofibrate) oral tablet 2 TriCor (fenofibrate) oral micronized capsule Table 3. Effects of Fenofibric Acid Delayed-Release Capsules or Fenofibrate Co-Administration on Systemic Exposure of Other Drugs Dosage Regimen of Fenofibric Acid Delayed-Release Capsules or Fenofibrate Dosage Regimen of Co-Administered Drug Change in Co-Administered Drug Exposure Analyte AUC C max Lipid-lowering agents Trilipix 135 mg once daily for 10 days Rosuvastatin, 40 mg once daily for 10 days Rosuvastatin ↑6% ↑20% Fenofibrate 160 mg 1 once daily for 10 days Atorvastatin, 20 mg once daily for 10 days Atorvastatin ↓17% 0% Fenofibrate 3 x 67 mg 2 as a single dose Pravastatin, 40 mg as a single dose Pravastatin ↑13% ↑13% 3α-Hydroxyl-iso-pravastatin ↑26% ↑29% Fenofibrate 160 mg 1 as a single dose Fluvastatin, 40 mg as a single dose (+)-3R, 5S-Fluvastatin ↑15% ↑16% Fenofibrate 160 mg 1 once daily for 7 days Simvastatin, 80 mg once daily for 7 days Simvastatin acid ↓36% ↓11% Simvastatin ↓11% ↓17% Active HMG-CoA Inhibitors ↓12% ↓1% Total HMG-CoA Inhibitors ↓8% ↓10% Anti-diabetic agents Fenofibrate 145 mg 1 once daily for 10 days Glimepiride, 1 mg as a single dose Glimepiride ↑35% ↑18% Fenofibrate 54 mg 1 3 times daily for 10 days Metformin, 850 mg 3 times daily for 10 days Metformin ↑3% ↑6% Fenofibrate 145 mg 1 once daily for 14 days Rosiglitazone, 8 mg once daily for 5 days Rosiglitazone ↑6% ↓1% 1 TriCor (fenofibrate) oral tablet 2 TriCor (fenofibrate) oral micronized capsule

12.1 Mechanism of Action The active moiety of fenofibric acid delayed-release capsule 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-modifying 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 α (PPARα). Through this mechanism, fenofibric acid increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of Apo CIII (an inhibitor of lipoprotein lipase activity). Activation of PPARα also induces an increase in the synthesis of HDL-C and Apo AI and AII.

12.3 Pharmacokinetics Fenofibric acid delayed-release capsules contain fenofibric acid, which is the only circulating pharmacologically active moiety in plasma after oral administration of fenofibric acid delayed-release capsules. Fenofibric acid is also the circulating pharmacologically active moiety in plasma after oral administration of fenofibrate, the ester of fenofibric acid. Plasma concentrations of fenofibric acid after administration of one 135 mg fenofibric acid delayed release capsule are equivalent to those after one 200 mg capsule of micronized fenofibrate administered under fed conditions. Absorption Fenofibric acid is well absorbed throughout the gastrointestinal tract. The absolute bioavailability of fenofibric acid is approximately 81%. Peak plasma levels of fenofibric acid occur within 4 to 5 hours after a single dose administration of fenofibric acid delayed-release capsule under fasting conditions. Fenofibric acid exposure in plasma, as measured by C max and AUC, is not significantly different when a single 135 mg dose of fenofibric acid delayed-release capsule is administered under fasting or nonfasting conditions. Distribution Upon multiple dosing of fenofibric acid delayed-release capsules, fenofibric acid levels reach steady state within 8 days. Plasma concentrations of fenofibric acid at steady state are approximately slightly more than double those following a single dose. Serum protein binding is approximately 99% in normal and dyslipidemic subjects. Metabolism Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine. In vivo metabolism data after fenofibrate administration indicate that fenofibric acid does not undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent. Elimination After absorption, fenofibric acid delayed-release capsules are primarily excreted in the urine in the form of fenofibric acid and fenofibric acid glucuronide. Fenofibric acid is eliminated with a half-life of approximately 20 hours, allowing once daily administration of fenofibric acid delayed-release capsules. Specific Populations Geriatrics In five elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following a single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that an equivalent dose of fenofibric acid delayed-release capsules can be used in elderly subjects with normal renal function, without increasing accumulation of the drug or metabolites [see Use in Specific Populations (8.5)] . Pediatrics The pharmacokinetics of fenofibric acid delayed-release capsules has not been studied in pediatric populations. Gender No pharmacokinetic difference between males and females has been observed for fenofibric acid delayed-release capsules. Race The influence of race on the pharmacokinetics of fenofibric acid delayed-release capsules has not been studied; however, fenofibric acid is not metabolized by enzymes known for exhibiting inter-ethnic variability. Renal Impairment The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate, and severe renal impairment. Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73m 2 ) showed a 2.7-fold increase in exposure for fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared to that of healthy subjects. Patients with mild to moderate renal impairment (eGFR 30 to 59 mL/min/1.73m 2 ) had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of fenofibric acid delayed-release capsules 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)] . Hepatic Impairment No pharmacokinetic studies have been conducted in patients with hepatic impairment. Drug-drug Interactions In vitro studies using human liver microsomes indicate that fenofibric acid is not an inhibitor of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. It is a weak inhibitor of CYP2C8, CYP2C19, and CYP2A6, and mild-to-moderate inhibitor of CYP2C9 at therapeutic concentrations. Comparison of atorvastatin exposures when atorvastatin (80 mg once daily for 10 days) is given in combination with fenofibric acid (fenofibric acid delayed-release capsule 135 mg once daily for 10 days) and ezetimibe (10 mg once daily for 10 days) versus when atorvastatin is given in combination with ezetimibe only (ezetimibe 10 mg once daily and atorvastatin, 80 mg once daily for 10 days): The C max decreased by 1% for atorvastatin and ortho-hydroxy-atorvastatin and increased by 2% for para-hydroxy-atorvastatin. The AUC decreased 6% and 9% for atorvastatin and ortho-hydroxy-atorvastatin, respectively, and did not change for para-hydroxy-atorvastatin. Comparison of ezetimibe exposures when ezetimibe (10 mg once daily for 10 days) is given in combination with fenofibric acid (fenofibric acid delayed-release capsule 135 mg once daily for 10 days) and atorvastatin (80 mg once daily for 10 days) versus when ezetimibe is given in combination with atorvastatin only (ezetimibe 10 mg once daily and atorvastatin, 80 mg once daily for 10 days): The C max increased by 26% and 7% for total and free ezetimibe, respectively. The AUC increased by 27% and 12% for total and free ezetimibe, respectively. Table 2 describes the effects of co-administered drugs on fenofibric acid systemic exposure. Table 3 describes the effects of co-administered fenofibric acid on other drugs. Table 2. Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Fenofibric Acid Delayed-Release Capsules or Fenofibrate Administration Co-Administered Drug Dosage Regimen of Co-Administered Drug Dosage Regimen of Fenofibric Acid Delayed-Release Capsules or Fenofibrate Changes in Fenofibric Acid Exposure AUC C max Lipid-lowering agents Rosuvastatin 40 mg once daily for 10 days Fenofibric acid delayed-release capsule 135 mg once daily for 10 days ↓2% ↓2% Atorvastatin 20 mg once daily for 10 days Fenofibrate 160 mg 1 once daily for 10 days ↓2% ↓4% Atorvastatin + ezetimibe Atorvastatin, 80 mg once daily and ezetimibe, 10 mg once daily for 10 days Fenofibric acid delayed-release capsule 135 mg once daily for 10 days ↑5% ↑5% Pravastatin 40 mg as a single dose Fenofibrate 3 x 67 mg 2 as a single dose ↓1% ↓2% Fluvastatin 40 mg as a single dose Fenofibrate 160 mg 1 as a single dose ↓2% ↓10% Simvastatin 80 mg once daily for 7 days Fenofibrate 160 mg 1 once daily for 7 days ↓5% ↓11% Anti-diabetic agents Glimepiride 1 mg as a single dose Fenofibrate 145 mg 1 once daily for 10 days ↑1% ↓1% Metformin 850 mg 3 times daily for 10 days Fenofibrate 54 mg 1 3 times daily for 10 days ↓9% ↓6% Rosiglitazone 8 mg once daily for 5 days Fenofibrate 145 mg 1 once daily for 14 days ↑10% ↑3% Gastrointestinal agents Omeprazole 40 mg once daily for 5 days Fenofibric acid delayed-release capsule 135 mg as a single dose fasting ↑6% ↑17% Omeprazole 40 mg once daily for 5 days Fenofibric acid delayed-release capsule 135 mg as a single dose with food ↑4% ↓2% 1 TriCor (fenofibrate) oral tablet 2 TriCor (fenofibrate) oral micronized capsule Table 3. Effects of Fenofibric Acid Delayed-Release Capsules or Fenofibrate Co-Administration on Systemic Exposure of Other Drugs Dosage Regimen of Fenofibric Acid Delayed-Release Capsules or Fenofibrate Dosage Regimen of Co-Administered Drug Change in Co-Administered Drug Exposure Analyte AUC C max Lipid-lowering agents Trilipix 135 mg once daily for 10 days Rosuvastatin, 40 mg once daily for 10 days Rosuvastatin ↑6% ↑20% Fenofibrate 160 mg 1 once daily for 10 days Atorvastatin, 20 mg once daily for 10 days Atorvastatin ↓17% 0% Fenofibrate 3 x 67 mg 2 as a single dose Pravastatin, 40 mg as a single dose Pravastatin ↑13% ↑13% 3α-Hydroxyl-iso-pravastatin ↑26% ↑29% Fenofibrate 160 mg 1 as a single dose Fluvastatin, 40 mg as a single dose (+)-3R, 5S-Fluvastatin ↑15% ↑16% Fenofibrate 160 mg 1 once daily for 7 days Simvastatin, 80 mg once daily for 7 days Simvastatin acid ↓36% ↓11% Simvastatin ↓11% ↓17% Active HMG-CoA Inhibitors ↓12% ↓1% Total HMG-CoA Inhibitors ↓8% ↓10% Anti-diabetic agents Fenofibrate 145 mg 1 once daily for 10 days Glimepiride, 1 mg as a single dose Glimepiride ↑35% ↑18% Fenofibrate 54 mg 1 3 times daily for 10 days Metformin, 850 mg 3 times daily for 10 days Metformin ↑3% ↑6% Fenofibrate 145 mg 1 once daily for 14 days Rosiglitazone, 8 mg once daily for 5 days Rosiglitazone ↑6% ↓1% 1 TriCor (fenofibrate) oral tablet 2 TriCor (fenofibrate) oral micronized capsule

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3 DOSAGE FORMS AND STRENGTHS • 45 mg capsules with a brown opaque cap/ yellow opaque body size ‘3’ hard gelatin capsule imprinted with ‘A’ on the cap in white ink and ‘138’ on the body in black ink, filled with white to off white mini tablets. • 135 mg capsules with a blue opaque cap/ yellow opaque body size ‘0’ hard gelatin capsule imprinted with ‘A’ on the cap in white ink and ‘139’ on the body in black ink, filled with white to off white mini tablets. Oral Delayed Release Capsules: 45 mg and 135 mg (3)

Fenofibric Acid Fenofibric Acid FENOFIBRIC ACID FENOFIBRIC ACID HYPROMELLOSE, UNSPECIFIED POVIDONE K30 WATER HYDROXYPROPYL CELLULOSE (70000 WAMW) SILICON DIOXIDE SODIUM STEARYL FUMARATE METHACRYLIC ACID TALC TRIETHYL CITRATE GELATIN TITANIUM DIOXIDE FERRIC OXIDE YELLOW FERRIC OXIDE RED SHELLAC PROPYLENE GLYCOL POTASSIUM HYDROXIDE FERROSOFERRIC OXIDE brown opaque cap yellow opaque body A;138 Fenofibric Acid Fenofibric Acid FENOFIBRIC ACID FENOFIBRIC ACID HYPROMELLOSE, UNSPECIFIED POVIDONE K30 WATER HYDROXYPROPYL CELLULOSE (70000 WAMW) SILICON DIOXIDE SODIUM STEARYL FUMARATE METHACRYLIC ACID TALC TRIETHYL CITRATE GELATIN TITANIUM DIOXIDE FERRIC OXIDE YELLOW FD&C BLUE NO. 2 SHELLAC PROPYLENE GLYCOL POTASSIUM HYDROXIDE FERROSOFERRIC OXIDE blue opaque cap yellow opaque body A;139

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Fenofibric acid delayed-release capsules No carcinogenicity and fertility studies have been conducted with choline fenofibrate or fenofibric acid. However, because fenofibrate is rapidly converted to its active metabolite, fenofibric acid, either during or immediately following absorption both in animals and humans, studies conducted with fenofibrate are relevant for the assessment of the toxicity profile of fenofibric acid. A similar toxicity spectrum is expected after treatment with either fenofibric acid delayed-release capsules or fenofibrate. Fenofibrate 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 6 times the maximum recommended human dose (MRHD), based on body surface area comparisons (mg/m 2 ). At a dose of 200 mg/kg/day (6 times the MRHD), the incidence of liver carcinomas was significantly increased in both sexes. A statistically significant increase in pancreatic carcinomas was observed in males at 1 and 6 times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed at 6 times the MRHD in males. In a second 24-month rat carcinogenicity study in a different strain of rats (Sprague-Dawley), (doses of 10 and 60 mg/kg/day (0.3 and 2 times the MRHD), produced significant increases in the incidence of pancreatic acinar adenomas in both sexes and increases in interstitial cell tumors of the testes at 2 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 2 times the MRHD), clofibrate (400 mg/kg/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the MRHD). Fenofibrate increased pancreatic acinar adenomas in both sexes. Clofibrate increased hepatocellular carcinoma and pancreatic acinar adenomas in males and hepatic neoplastic nodules in females. Gemfibrozil increased hepatic neoplastic nodules in males and females, while all three drugs increased testicular interstitial cell tumors in males. In a 21-month study in CF-1 mice, fenofibrate 10, 45, and 200 mg/kg/day (approximately 0.2, 1, and 3 times the MRHD on the basis of mg/m2 surface area) significantly increased the liver carcinomas in both sexes at 3 times the MRHD. In a second 18-month study at 10, 60, and 200 mg/kg/day, fenofibrate significantly increased the liver carcinomas in male and female mice at 3 times the MRHD. Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual. Mutagenesis: Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, and micronucleus in vivo /rat. In addition, fenofibric acid, has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and sister chromatid exchange in human lymphocytes, and unscheduled DNA synthesis in primary rat hepatocytes. Impairment of Fertility: In a fertility study, rats were given oral dietary doses of fenofibrate. Males received doses for 61 days prior to mating and females for 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/m 2 surface area comparisons).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Fenofibric acid delayed-release capsules No carcinogenicity and fertility studies have been conducted with choline fenofibrate or fenofibric acid. However, because fenofibrate is rapidly converted to its active metabolite, fenofibric acid, either during or immediately following absorption both in animals and humans, studies conducted with fenofibrate are relevant for the assessment of the toxicity profile of fenofibric acid. A similar toxicity spectrum is expected after treatment with either fenofibric acid delayed-release capsules or fenofibrate. Fenofibrate 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 6 times the maximum recommended human dose (MRHD), based on body surface area comparisons (mg/m 2 ). At a dose of 200 mg/kg/day (6 times the MRHD), the incidence of liver carcinomas was significantly increased in both sexes. A statistically significant increase in pancreatic carcinomas was observed in males at 1 and 6 times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed at 6 times the MRHD in males. In a second 24-month rat carcinogenicity study in a different strain of rats (Sprague-Dawley), (doses of 10 and 60 mg/kg/day (0.3 and 2 times the MRHD), produced significant increases in the incidence of pancreatic acinar adenomas in both sexes and increases in interstitial cell tumors of the testes at 2 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 2 times the MRHD), clofibrate (400 mg/kg/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the MRHD). Fenofibrate increased pancreatic acinar adenomas in both sexes. Clofibrate increased hepatocellular carcinoma and pancreatic acinar adenomas in males and hepatic neoplastic nodules in females. Gemfibrozil increased hepatic neoplastic nodules in males and females, while all three drugs increased testicular interstitial cell tumors in males. In a 21-month study in CF-1 mice, fenofibrate 10, 45, and 200 mg/kg/day (approximately 0.2, 1, and 3 times the MRHD on the basis of mg/m2 surface area) significantly increased the liver carcinomas in both sexes at 3 times the MRHD. In a second 18-month study at 10, 60, and 200 mg/kg/day, fenofibrate significantly increased the liver carcinomas in male and female mice at 3 times the MRHD. Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual. Mutagenesis: Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, and micronucleus in vivo /rat. In addition, fenofibric acid, has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and sister chromatid exchange in human lymphocytes, and unscheduled DNA synthesis in primary rat hepatocytes. Impairment of Fertility: In a fertility study, rats were given oral dietary doses of fenofibrate. Males received doses for 61 days prior to mating and females for 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/m 2 surface area comparisons).

ANDA208705

Fenofibric Acid

Fenofibric Acid

46708-244

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 45 mg Fenofibric Acid Delayed-Release Capsules 45 mg - 30 Capsules HDPE Bottle Pack Each delayed release capsule contains: choline fenofibrate equivalent to 45 mg of fenofibric acid. 46708-244-30 30's bottle pack

Indications and Usage, Combination With a Statin – removal (1) 04/2015 Dosage and Administration, Combination With a Statin – removal (2) 04/2015

17 PATIENT COUNSELING INFORMATION See Medication Guide 17.1 Patient Counseling Patients should be advised: · of the potential benefits and risks of fenofibric acid delayed-release capsules. · to read the Medication Guide before starting Fenofibric acid delayed-release capsules therapy and to reread it each time the prescription is renewed. · of medications that should not be taken in combination with fenofibric acid delayed-release capsules. · to continue to follow an appropriate lipid-modifying diet while taking fenofibric acid delayed-release capsules. · to take fenofibric acid delayed-release capsules once daily, without regard to food, at the prescribed dose, swallowing each capsule whole. · to return for routine monitoring. · to 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 a new medication that they are taking fenofibric acid delayed-release capsules. · to inform their physician of any muscle pain, tenderness, or weakness; onset of abdominal pain; or any other new symptoms. Manufactured by: Alembic Pharmaceuticals Limited (Formulation Division), Panelav 389350, Gujarat, India Manufactured for: Alembic Pharmaceuticals, Inc. 750 Route 202, Bridgewater, NJ 08807 USA Revised: 02/2017 MEDICATION GUIDE Fenofibric Acid ( FEN-oh-FYE-bric AS-id ) Delayed-Release Capsules Read this Medication Guide before you start taking fenofibric acid delayed-release capsules and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about fenofibric acid delayed-release capsules ? Fenofibric acid delayed-release capsules can cause muscle pain, tenderness or weakness, which may be symptoms of a rare but serious muscle condition called rhabdomyolysis. In some cases rhabdomyolysis can cause kidney damage and death. The risk of rhabdomyolysis may be higher when fenofibric acid delayed-release capsules are given with statins. If you take a statin, tell your healthcare provider. What are fenofibric acid delayed-release capsules ? Fenofibric acid delayed-release capsules are a prescription medicine used to treat cholesterol in the blood by lowering the total amount of triglycerides and LDL (bad) cholesterol, and increasing the HDL (good) cholesterol. Fenofibric acid delayed-release capsules have not been shown to lower your risk of having heart problems or a stroke. You should be on a low fat and low cholesterol diet while you take fenofibric acid delayed-release capsules. The safety and effectiveness of fenofibric acid delayed-release capsules in children is not known. Who should not take fenofibric acid delayed-release capsules ? Do not take fenofibric acid delayed-release capsules if you: · are allergic to fenofibric acid, or any of the ingredients in fenofibric acid delayed-release capsules. See the end of this Medication Guide for a list of all the ingredients in fenofibric acid delayed-release capsules. · have severe kidney disease. · have liver disease. · have gallbladder disease. · are a nursing mother. Talk to your healthcare provider before you take fenofibric acid delayed-release capsules if you have any of these conditions. What should I tell my healthcare provider before taking fenofibric acid delayed-release capsules ? Before taking fenofibric acid delayed-release capsules , tell your healthcare provider about all your medical conditions, including if you: · are allergic to any medicines. · have ever had kidney problems. · have ever had liver problems. · have ever had gallbladder problems. · are pregnant or if you plan to become pregnant. It is not known if fenofibric acid delayed-release capsules will harm your unborn baby. · are breastfeeding or plan to breastfeed. It is not known if fenofibric acid passes into your breast milk. You and your healthcare provider should decide if you will take fenofibric acid delayed-release capsules or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Using fenofibric acid delayed-release capsules with certain other medicines can affect the way these medicines work and other medicines may affect how fenofibric acid delayed-release capsules works. In some cases, using fenofibric acid delayed-release capsules with other medicines can cause serious side effects. Know all the medicines you take. Keep a list of them and show it to your healthcare provider when you get a new medicine. It is especially important to tell your healthcare provider if you take any of the medicines listed below: · anticoagulants , also known as blood thinners (warfarin, Coumadin) · bile acid resins · cyclosporine Ask your healthcare provider if you are not sure if your medicine is one of these. How should I take fenofibric acid delayed-release capsules ? · You should be on a low fat and low cholesterol diet while you take fenofibric acid delayed-release capsules. · Take fenofibric acid delayed-release capsules one time each day as prescribed by your healthcare provider. · Take fenofibric acid delayed-release capsules with or without food. · Swallow fenofibric acid delayed-release capsules whole. Do not break, crush, dissolve, or chew fenofibric acid delayed-release capsules before swallowing. If you cannot swallow fenofibric acid delayed-release capsules whole, tell your healthcare provider, you may need a different medicine. · If you miss a dose of fenofibric acid delayed-release capsules, take it as soon as you remember. If it is almost time for your next dose, just skip the missed dose. Take the next dose at your regular time. If you are not sure about your dosing, call your healthcare provider. Do not take more than one dose of fenofibric acid delayed-release capsules a day unless your healthcare provider tells you to. · If you take too much fenofibric acid delayed-release capsules, contact your healthcare provider or your local emergency department. · Do not change your dose or stop fenofibric acid delayed-release capsules unless your healthcare provider tells you to. · Your healthcare provider may do blood tests before you start taking fenofibric acid delayed-release capsules and during treatment. See your healthcare provider regularly to check your cholesterol and triglyceride levels and to check for side effects. What are the possible side effects with fenofibric acid delayed-release capsules ? Fenofibric acid delayed-release capsules may cause serious side effects, including: · muscle pain, tenderness, or weakness. See “What is the most important information that I should know about fenofibric acid delayed-release capsules?” · tiredness and fever. · abdominal pain, nausea, or vomiting. These may be signs of inflammation (swelling) of the gallbladder or pancreas. Call your healthcare provider right away if you have any of these serious side effects. The most common side effects with fenofibric acid delayed-release capsules include: · headache · heartburn (indigestion) · nausea · muscle aches · increases in muscle or liver enzymes that are measured by blood tests Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of fenofibric acid delayed-release capsules. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How do I store fenofibric acid delayed-release capsules ? · Store fenofibric acid delayed-release capsules between 59° to 86°F (15° to 30°C). · Protect fenofibric acid delayed-release capsules from moisture. Keep fenofibric acid delayed-release capsules and all medicines out of the reach of children. General information about the safe and effective use of fenofibric acid delayed-release capsules Medicines are sometimes prescribed for conditions that are not mentioned in the Medication Guide. Do not use fenofibric acid delayed-release capsules for a condition for which it was not prescribed. Do not give fenofibric acid delayed-release capsules to other people, even if they have the same condition you have. It may harm them. This Medication Guide summarizes the most important information about fenofibric acid delayed-release capsules. If you would like more information, talk to your healthcare provider. You can also ask your pharmacist or healthcare provider for information that is written for health professionals. For more information call 1-866 210 9797. What are the ingredients in fenofibric acid delayed-release capsules ? Active Ingredient: Fenofibric acid Inactive Ingredients: Hypromellose, povidone, water, hydroxylpropyl cellulose, colloidal silicon dioxide, sodium stearyl fumarate, methacrylic acid copolymer, talc, triethyl citrate. The capsule shell of the 45 mg capsule contains the following inactive ingredients: gelatin, titanium dioxide, iron oxide yellow, and iron oxide red. The capsule shell of the 135 mg capsule contains the following inactive ingredients: gelatin, titanium dioxide, iron oxide yellow, and FD&C Blue #2. The capsule shells are printed with edible white ink and black ink. The edible white ink contains shellac, propylene glycol, potassium hydroxide, and titanium dioxide and the edible black ink contains shellac, propylene glycol, iron oxide black and, potassium hydroxide. This Medication Guide has been approved by the U.S. Food and Drug Administration. Brands listed are the trademarks of their respective owners. Manufactured by: Alembic Pharmaceuticals Limited (Formulation Division), Panelav 389350, Gujarat, India Manufactured for: Alembic Pharmaceuticals, Inc. 750 Route 202, Bridgewater, NJ 08807 USA Revised: 02/2017

Medication Guide .

14 CLINICAL STUDIES 14.1 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 135 mg once daily of fenofibric acid delayed-release capsules decreased primarily VLDL-TG and VLDL-C. Treatment of patients with elevated TG often results in an increase of LDL-C (Table 4). Table 4. Effects of Fenofibrate in Patients With Severe Hypertriglyceridemia Study 1 Placebo Fenofibrate Baseline TG levels 350 to 499 mg/dL N Baseline Mean (mg/dL) Endpoint Mean (mg/dL) Mean % Change N Baseline Mean (mg/dL) Endpoint Mean (mg/dL) Mean % Change Triglycerides 28 449 450 -0.5 27 432 223 -46.2 * VLDL Triglycerides 19 367 350 2.7 19 350 178 -44.1 * Total Cholesterol 28 255 261 2.8 27 252 227 -9.1 * HDL Cholesterol 28 35 36 4 27 34 40 19.6 * LDL Cholesterol 28 120 129 12 27 128 137 14.5 VLDL Cholesterol 27 99 99 5.8 27 92 46 -44.7 * Study 2 Placebo Fenofibrate Baseline TG levels 500 to 1500 mg/dL N Baseline Mean (mg/dL) Endpoint Mean (mg/dL) Mean % Change N Baseline Mean (mg/dL) Endpoint Mean (mg/dL) Mean % Change Triglycerides 44 710 750 7.2 48 726 308 -54.5 * VLDL Triglycerides 29 537 571 18.7 33 543 205 -50.6 * Total Cholesterol 44 272 271 0.4 48 261 223 -13.8 * HDL Cholesterol 44 27 28 5 48 30 36 22.9 * LDL Cholesterol 42 100 90 -4.2 45 103 131 45 * VLDL Cholesterol 42 137 142 11 45 126 54 -49.4 * * = p < 0.05 vs. Placebo 14.2 Primary Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia The effects of fenofibrate at a dose equivalent to fenofibric acid delayed-release capsule 135 mg once daily 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 (Table 5). Table 5. Mean Percent Change in Lipid Parameters at End of Treatment † Treatment Group Total-C (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) TG (mg/dL) Pooled Cohort Mean baseline lipid values (n = 646) 306.9 213.8 52.3 191 All Fenofibrate (n = 361) -18.7% * -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 Mean baseline lipid values (n = 334) 307.7 227.7 58.1 101.7 All Fenofibrate (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 Mean baseline lipid values (n = 242) 312.8 219.8 46.7 231.9 All Fenofibrate (n = 126) -16.8% * -20.1% * +14.6% * -35.9% * Placebo (n = 116) -3% -6.6% +2.3% +0.9% † Duration of study treatment was 3 to 6 months * p = < 0.05 vs. Placebo In a subset of the subjects, measurements of Apo B were conducted. Fenofibrate treatment significantly reduced Apo B from baseline to endpoint as compared with placebo (-25.1% vs. 2.4%, p < 0.0001, n = 213 and 143, respectively).

8.5 Geriatric Use Fenofibric acid delayed-release capsules are substantially excreted by the kidney as fenofibric acid and fenofibric acid glucuronide, 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 a 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 fenofibric acid delayed-release capsules.

8.3 Nursing Mothers Fenofibric acid delayed-release capsules should not be used in nursing mothers. A decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of fenofibric acid delayed-release capsules in pediatric patients have not been established.

8.1 Pregnancy Pregnancy Category: C The safety of fenofibric acid delayed-release capsules in pregnant women has not been established. There are no adequate and well controlled studies of fenofibric acid delayed-release capsules in pregnant women. Fenofibric acid delayed-release capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In pregnant rats given oral dietary doses of 14, 127, and 361 mg/kg/day from gestation day 6 to 15 during the period of organogenesis, adverse developmental findings were not observed at 14 mg/kg/day (less than 1 times the maximum recommended human dose [MRHD], based on body surface area comparisons; mg/m 2 ). At higher multiples of human doses evidence of maternal toxicity was observed. In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 6 to 18 during the period of organogenesis and allowed to deliver, aborted litters were observed at 150 mg/kg/day (10 times the MRHD, based on body surface area comparisons; mg/m 2 ). No developmental findings were observed at 15 mg/kg/day (at less than 1 times the MRHD, based on body surface area comparisons; mg/m 2 ). In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), maternal toxicity was observed at less than 1 times the MRHD, based on body surface area comparisons; mg/m 2 .

8 USE IN SPECIFIC POPULATIONS Geriatric Use: Dose selection for the elderly should be made on the basis of renal function (8.5). Renal Impairment: Fenofibric acid delayed-release capsules should be avoided in patients with severe renal impairment. Dose adjustment is required in patients with mild to moderate renal impairment (8.6). 8.1 Pregnancy Pregnancy Category: C The safety of fenofibric acid delayed-release capsules in pregnant women has not been established. There are no adequate and well controlled studies of fenofibric acid delayed-release capsules in pregnant women. Fenofibric acid delayed-release capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In pregnant rats given oral dietary doses of 14, 127, and 361 mg/kg/day from gestation day 6 to 15 during the period of organogenesis, adverse developmental findings were not observed at 14 mg/kg/day (less than 1 times the maximum recommended human dose [MRHD], based on body surface area comparisons; mg/m 2 ). At higher multiples of human doses evidence of maternal toxicity was observed. In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 6 to 18 during the period of organogenesis and allowed to deliver, aborted litters were observed at 150 mg/kg/day (10 times the MRHD, based on body surface area comparisons; mg/m 2 ). No developmental findings were observed at 15 mg/kg/day (at less than 1 times the MRHD, based on body surface area comparisons; mg/m 2 ). In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), maternal toxicity was observed at less than 1 times the MRHD, based on body surface area comparisons; mg/m 2 . 8.3 Nursing Mothers Fenofibric acid delayed-release capsules should not be used in nursing mothers. A decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of fenofibric acid delayed-release capsules in pediatric patients have not been established. 8.5 Geriatric Use Fenofibric acid delayed-release capsules are substantially excreted by the kidney as fenofibric acid and fenofibric acid glucuronide, 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 a 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 fenofibric acid delayed-release capsules. 8.6 Renal Impairment The use of fenofibric acid delayed-release capsules should be avoided in patients who have 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 fenofibric acid delayed-release capsules have not been evaluated in subjects with hepatic impairment [see Contraindications (4) and Clinical Pharmacology (12.3)] .

16 HOW SUPPLIED/STORAGE AND HANDLING Fenofibric acid delayed-release capsules 45 mg have a brown opaque cap/ yellow opaque body size ‘3’ hard gelatin capsule imprinted with ‘A’ on the cap in white ink and ‘138’ on the body in black ink, filled with white to off white mini tablets. NDC 46708-244-30 30 Capsules HDPE Bottle Pack NDC 46708-244-90 90 Capsules HDPE Bottle Pack NDC 46708-244-91 1000 Capsules HDPE Bottle Pack Fenofibric acid delayed-release capsules 135 mg have a blue opaque cap/ yellow opaque body size ‘0’ hard gelatin capsule imprinted with ‘A’ on the cap in white ink and ‘139’ on the body in black ink, filled with white to off white mini tablets. NDC 46708-245-30 30 Capsules HDPE Bottle Pack NDC 46708-245-90 90 Capsules HDPE Bottle Pack NDC 46708-245-91 1000 Capsules HDPE Bottle Pack Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep out of the reach of children. Protect from moisture.