Fenofibric Acid Delayed-Release

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 TWi Pharmaceuticals, Inc. at 1-844-518-2989 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 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 5.0% of patients treated with fenofibrate and in 3.0% 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 * Dosage equivalent to 135 mg fenofibric acid delayed-release capsules 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 3.0% 1.6% Increased Creatine Phosphokinase 3.0% 1.4% RESPIRATORY Respiratory Disorder 6.2% 5.5% Rhinitis 2.3% 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. 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: Dizziness 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of fenofibrate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: rhabdomyolysis, pancreatitis, renal failure, muscle spasms, acute renal failure, hepatitis, cirrhosis, anemia, asthenia, severely depressed HDL-cholesterol levels, and interstitial lung disease. Photosensitivity reactions to fenofibrate have occurred days to months after initiation; in some of these cases, patients reported a prior photosensitivity reaction to ketoprofen.

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 ( 8.2 )]. 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 ). Lactation ( 4 , 8.2 ). Known hypersensitivity to fenofibric acid or fenofibrate ( 4 , 5.9 ).

11 DESCRIPTION Fenofibric acid delayed-release capsules are 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. The melting point is approximately 210°C. Choline fenofibrate is a white to yellow 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, hydroxylpropyl cellulose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer, silicon dioxide, talc, triethyl citrate. The capsule shell of the 45 mg capsule contains the following inactive ingredients: ammonia, gelatin, propylene glycol, shellac, sodium lauryl sulfate, titanium dioxide, black iron oxide, red iron oxide and yellow iron oxide. The capsule shell of the 135 mg capsule contains the following inactive ingredients: ammonia, gelatin, propylene glycol, shellac, sodium lauryl sulfate, titanium dioxide, black iron oxide and yellow iron oxide FD&C Red No. 40 and FD&C Blue No. 1. molecular-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 capsules 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 HDL-C 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 capsules 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 capsules 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 capsules 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/1.73 m 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 30-59 mL/min/1.73 m 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 capsules 135 mg once daily for 10 days) and ezetimibe (10 mg once daily for 10 days) versus when atorvastatin is given in combination with ezetimibe only (ezetimibe 10 mg once daily and atorvastatin, 80 mg once daily for 10 days): The C max decreased by 1% for atorvastatin and ortho-hydroxy-atorvastatin and increased by 2% for parahydroxy-atorvastatin. The AUC decreased 6% and 9% for atorvastatin and orthohydroxy-atorvastatin, respectively, and did not change for para-hydroxy-atorvastatin. Comparison of ezetimibe exposures when ezetimibe (10 mg once daily for 10 days) is given in combination with fenofibric acid (fenofibric acid delayed-release capsules 135 mg once daily for 10 days) and atorvastatin (80 mg once daily for 10 days) versus when ezetimibe is given in combination with atorvastatin only (ezetimibe 10 mg once daily and atorvastatin, 80 mg once daily for 10 days): The C 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 Coadministered Drugs on Fenofibric Acid Systemic Exposure from Fenofibric Acid Delayed-Release Capsules or Fenofibrate Administration 1 TriCor ® (fenofibrate) oral tablet 2 TriCor ® (fenofibrate) oral micronized capsule Co-Administered Drug Dosage Regimen of Co-Administered Drug Dosage Regiment 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 Capsules 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 Capsules 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 Capsules 135 mg as a single dose fasting ↑6% ↑17% Omeprazole 40 mg once daily for 5 days Fenofibric Acid Delayed-Release Capsules 135 mg as a single dose with food ↑4% ↓2% Table 3. Effects of Fenofibric Acid Delayed-Release Capsules or Fenofibrate Co-Administration on Systemic Exposure of Other Drugs 1 TriCor ® (fenofibrate) oral tablet 2 TriCor ® (fenofibrate) oral micronized capsule Dosage Regimen of Fenofibric Acid Delayed-Release Capsules or Fenofibrate Dosage Regimen of Co-Administered Drug Change in Coadministered Drug Exposure Analyte AUC C max Lipid-lowering agents Fenofibric Acid Delayed-Release Capsules 135 mg once daily for 10 days Rosuvastatin, 40 mg once daily for 10 days Rosuvastatin ↑6% ↑20% Fenofibrate 160 mg 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%

12.1 Mechanism of Action The active moiety of fenofibric acid delayed-release capsules is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been 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 capsules 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 capsules 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/1.73 m 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 30-59 mL/min/1.73 m 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 capsules 135 mg once daily for 10 days) and ezetimibe (10 mg once daily for 10 days) versus when atorvastatin is given in combination with ezetimibe only (ezetimibe 10 mg once daily and atorvastatin, 80 mg once daily for 10 days): The C max decreased by 1% for atorvastatin and ortho-hydroxy-atorvastatin and increased by 2% for parahydroxy-atorvastatin. The AUC decreased 6% and 9% for atorvastatin and orthohydroxy-atorvastatin, respectively, and did not change for para-hydroxy-atorvastatin. Comparison of ezetimibe exposures when ezetimibe (10 mg once daily for 10 days) is given in combination with fenofibric acid (fenofibric acid delayed-release capsules 135 mg once daily for 10 days) and atorvastatin (80 mg once daily for 10 days) versus when ezetimibe is given in combination with atorvastatin only (ezetimibe 10 mg once daily and atorvastatin, 80 mg once daily for 10 days): The C 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 Coadministered Drugs on Fenofibric Acid Systemic Exposure from Fenofibric Acid Delayed-Release Capsules or Fenofibrate Administration 1 TriCor ® (fenofibrate) oral tablet 2 TriCor ® (fenofibrate) oral micronized capsule Co-Administered Drug Dosage Regimen of Co-Administered Drug Dosage Regiment 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 Capsules 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 Capsules 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 Capsules 135 mg as a single dose fasting ↑6% ↑17% Omeprazole 40 mg once daily for 5 days Fenofibric Acid Delayed-Release Capsules 135 mg as a single dose with food ↑4% ↓2% Table 3. Effects of Fenofibric Acid Delayed-Release Capsules or Fenofibrate Co-Administration on Systemic Exposure of Other Drugs 1 TriCor ® (fenofibrate) oral tablet 2 TriCor ® (fenofibrate) oral micronized capsule Dosage Regimen of Fenofibric Acid Delayed-Release Capsules or Fenofibrate Dosage Regimen of Co-Administered Drug Change in Coadministered Drug Exposure Analyte AUC C max Lipid-lowering agents Fenofibric Acid Delayed-Release Capsules 135 mg once daily for 10 days Rosuvastatin, 40 mg once daily for 10 days Rosuvastatin ↑6% ↑20% Fenofibrate 160 mg 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%

20230202

5

3 DOSAGE FORMS AND STRENGTHS • 45 mg capsules with a burnt umber opaque cap imprinted with "TWi T109" in white ink and a mustard opaque body imprinted with "45mg" in black ink. • 135 mg capsules with a blue opaque cap imprinted with "TWi T112" in white ink and a yellow opaque body imprinted with "135mg" in black ink. Oral Delayed Release Capsules: 45 mg and 135 mg ( 3 ) .

Fenofibric Acid Delayed-Release Fenofibric Acid CHOLINE FENOFIBRATE FENOFIBRIC ACID HYDROXYPROPYL CELLULOSE (TYPE M) HYPROMELLOSE 2208 (4000 MPA.S) LACTOSE MONOHYDRATE MAGNESIUM STEARATE METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER (1:1) TYPE A silicon dioxide TALC TRIETHYL CITRATE FERROSOFERRIC OXIDE GELATIN SODIUM LAURYL SULFATE SHELLAC PROPYLENE GLYCOL FERRIC OXIDE RED TITANIUM DIOXIDE FERRIC OXIDE YELLOW AMMONIA Mustard Burbt umber TWi;T109;45mg Fenofibric Acid Delayed-Release Fenofibric Acid CHOLINE FENOFIBRATE FENOFIBRIC ACID HYDROXYPROPYL CELLULOSE (TYPE M) HYPROMELLOSE 2208 (4000 MPA.S) LACTOSE MONOHYDRATE MAGNESIUM STEARATE METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER (1:1) TYPE A SILICON DIOXIDE TALC TRIETHYL CITRATE GELATIN SHELLAC PROPYLENE GLYCOL SODIUM LAURYL SULFATE TITANIUM DIOXIDE FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE AMMONIA FD&C RED NO. 40 FD&C BLUE NO. 1 TWi;T112;135mg

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) of 300 mg fenofibrate daily, equivalent to 135 mg fenofibric acid delayed-release capsules daily, based on body surface area comparisons. At a dose of 200 mg/kg/day (at 6 times the MRHD), the incidence of liver carcinomas was significantly increased in both sexes. A statistically significant increase in pancreatic carcinomas was observed in males at 1 and 6 times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed at 6 times the MRHD in males. In a second 24-month 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 testicular interstitial cell tumors in males at 2 times the MRHD. A 117-week carcinogenicity study was conducted in rats comparing three drugs: fenofibrate 10 and 60 mg/kg/day (0.3 and 2 times the MRHD, based on body surface area comparisons), clofibrate (400 mg/kg/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the human dose, based on mg/m 2 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 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, based on body surface area comparisons) 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 mice and liver adenomas in female mice at 3 times the MRHD. Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual. 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. 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 body 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) of 300 mg fenofibrate daily, equivalent to 135 mg fenofibric acid delayed-release capsules daily, based on body surface area comparisons. At a dose of 200 mg/kg/day (at 6 times the MRHD), the incidence of liver carcinomas was significantly increased in both sexes. A statistically significant increase in pancreatic carcinomas was observed in males at 1 and 6 times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed at 6 times the MRHD in males. In a second 24-month 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 testicular interstitial cell tumors in males at 2 times the MRHD. A 117-week carcinogenicity study was conducted in rats comparing three drugs: fenofibrate 10 and 60 mg/kg/day (0.3 and 2 times the MRHD, based on body surface area comparisons), clofibrate (400 mg/kg/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the human dose, based on mg/m 2 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 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, based on body surface area comparisons) 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 mice and liver adenomas in female mice at 3 times the MRHD. Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual. 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. 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 body surface area comparisons).

ANDA210469

Fenofibric Acid Delayed-Release

Fenofibric Acid

24979-109

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 24979-109-07 Fenofibric Acid Delayed-Release Capsules 45 mg 90-count Rx Only bottle-label-45mg

Warnings and Precautions, Hypersensitivity Reactions ( 5.9 ) 05/2018

Patient Counseling Patients should be advised: of the potential benefits and risks of fenofibric acid delayed-release capsules. not to use fenofibric acid delayed-release capsules if there is a known hypersensitivity to fenofibrate or fenofibric acid. of medications that should not be taken in combination with fenofibric acid delayed-release capsules. that if they are taking coumarin anticoagulants, fenofibric acid delayed-release capsules may increase their anti-coagulanteffect, and increased monitoring may be necessary. 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 to their physician’s office 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. not to breastfeed during treatment with fenofibric acid delayed-release capsules and for 5 days after the final dose. Manufactured for: TWi Pharmaceuticals USA, Inc. Paramus, NJ 07652 Manufactured by: TWi Pharmaceuticals, Inc. Taoyuan City, 32063, Taiwan Material# TLM-xxx-01 Revised: 04/2019 image description

17 PATIENT COUNSELING INFORMATION

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 1,500 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 * = p < 0.05 vs. Placebo 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 1,500 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 5.0 48 30 36 22.9* LDL Cholesterol 42 100 90 -4.2 45 103 131 45.0* VLDL Cholesterol 42 137 142 11.0 45 126 54 -49.4* 14.2 Primary Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia The effects of fenofibrate at a dose equivalent to fenofibric acid delayed-release capsules 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 † † Duration of study treatment was 3 to 6 months * p = <0.05 vs. Placebo 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 52.3 191.0 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) -3.0% -6.6% +2.3% +0.9% 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.

8.2 Lactation Risk Summary There is no available information on the presence of fenofibrate in human milk, effects of the drug on the breastfed infant, or the effects on milk production. Fenofibrate is present in the milk of rats, and is therefore likely to be present in human milk. Because of the potential for serious adverse reactions in breastfed infants, such as disruption of infant lipid metabolism, women should not breastfeed during treatment with fenofibric acid delayed-release capsules and for 5 days after the final dose [see Contraindications ( 4 )].

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

8.1 Pregnancy Risk Summary Limited available data with fenofibrate use in pregnant women are insufficient to determine a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no evidence of embryo-fetal toxicity was observed with oral administration of fenofibrate in rats and rabbits during organogenesis at doses less than or equivalent to the maximum recommended clinical dose of 135 mg daily, based on body surface area (mg/m 2 ). Adverse reproductive outcomes occurred at higher doses in the presence of maternal toxicity (see Data). Fenofibric acid delayed-release capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In 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 135 mg fenofibric acid delayed-release capsules daily, based on body surface area comparisons). Increased fetal skeletal malformations were observed at maternally toxic doses (361 mg/kg/day, corresponding to 12 times the clinical exposure at the MRHD) that significantly suppressed maternal body weight gain. In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 618 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 (≥ 2 times the clinical exposure at the MRHD) in the presence of maternal toxicity (decreased weight gain). Decreased pup survival was noted at 300 mg/kg/day (10 times the clinical exposure at the MRHD), which was associated with decreased maternal body weight gain/maternal neglect.

8 USE IN SPECIFIC POPULATIONS • Geriatric Use: Dose selection should be made based on renal function ( 8.5 ) . • Renal Impairment: Avoid use in severe renal impairment patients. Dose adjustment is required in mild to moderate renal impairment patients ( 8.6 ) . 8.1 Pregnancy Risk Summary Limited available data with fenofibrate use in pregnant women are insufficient to determine a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no evidence of embryo-fetal toxicity was observed with oral administration of fenofibrate in rats and rabbits during organogenesis at doses less than or equivalent to the maximum recommended clinical dose of 135 mg daily, based on body surface area (mg/m 2 ). Adverse reproductive outcomes occurred at higher doses in the presence of maternal toxicity (see Data). Fenofibric acid delayed-release capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In 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 135 mg fenofibric acid delayed-release capsules daily, based on body surface area comparisons). Increased fetal skeletal malformations were observed at maternally toxic doses (361 mg/kg/day, corresponding to 12 times the clinical exposure at the MRHD) that significantly suppressed maternal body weight gain. In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 618 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 (≥ 2 times the clinical exposure at the MRHD) in the presence of maternal toxicity (decreased weight gain). Decreased pup survival was noted at 300 mg/kg/day (10 times the clinical exposure at the MRHD), which was associated with decreased maternal body weight gain/maternal neglect. 8.2 Lactation Risk Summary There is no available information on the presence of fenofibrate in human milk, effects of the drug on the breastfed infant, or the effects on milk production. Fenofibrate is present in the milk of rats, and is therefore likely to be present in human milk. Because of the potential for serious adverse reactions in breastfed infants, such as disruption of infant lipid metabolism, women should not breastfeed during treatment with fenofibric acid delayed-release capsules and for 5 days after the final dose [see Contraindications ( 4 )]. 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 has 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 burnt umber opaque cap imprinted with "TWi T109" in white ink and a mustard opaque body imprinted with "45mg" in black ink. Bottles of 90 (NDC 24979-109-07). Fenofibric acid delayed-release capsules 135 mg have a blue opaque cap imprinted with "TWi T112" in white ink and a yellow opaque body imprinted with "135mg" in black ink. Bottles of 90 (NDC 24979-112-07). Store at 20° to 25°C (68° to 77°F) [See USP controlled room temperature]. Keep out of the reach of children. Protect from moisture.