Fenofibrate

6 ADVERSE REACTIONS Most common adverse reactions (> 2% and greater than 1% in placebo) are abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 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 rates observed in clinical practice. Adverse events reported by 2% or more of patients treated with fenofibrate and greater than placebo during double-blind, placebo-controlled trials, regardless of causality, are listed in Table 1. Adverse reactions led to discontinuation of treatment in 5.0% of patients treated with fenofibrate and in 3.0% treated with placebo. Increases in liver function tests were the most frequent events, causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials. $ Table 1 Adverse Reactions Reported by 2% or More of Patients Treated with Fenofibrate and Greater than Placebo During the Double-Blind, Placebo-Controlled Trials Body System Adverse Reaction Fenofibrate Dosage equivalent to 130 mg 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 Abnormal Liver Function Tests 7.5% Significantly different from placebo 1.4% Nausea 2.3% 1.9% Constipation 2.1% 1.4% Metabolic and Nutritional Disorders 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of fenofibrate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: myalgia, rhabdomyolysis, pancreatitis, renal failure, muscle spasms, acute renal failure, hepatitis, cirrhosis, anemia, arthralgia, asthenia, severely depressed HDL-cholesterol levels and interstitial lung disease. Photosensitivity reactions have occurred days to months after initiation; in some of these cases, patients reported a prior photosensitivity reaction to ketoprofen.

4 CONTRAINDICATIONS 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 fenofibrate ( 4 , 5.9 ) Fenofibrate is 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 pre-existing gallbladder disease [see Warnings and Precautions ( 5.5 )]. nursing mothers [see Use in Specific Populations ( 8.3 )] . patients with known hypersensitivity to fenofibric acid or fenofibrate [see Warnings and Precautions ( 5.9 )].

11 DESCRIPTION Fenofibrate, is a lipid regulating agent available as capsules for oral administration. Each capsule contains 43 mg or 130 mg of micronized fenofibrate. The chemical name for fenofibrate is 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, l-methylethyl ester with the following structural formula: Fenofibrate The empirical formula is C 20 H 21 O 4 Cl and the molecular weight is 360.83; fenofibrate is insoluble in water. The melting point is 79°-82°C. Fenofibrate is a white solid which is stable under ordinary conditions. Inactive Ingredients: Each gelatin capsule contains sugar spheres, hypromellose, sodium lauryl sulfate, dimethicone, simethicone, and talc. The gelatin capsules also contain black iron oxide, D&C Yellow #10, Indigo carmine FD&C Blue #2, shellac, soya lecithin, sulfur dioxide, titanium dioxide and yellow iron oxide. Fenofibrate

2 DOSAGE AND ADMINISTRATION Fenofibrate capsules can be taken without regard to meals ( 2.1 ). Primary hypercholesterolemia and mixed dyslipidemia: 130 mg per day ( 2.2 ). Severe Hypertriglyceridemia: 43 to 130 mg per day; the dose should be adjusted according to patient response ( 2.3 ). Renally impaired patients: Initial dose of 43 mg per day ( 2.4 ). Geriatric patients: Select the dose on the basis of renal function ( 2.5 ). 2.1 General Consideration Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibrate capsules, and should continue this diet during treatment with fenofibrate. Fenofibrate capsules can be given without regard to meals. Patients should be advised to swallow fenofibrate capsules whole. Do not open, crush, dissolve or chew capsules. The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality. Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be an important ancillary measure. Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus should be looked for and adequately treated. Estrogen therapy, thiazide diuretics and beta-blockers are sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia . Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of fenofibrate if lipid levels fall significantly below the targeted range. Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 130 mg once daily. 2.2 Primary Hypercholesterolemia and Mixed Dyslipidemia The initial dose of fenofibrate capsules is 130 mg per day. 2.3 Severe Hypertriglyceridemia The initial dose is 43 to 130 mg per day. 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 130 mg per day. 2.4 Impaired Renal Function Treatment with fenofibrate should be initiated at a dose of 43 mg per day in patients having mild to moderately impaired renal function, and increased only after evaluation of the effects on renal function and lipid levels at this dose. The use of fenofibrate should be avoided in patients with severe renal impairment [ see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 ) ]. 2.5 Geriatric Patients Dose selection for the elderly should be made on the basis of renal function [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 ) ].

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

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

7 DRUG INTERACTIONS Coumarin Anticoagulants ( 7.1 ) Immunosuppressants ( 7.2 ) Bile-Acid Binding Resins ( 7.3 ) 7.1 Coumarin Anticoagulants Potentiation of coumarin-type anticoagulant effects has been observed with prolongation of the PT/INR. Caution should be exercised when coumarin anticoagulants are given in conjunction with fenofibrate. The dosage of the anticoagulants should be reduced to maintain the PT/INR at the desired level to prevent bleeding complications. Frequent PT/INR determinations are advisable until it has been definitely determined that the PT/INR has stabilized [ see Warnings and Precautions ( 5.6 ) ]. 7.2 Immunosuppressants Immunosuppressants such as cyclosporine and tacrolimus can produce nephrotoxicity with decrease in creatinine clearance and because renal excretion is the primary elimination route of fibrate drugs including fenofibrate, there is a risk that an interaction will lead to deterioration of renal function. The benefits and risks of using fenofibrate with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed. 7.3 Bile-Acid Binding Resins Since bile acid binding resins may bind other drugs given concurrently, patients should take fenofibrate at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption. 7.4 Colchicine Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The active moiety of fenofibrate is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been extensively studied through oral administration of fenofibrate. The lipid-lowering effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor α (PPAR α ). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting decrease in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation) to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARα also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol. Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid. 12.2 Pharmacodynamics A variety of clinical studies have demonstrated that elevated levels of total-C, DL-C, and Apo B, an LDL membrane complex, are associated with human atherosclerosis. Similarly, decreased levels of HDL-C and its transport complex, apolipoprotein A (Apo AI and Apo All) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C, LDL-C, and triglycerides, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering TG on the risk of cardiovascular morbidity and mortality has not been determined. Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides, and triglyceride-rich lipoprotein in treated patients. In addition, treatment with fenofibrate results in increases in high density lipoprotein (HDL) and apoproteins Apo AI and Apo AII. 12.3 Pharmacokinetics Fenofibrate is a pro-drug of the active chemical moiety fenofibric acid. Fenofibrate is converted by ester hydrolysis in the body to fenofibric acid which is the active constituent measurable in the circulation. • Absorption: The absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, fenofibrate is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabeled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid from fenofibrate occur within 4 to 8 hours after administration. There was less than dose-proportional increase in the systemic exposure of fenofibric acid from 43 mg and 130 mg of fenofibrate under fasting conditions. Doses of three-capsules of 43 mg fenofibrate given concurrently were dose equivalent to single-capsule doses of 130 mg. The extent of absorption of fenofibric acid was unaffected when fenofibrate was taken either in fasted state or with a low-fat meal. However, the C max of fenofibrate increased in the presence of a low-fat meal. T max was unaffected in the presence of a low-fat meal. In the presence of a high-fat meal, there was a 26% increase in AUC and 108% increase in C max of fenofibric acid from fenofibrate relative to fasting state. • Distribution: In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within a week of dosing and did not demonstrate accumulation across time following multiple dose administration. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects. • Metabolism: Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate is detected in plasma. Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. 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 indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (eg, cytochrome P450) to a significant extent. • Elimination: After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabeled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces. Fenofibrate acid from fenofibrate is eliminated with a half-life of 23 hours, allowing once daily dosing. • Geriatrics: In 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 a similar dosage regimen can be used in the elderly with normal renal function, without increasing accumulation of the drug or metabolites [see Dosage and Administration (2.4) and Use in Special Populations(8.5) ]. • Pediatrics: The pharmacokinetics of fenofibrate has not been studied in pediatric populations. • Gender: No pharmacokinetic difference between males and females has been observed for fenofibrate. • Race: The influence of race on the pharmacokinetics of fenofibrate has not been studied; however, fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability. • Renal Impairment: The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate, and severe renal impairment. Patients with severe renal impairment (creatinine clearance [CrCl] ≤ 30 mL/min or estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73m 2 ) showed 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 (CrCl 30-80 mL/min or eGFR 30-59 mL/min/1.73m 2 ) renal impairment had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of fenofibrate should be avoided in patients who have severe renal impairment and dose reduction is required in patients having mild to moderate renal impairment [see Dosage and Administration (2.4)] . • Hepatic Impairment: No pharmacokinetic studies have been conducted in patients having hepatic impairment. • Drug-Drug Interactions: In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitor of CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations. 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 exposure to other drugs. Co-Administered Drug Dosage Regimen of Co-Administered Drug Dosage Regimen of Fenofibrate Changes in Fenofibric Acid Exposure AUC C max No dosing adjustments required for fenofibrate capsules with the following co-administered drugs Lipid-lowing agents Atorvastatin 20 mg once daily for 10 days Fenofibrate 160 mg TriCor (fenofibrate) oral tablet once daily for 10 days ↓2% ↓4% Pravastatin 40 mg as a single dose Fenofibrate 3 x 67 mg TriCor (fenofibrate) oral micronized capsule as a single dose ↓1% ↓2% Fluvastatin 40 mg as a single dose Fenofibrate 160 mg as a single dose ↓2% ↓10% Anti-diabetic agents Glimepiride 1 mg once daily as a single dose Fenofibrate 145 mg once daily for 10 days ↑1% ↓1% Metformin 850 mg three times daily for 10 days Fenofibrate 54 mg three times daily for 10 days ↓9% ↓6% Rosiglitazone 8 mg once daily for 5 days Fenofibrate 145 mg once daily for 14 days ↑10% ↑3% $ Table 3 Effects of Fenofibrate Capsules or Fenofibrate Co-Administration on Systemic Exposure of Other Drugs Dosage Regimen of Fenofibrate Dosage Regimen of Co-Administered Drug Changes in Co-Administered Drug Exposure Analyte AUC C max No dosing adjustments required for these co-administered drugs with fenofibrate capsules Lipid-lowing agents 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 once daily for 10 days Pravastatin, 40 mg once daily for 10 days Pravastatin ↑28% ↑36% 3α-Hydroxyl-iso-pravastatin ↑39% ↑55% Fenofibrate 160 mg 1 as a single dose Fluvastatin, 40 mg as a single dose (+)-3R, 5S-Fluvastatin ↑15% ↑16% Anti-diabetic agents Fenofibrate 145 mg 1 once daily for 10 days Glimepiride, 1 mg once daily as a single dose Glimepiride ↑35% ↑18% Fenofibrate 54 mg 1 three times daily for 10 days Metformin, 850 mg three 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 fenofibrate is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been extensively studied through oral administration of fenofibrate. The lipid-lowering effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor α (PPAR α ). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting decrease in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation) to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARα also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol. Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid.

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

12.3 Pharmacokinetics Fenofibrate is a pro-drug of the active chemical moiety fenofibric acid. Fenofibrate is converted by ester hydrolysis in the body to fenofibric acid which is the active constituent measurable in the circulation. • Absorption: The absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, fenofibrate is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabeled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid from fenofibrate occur within 4 to 8 hours after administration. There was less than dose-proportional increase in the systemic exposure of fenofibric acid from 43 mg and 130 mg of fenofibrate under fasting conditions. Doses of three-capsules of 43 mg fenofibrate given concurrently were dose equivalent to single-capsule doses of 130 mg. The extent of absorption of fenofibric acid was unaffected when fenofibrate was taken either in fasted state or with a low-fat meal. However, the C max of fenofibrate increased in the presence of a low-fat meal. T max was unaffected in the presence of a low-fat meal. In the presence of a high-fat meal, there was a 26% increase in AUC and 108% increase in C max of fenofibric acid from fenofibrate relative to fasting state. • Distribution: In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within a week of dosing and did not demonstrate accumulation across time following multiple dose administration. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects. • Metabolism: Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate is detected in plasma. Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. 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 indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (eg, cytochrome P450) to a significant extent. • Elimination: After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabeled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces. Fenofibrate acid from fenofibrate is eliminated with a half-life of 23 hours, allowing once daily dosing. • Geriatrics: In 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 a similar dosage regimen can be used in the elderly with normal renal function, without increasing accumulation of the drug or metabolites [see Dosage and Administration (2.4) and Use in Special Populations(8.5) ]. • Pediatrics: The pharmacokinetics of fenofibrate has not been studied in pediatric populations. • Gender: No pharmacokinetic difference between males and females has been observed for fenofibrate. • Race: The influence of race on the pharmacokinetics of fenofibrate has not been studied; however, fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability. • Renal Impairment: The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate, and severe renal impairment. Patients with severe renal impairment (creatinine clearance [CrCl] ≤ 30 mL/min or estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73m 2 ) showed 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 (CrCl 30-80 mL/min or eGFR 30-59 mL/min/1.73m 2 ) renal impairment had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of fenofibrate should be avoided in patients who have severe renal impairment and dose reduction is required in patients having mild to moderate renal impairment [see Dosage and Administration (2.4)] . • Hepatic Impairment: No pharmacokinetic studies have been conducted in patients having hepatic impairment. • Drug-Drug Interactions: In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitor of CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations. 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 exposure to other drugs. Co-Administered Drug Dosage Regimen of Co-Administered Drug Dosage Regimen of Fenofibrate Changes in Fenofibric Acid Exposure AUC C max No dosing adjustments required for fenofibrate capsules with the following co-administered drugs Lipid-lowing agents Atorvastatin 20 mg once daily for 10 days Fenofibrate 160 mg TriCor (fenofibrate) oral tablet once daily for 10 days ↓2% ↓4% Pravastatin 40 mg as a single dose Fenofibrate 3 x 67 mg TriCor (fenofibrate) oral micronized capsule as a single dose ↓1% ↓2% Fluvastatin 40 mg as a single dose Fenofibrate 160 mg as a single dose ↓2% ↓10% Anti-diabetic agents Glimepiride 1 mg once daily as a single dose Fenofibrate 145 mg once daily for 10 days ↑1% ↓1% Metformin 850 mg three times daily for 10 days Fenofibrate 54 mg three times daily for 10 days ↓9% ↓6% Rosiglitazone 8 mg once daily for 5 days Fenofibrate 145 mg once daily for 14 days ↑10% ↑3% $ Table 3 Effects of Fenofibrate Capsules or Fenofibrate Co-Administration on Systemic Exposure of Other Drugs Dosage Regimen of Fenofibrate Dosage Regimen of Co-Administered Drug Changes in Co-Administered Drug Exposure Analyte AUC C max No dosing adjustments required for these co-administered drugs with fenofibrate capsules Lipid-lowing agents 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 once daily for 10 days Pravastatin, 40 mg once daily for 10 days Pravastatin ↑28% ↑36% 3α-Hydroxyl-iso-pravastatin ↑39% ↑55% Fenofibrate 160 mg 1 as a single dose Fluvastatin, 40 mg as a single dose (+)-3R, 5S-Fluvastatin ↑15% ↑16% Anti-diabetic agents Fenofibrate 145 mg 1 once daily for 10 days Glimepiride, 1 mg once daily as a single dose Glimepiride ↑35% ↑18% Fenofibrate 54 mg 1 three times daily for 10 days Metformin, 850 mg three 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%

20230105

5

3 DOSAGE FORMS AND STRENGTHS Oral capsules: 43 mg and 130 mg ( 3 ). 43 mg capsules, imprinted with "43" and a segmented band, on the light green cap and "ANTARA" and "LUPIN" on the white to off-white body. 130 mg capsules, imprinted with "130" and a segmented band, on the dark green cap and "ANTARA" and "LUPIN" on the white body.

Fenofibrate fenofibrate FENOFIBRATE FENOFIBRIC ACID D&C YELLOW NO. 10 DIMETHICONE FD&C BLUE NO. 1 FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE GELATIN HYPROMELLOSES LECITHIN, SOYBEAN SHELLAC SODIUM LAURYL SULFATE SUCROSE SULFUR DIOXIDE TALC TITANIUM DIOXIDE Light Green Off White 43;ANTARA;LUPIN Fenofibrate fenofibrate FENOFIBRATE FENOFIBRIC ACID D&C BLACK NO. 2 DIMETHICONE FD&C BLUE NO. 2 FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE GELATIN HYPROMELLOSES LECITHIN, SOYBEAN SHELLAC SODIUM LAURYL SULFATE SUCROSE SULFUR DIOXIDE TALC TITANIUM DIOXIDE Dark Green White 130;ANTARA;LUPIN

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Two dietary carcinogenicity studies have been conducted in rats with fenofibrate. In the first 24-month study, Wistar rats were dosed with fenofibrate at 10, 45, and 200 mg/kg/day, approximately 0.3, 1, and 6 times the maximum recommended human dose (MRHD), based on body surface area comparisons (mg/m 2 ). At a dose of 200 mg/kg/day (at 6 times the MRHD), the incidence of liver carcinomas was significantly increased in both sexes. A statistically significant increase in pancreatic carcinomas was observed in males at 1 and 6 times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed at 6 times the MRHD in males. In a second 24-month 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), 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 on the basis of mg/m 2 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 mice and liver adenomas in female mice at 3 times the MRHD. Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual. Mutagenesis: Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and unscheduled DNA synthesis in primary rat hepatocytes. Impairment of Fertility: In fertility studies rats were given oral dietary doses of fenofibrate, males received 61 days prior to mating and females 15 days prior to mating through weaning which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (~10 times the MRHD, based on mg/m 2 surface area comparisons).

NDA021695

Fenofibrate

fenofibrate

68180-130

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 68180-130-06 Fenofibrate Capsules 43 mg Rx only 30 capsules Lupin Pharmaceuticals, Inc. NDC 68180-131-06 Fenofibrate Capsules 130 mg Rx only 30 capsules Lupin Pharmaceuticals, Inc. NDC 68180-130-06 Fenofibrate Capsules 43 mg Rx only 30 capsules Lupin Pharmaceuticals, Inc. NDC 68180-131-06 Fenofibrate Capsules 130 mg Rx only 30 capsules Lupin Pharmaceuticals, Inc.

RECENT MAJOR CHANGES Warnings and Precautions ( 5.9 ) 03/2018

Distributed by: Lupin Pharmaceuticals, Inc. Baltimore, Maryland 21202 United States Address Medical Inquiries to: Lupin Pharmaceuticals, Inc. 111 South Calvert Street, 21 st Floor Baltimore, MD 21202 or Call: 1-800-399-2561 April 28, 2019 ID#: 258869

17 PATIENT COUNSELING INFORMATION Patients should be advised: of the potential benefits and risks of fenofibrate capsule. not to use fenofibrate capsule if there is a known hypersensitivity to fenofibrate capsules or fenofibric acid. that if they are taking coumarin anticoagulants, fenofibrate may increase their anticoagulant effect, and increased monitoring may be necessary. of medications that should not be taken in combination with fenofibrate capsules. to continue to follow an appropriate lipid-modifying diet while taking fenofibrate capsules. to take fenofibrate capsule once daily, without regard to food, at the prescribed dose, swallowing each capsule whole. 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 fenofibrate capsules. to inform their physician of any muscle pain, tenderness or weakness; onset of abdominal pain; or any other new symptoms. to return to their physician's office for routine monitoring.

14 CLINICAL STUDIES 14.1 Primary Hypercholesterolemia (Heterozygous Familial and Non familial) and Mixed Dyslipidemia The effects of fenofibrate at a dose equivalent to 130 mg fenofibrate per day were assessed from four randomized, placebo-controlled, double-blind, parallel group studies including patients with the following mean baseline lipid values: total-C 306.9 mg/dL; LDL-C 213.8 mg/dL; HDL-C 52.3 mg/dL; and triglycerides 191.0 mg/dL. Fenofibrate therapy lowered LDL-C, Total-C, and the LDL-C/HDL-C ratio. Fenofibrate therapy also lowered triglycerides and raised HDL-C (See Table 4). $ Table 4 Mean Percent Change in Lipid Parameters at End of Treatment † †Duration of study treatment was 3 to 6 months. *p=<0.05 vs. placebo Treatment Group Total-C LDL-C HDL-C TG Pooled Cohort Mean baseline lipid values (N=646) 306.9 mg/dL 213.8 mg/dL 52.3 mg/dL 191.0 mg/dL All FEN (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 (Type IIa) Mean baseline lipid values (N=334) 307.7 mg/dL 227.7 mg/dL 58.1 mg/dL 101.7 mg/dL All FEN (n=193) -22.4%* -31.4%* +9.8%* -23.5%* Placebo (n=141) +0.2% -2.2% +2.6% +11.7% Baseline LDL-C > 160 mg/dL and TG ≥ 150 mg/dL (Type IIb) Mean baseline lipid values (N=242) 312.8 mg/dL 219.8 mg/dL 46.7 mg/dL 231.9 mg/dL All FEN (n=126) -16.8%* -20.1%* +14.6%* -35.9%* Placebo (n=116) -3.0% -6.6% +2.3% +0.9% In 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). 14.2 Severe Hypertriglyceridemia The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials of 147 hypertriglyceridemic patients. Patients were treated for eight weeks under protocols that differed only in that one entered patients with baseline TG levels of 500 to 1500 mg/dL, and the other TG levels of 350 to 499 mg/dL. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia, treatment with fenofibrate at dosages equivalent to 130 mg fenofibrate capsules per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol Treatment of patients with elevated triglycerides often results in an increase of LDL-C (See Table 5). $ Table 5 Effects of Fenofibrate in Patients with Hypertriglyceridemia * p < 0.05 vs. placebo Study 1 Placebo Fenofibrate Baseline TG levels 350 to 499 mg/dL N Baseline (mean) Endpoint (mean) % Change (mean) N Baseline (mean) Endpoint (mean) % Change (mean) 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 1.2 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) Endpoint (mean) % Change (mean) N Baseline (mean) Endpoint (mean) % Change (mean) 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 * The effect of fenofibrate on serum triglycerides was studied in a double-blind, randomized, 3 arm parallel-group trial of 146. The study population was comprised of 61% male and 39% female patients. Approximately 70% of patients had hypertension and 32% had diabetes. Patients were treated for eight weeks with either fenofibrate capsules 130 mg taken once daily with meals, fenofibrate capsules 130 mg taken once daily between meals, or placebo. Fenofibrate capsules 130 mg, whether taken with meals or between meals, had comparable effects on TG and all lipid parameters (See Table 6). $ Table 6 Fenofibrate Treatment in Patients with Hypertriglyceridemia *p < 0.05 vs placebo **p < 0.05 vs placebo (log transformed data) Placebo (n=50) fenofibrate capsules with meals (n=54) fenofibrate capsules between meals (n=42) Baseline mg/dL (mean) % Change at endpoint (mean) Baseline mg/dL (mean) % Change at endpoint (mean) Baseline mg/dL (mean) % Change at endpoint (mean) Triglycerides 479 +0.7 475 -36.7* 487 -36.6* Total Cholesterol 237 -0.8 248 -5.1 241 -3.4 HDL Cholesterol 35 +0.8 36 +13.7* 36 +14.3* Non-HDL Cholesterol 202 -1.1 212 -8.2** 205 -6.6** LDL Cholesterol 115 +3.2 120 +15.4* 122 +14.5 VLDL Cholesterol 87 -1.6 92 -34.4* 83 -30.4* The effect of fenofibrate on cardiovascular morbidity and mortality has not been determined.

8.5 Geriatric Use Fenofibric acid is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Fenofibric acid exposure is not influenced by age. Since elderly patients have 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 fenofibrate.

8.3 Nursing Mothers Fenofibrate 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 Safety and effectiveness have not been established in pediatric patients.

8.1 Pregnancy Pregnancy Category: C Safety in pregnant women has not been established. There are no adequate and well controlled studies of fenofibrate in pregnant women. Fenofibrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In female rats given oral dietary doses of 15, 75, and 300 mg/kg/day of fenofibrate from 15 days prior to mating through weaning, maternal toxicity was observed at 0.3 times the maximum recommended human dose (MRHD), based on body surface area comparisons; mg/m 2 . 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, adverse developmental findings were not observed at 14 mg/kg/day (less than 1 times the 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: Determine dose selection based on renal function ( 8.5 ). Renal impairment: Avoid in patients with severe renal impairment; dose reduction required in patients with mild to moderate renal impairment ( 8.6 ). 8.1 Pregnancy Pregnancy Category: C Safety in pregnant women has not been established. There are no adequate and well controlled studies of fenofibrate in pregnant women. Fenofibrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In female rats given oral dietary doses of 15, 75, and 300 mg/kg/day of fenofibrate from 15 days prior to mating through weaning, maternal toxicity was observed at 0.3 times the maximum recommended human dose (MRHD), based on body surface area comparisons; mg/m 2 . 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, adverse developmental findings were not observed at 14 mg/kg/day (less than 1 times the 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 Fenofibrate 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 Safety and effectiveness have not been established in pediatric patients. 8.5 Geriatric Use Fenofibric acid is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Fenofibric acid exposure is not influenced by age. Since elderly patients have 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 fenofibrate. 8.6 Renal Impairment Fenofibrate should be avoided in patients with severe renal impairment [ see Contraindications ( 4 ) ]. Dose reduction is required in patients with mild to moderate renal impairment [ see Dosage and Administration ( 2.4 ) and Clinical Pharmacology ( 12.3 ) ]. Monitoring renal function in patients with renal impairment is recommended. 8.7 Hepatic Impairment The use of fenofibrate has not been evaluated in subjects with hepatic impairment [see Contraindications ( 4 ) and Clinical Pharmacology ( 12.3 ) ].

16 HOW SUPPLIED/STORAGE AND HANDLING Fenofibrate Capsules are available in two strengths: 43 mg capsules, imprinted with "43" and a segmented band, on the light green cap and "ANTARA" and "LUPIN" on the white to off-white body, available in bottles of 30 (NDC # 68180-130-06). 130 mg capsules, imprinted with "130" and a segmented band, on the dark green cap and "ANTARA" and "LUPIN" on the white body, available in bottles of 30 (NDC # 68180-131-06) and 90 (NDC # 68180-131-09). Storage: Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [See USP Controlled Room Temperature] in a tightly closed container.