Fenofibrate

6 ADVERSE REACTIONS The most common adverse reactions (> 2% and at least 1% greater than placebo) are abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact 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 the rates observed in practice. Adverse events reported by 2% or more of patients treated with fenofibrate (and greater than placebo) during the double-blind, placebo-controlled trials, regardless of causality, are listed in Table 1 below. 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 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 1 Significantly different from Placebo. BODY SYSTEM Fenofibrate Dosage equivalent to 160 mg fenofibrate. Placebo Adverse Reaction (N=439) (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% METABOLIC AND NUTRITIONAL DISORDERS Abnormal Liver Function Tests 7.5% 1 1.4% Increased ALT 3.0% 1.6% Increased CPK 3.0% 1.4% Increased AST 3.4% 1 0.5% RESPIRATORY Respiratory Disorder 6.2% 5.5% Rhinitis 2.3% 1.1% 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of fenofibrate: myalgia, rhabdomyolysis, pancreatitis, acute renal failure, muscle spasm, hepatitis, cirrhosis, anemia, arthralgia, decreases in hemoglobin, decreases in hematocrit, white blood cell decreases, asthenia, and severely depressed HDL-cholesterol levels. 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.

4 CONTRAINDICATIONS • Severe renal dysfunction, including patients receiving dialysis ( 4 , 8.6 , 12.3 ). • Active liver disease ( 4 , 5.3 ). • Gallbladder disease ( 4 , 5.5 ). • Known hypersensitivity to fenofibrate ( 4 ). • Nursing mothers ( 4 , 8.3 ). 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 preexisting gallbladder disease [see WARNINGS AND PRECAUTIONS ( 5.5 )] . • nursing mothers [see USE IN SPECIFIC POPULATIONS ( 8.3 )] • patients with known hypersensitivity to fenofibrate or fenofibric acid [see WARNINGS AND PRECAUTIONS ( 5.9 )].

11 DESCRIPTION Fenofibrate, is a lipid regulating agent available as tablets for oral administration. Each tablet contains 54 mg or 160 mg of fenofibrate. The chemical name for fenofibrate is 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester with the following structural formula: The empirical formula is C 20 H 21 ClO 4 and the molecular weight is 360.8; fenofibrate is very soluble in methylene chloride, slightly soluble in alcohol and practically insoluble in water. The melting point is 79 to 82°C. Fenofibrate is a white or almost white, crystalline powder, non-hydroscopic which is stable under ordinary conditions. Each fenofibrate tablet USP, contains the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose 2910, lactose monohydrate, microcrystalline cellulose, simethicone emulsion (30%), sodium lauryl sulphate, sodium starch glycolate and sodium stearyl fumarate. The film-coating material contains polyethylene glycol 3350, polyethylene glycol 6000, polyvinyl alcohol, talc and titanium dioxide. Each fenofibrate tablet USP, 54 mg contains iron oxide yellow as an additional film coating ingredient. Fenofibrate tablet USP complies as per USP dissolution test 3. Image 1

2 DOSAGE AND ADMINISTRATION • Primary hypercholesterolemia or mixed dyslipidemia: Initial dose of 160 mg once daily ( 2.2 ). • Severe hypertriglyceridemia: Initial dose of 54 to 160 mg once daily. Maximum dose is 160 mg ( 2.3 ). • Renally impaired patients: Initial dose of 54 mg once daily ( 2.4 ). • Geriatric patients: Select the dose on the basis of renal function ( 2.5 ). • Should be given with meals ( 2.1 ). 2.1 General Considerations Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibrate tablet USP, and should continue this diet during treatment with fenofibrate tablet USP. Fenofibrate tablets USP should be given with meals, thereby optimizing the bioavailability of the medication. 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 tablet USP 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 160 mg once daily. 2.2 Primary Hypercholesterolemia or Mixed Dyslipidemia The initial dose of fenofibrate tablet USP is 160 mg once daily. 2.3 Severe Hypertriglyceridemia The initial dose is 54 to 160 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 160 mg once daily. 2.4 Impaired Renal Function Treatment with fenofibrate tablet USP should be initiated at a dose of 54 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 tablet USP should be avoided in patients with severe renal impairment [see USE IN SPECIFIC POPULATIONS ( 8.6 ) and CLINICAL PHARMACOLOGY ( 12.3 )]. 2.5 Geriatric Patients Dose selection for the elderly should be made on the basis of renal function [see USE IN SPECIFIC POPULATIONS ( 8.5 )] .

1 INDICATIONS AND USAGE Fenofibrate tablet USP is a peroxisome proliferator receptor alpha (PPARα) activator indicated as an adjunct to diet: • To reduce elevated LDL-C, Total-C, TG and Apo B, and to increase HDL-C in adult patients with primary hypercholesterolemia or mixed dyslipidemia ( 1.1 ). • For treatment of 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 or Mixed Dyslipidemia Fenofibrate tablet USP is indicated as adjunctive therapy to diet to reduce elevated low-density lipoprotein cholesterol (LDL-C), total cholesterol (Total-C), Triglycerides 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 tablet USP is 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 obviate 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 at a dose equivalent to 160 mg of fenofibrate tablet USP was not shown to reduce coronary heart disease morbidity and mortality in a large, randomized controlled trial of 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 fenofibric acid is highly bound to plasma proteins, hemodialysis should not be considered.

7 DRUG INTERACTIONS • Coumarin anticoagulants: ( 7.1 ). • Immunosuppressants: ( 7.2 ). • Bile acid 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 Immunosuppessants such as cyclosporine and tacrolimus can produce nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine, and because renal excretion is the primary elimination route of fibrate drugs including fenofibrate, there is a risk that an interaction will lead to deterioration of renal function. The benefits and risks of using fenofibrate tablet with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed and renal function monitored. 7.3 Bile Acid Binding Resins Since bile acid 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-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, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting decrease in TG produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARα also induces an increase in the synthesis of apolipoproteins 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, LDL-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 AII) 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 TG, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering triglycerides (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 (VLDL) in treated patients. In addition, treatment with fenofibrate results in increases in high density lipoprotein (HDL) and apolipoproteins apoAI and apoAII. 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 radiolabelled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid occur within 6 to 8 hours after administration. The absorption of fenofibrate is increased when administered with food. With fenofibrate tablets, the extent of absorption is increased by approximately 35% under fed as compared to fasting conditions. Distribution Upon multiple dosing of fenofibrate, fenofibric acid steady state is achieved within 5 days. Plasma concentrations of fenofibric acid at steady state are approximately double of those following a single dose. 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 (e.g., 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 radiolabelled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces. Fenofibric acid is eliminated with a half-life of 20 hours, allowing once daily dosing. Special Populations 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 elderly with normal renal function, without increasing accumulation of the drug or metabolites [see DOSAGE AND ADMINISTRATION ( 2.5 ) and USE IN SPECIFIC 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 (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 renal impairment (eGFR 30 to 59 mL/min/1.73m 2 ) had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of 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 with hepatic impairment. Drug Interactions In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations. Table 2 describes the effects of co-administered drugs on fenofibric acid systemic exposure. Table 3 describes the effects of co-administered fenofibrate or fenofibric acid on other drugs. Table 2. Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Fenofibrate Administration 1 Fenofibrate oral tablet 2 Fenofibrate oral micronized capsule Co-Administered Drug Dosage Regimen of Co-Administered Drug Dosage Regimen of Fenofibrate Plasma concentrations of fenofibric acid after administration of 54 mg and 160 mg tablets are equivalent under fed conditions to 67 and 200 mg capsules, respectively. Plasma concentrations of fenofibric acid after administration of one 145 mg tablet are equivalent under fed conditions to one 200 mg capsule. Changes in Fenofibric Acid Exposure AUC C max Lipid-lowering agents Atorvastatin 20 mg once daily for 10 days Fenofibrate 160 mg 1 once daily for 10 days ↓2% ↓4% 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% Anti-diabetic agents Glimepiride 1 mg as a single dose Fenofibrate 145 mg 1 once daily for 10 days ↑1% ↓1% Metformin 850 mg three times daily for 10 days Fenofibrate 54 mg 1 three 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% Table 3. Effects of fenofibrate Co-Administration on Systemic Exposure of Other Drugs 1 Fenofibrate oral tablet 2 Fenofibrate oral micronized capsule Dosage Regimen of Fenofibrate Plasma concentrations of fenofibric acid after administration of 54 mg and 160 mg tablets are equivalent under fed conditions to 67 and 200 mg capsules, respectively. Plasma concentrations of fenofibric acid after administration of one 145 mg tablet are equivalent under fed conditions to one 200 mg capsule. Dosage Regimen of Co- Administered Drug Change in Co-Administered Drug Exposure Analyte AUC C max Lipid-lowering 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 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 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-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, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting decrease in TG produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARα also induces an increase in the synthesis of apolipoproteins 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, LDL-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 AII) 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 TG, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering triglycerides (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 (VLDL) in treated patients. In addition, treatment with fenofibrate results in increases in high density lipoprotein (HDL) and apolipoproteins apoAI and apoAII.

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 radiolabelled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid occur within 6 to 8 hours after administration. The absorption of fenofibrate is increased when administered with food. With fenofibrate tablets, the extent of absorption is increased by approximately 35% under fed as compared to fasting conditions. Distribution Upon multiple dosing of fenofibrate, fenofibric acid steady state is achieved within 5 days. Plasma concentrations of fenofibric acid at steady state are approximately double of those following a single dose. 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 (e.g., 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 radiolabelled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces. Fenofibric acid is eliminated with a half-life of 20 hours, allowing once daily dosing. Special Populations 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 elderly with normal renal function, without increasing accumulation of the drug or metabolites [see DOSAGE AND ADMINISTRATION ( 2.5 ) and USE IN SPECIFIC 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 (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 renal impairment (eGFR 30 to 59 mL/min/1.73m 2 ) had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects. Based on these findings, the use of 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 with hepatic impairment. Drug Interactions In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations. Table 2 describes the effects of co-administered drugs on fenofibric acid systemic exposure. Table 3 describes the effects of co-administered fenofibrate or fenofibric acid on other drugs. Table 2. Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Fenofibrate Administration 1 Fenofibrate oral tablet 2 Fenofibrate oral micronized capsule Co-Administered Drug Dosage Regimen of Co-Administered Drug Dosage Regimen of Fenofibrate Plasma concentrations of fenofibric acid after administration of 54 mg and 160 mg tablets are equivalent under fed conditions to 67 and 200 mg capsules, respectively. Plasma concentrations of fenofibric acid after administration of one 145 mg tablet are equivalent under fed conditions to one 200 mg capsule. Changes in Fenofibric Acid Exposure AUC C max Lipid-lowering agents Atorvastatin 20 mg once daily for 10 days Fenofibrate 160 mg 1 once daily for 10 days ↓2% ↓4% 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% Anti-diabetic agents Glimepiride 1 mg as a single dose Fenofibrate 145 mg 1 once daily for 10 days ↑1% ↓1% Metformin 850 mg three times daily for 10 days Fenofibrate 54 mg 1 three 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% Table 3. Effects of fenofibrate Co-Administration on Systemic Exposure of Other Drugs 1 Fenofibrate oral tablet 2 Fenofibrate oral micronized capsule Dosage Regimen of Fenofibrate Plasma concentrations of fenofibric acid after administration of 54 mg and 160 mg tablets are equivalent under fed conditions to 67 and 200 mg capsules, respectively. Plasma concentrations of fenofibric acid after administration of one 145 mg tablet are equivalent under fed conditions to one 200 mg capsule. Dosage Regimen of Co- Administered Drug Change in Co-Administered Drug Exposure Analyte AUC C max Lipid-lowering 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 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 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%

20191101

3

3 DOSAGE FORMS AND STRENGTHS • Oral Tablets: 54 mg and 160 mg ( 3 ). • 54 mg yellow, round, biconvex, film coated tablets debossed with "LU" on one side and "J41" on the other side. • 160 mg white to off-white oval shaped, biconvex film coated tablets, debossed with "LU" on one side and "J42" on the other side.

Fenofibrate Fenofibrate FENOFIBRATE FENOFIBRIC ACID SILICON DIOXIDE CROSPOVIDONE (15 MPA.S AT 5%) HYPROMELLOSE, UNSPECIFIED LACTOSE MONOHYDRATE MICROCRYSTALLINE CELLULOSE SODIUM LAURYL SULFATE SODIUM STARCH GLYCOLATE TYPE A POTATO SODIUM STEARYL FUMARATE POLYETHYLENE GLYCOL 3350 POLYETHYLENE GLYCOL 6000 POLYVINYL ALCOHOL, UNSPECIFIED TALC TITANIUM DIOXIDE DIMETHICONE off-white biconvex LU;J42

13.1 Carcinogenesis and Mutagenesis and 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/m2 surface area). Fenofibrate increased pancreatic acinar adenomas in both sexes. Clofibrate increased hepatocellular carcinoma and pancreatic acinar adenomas in males and hepatic neoplastic nodules in females. Gemfibrozil increased hepatic neoplastic nodules in males and females,while all three drugs increased testicular interstitial cell tumors in males. In 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).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis and Mutagenesis and 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/m2 surface area). Fenofibrate increased pancreatic acinar adenomas in both sexes. Clofibrate increased hepatocellular carcinoma and pancreatic acinar adenomas in males and hepatic neoplastic nodules in females. Gemfibrozil increased hepatic neoplastic nodules in males and females,while all three drugs increased testicular interstitial cell tumors in males. In 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).

ANDA204019

Fenofibrate

Fenofibrate

63187-681

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Fenofibrate Tablets USP Rx only 160 mg NDC 63187-681-90 Bottle of 90 Tablets 63187-681-90

17 PATIENT COUNSELING INFORMATION Patients should be advised: • of the potential benefits and risks of fenofibrate tablet. • not to use fenofibrate tablet if there is a known hypersensitivity to fenofibrate or fenofibric acid. • of medications that should not be taken in combination with fenofibrate tablet. • that if they are taking coumarin anticoagulants, fenofibrate tablet may increase their anti-coagulant effect, and increased monitoring may be necessary. • to continue to follow an appropriate lipid-modifying diet while taking fenofibrate tablet. • to take fenofibrate tablet once daily, without regard to food, at the prescribed dose, swallowing each tablet whole. • to return for routine monitoring. • to inform their physician of all medications, supplements, and herbal preparations they are taking and any change to their medical condition. Patients should also be advised to inform their physicians prescribing a new medication that they are taking fenofibrate tablet. • to inform their physician of any muscle pain, tenderness, or weakness; onset of abdominal pain; or any other new symptoms. Trademarks are the property of their respective owners. Manufactured for: Lupin Pharmaceuticals, Inc. Baltimore, Maryland 21202 United States. Manufactured by: Lupin Limited Goa 403 722 INDIA. August 2015 ID#: 235905 Repackaged by: Proficient Rx LP Thousand Oaks, CA 91320

14 CLINICAL STUDIES 14.1 Primary Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia The effects of fenofibrate at a dose equivalent to 160 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. 1 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% 1 -20.6% 1 +11.0% 1 -28.9% 1 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 mg/dL 227.7 mg/dL 58.1 mg/dL 101.7 mg/dL All FEN (n=193) -22.4% 1 -31.4% 1 +9.8% 1 -23.5% 1 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 mg/dL 219.8 mg/dL 46.7 mg/dL 231.9 mg/dL All FEN (n=126) -16.8% 1 -20.1% 1 +14.6% 1 -35.9% 1 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 500 mg/dL. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia, treatment with fenofibrate at dosages equivalent to fenofibrate 160 mg per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol. Treatment of patients with elevated triglycerides often results in an increase of LDL-C (see Table 5). Table 5. Effects of Fenofibrate in Patients with Severe Hypertriglyceridemia * =p < 0.05 vs. Placebo Study 1 Placebo Fenofibrate Baseline TG levels 350 N Baseline Endpoint % Change N Baseline Endpoint % Change to 499 mg/dL (Mean) (Mean) (Mean) (Mean) (Mean) (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 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 N Baseline Endpoint % Change N Baseline Endpoint % Change to 1500 mg/dL (Mean) (Mean) (Mean) (Mean) (Mean) (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 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 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 to 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 maximum recommended human dose (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 use in patients with severe renal impairment. Dose reduction is 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 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 to 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 maximum recommended human dose (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 The use of fenofibrate 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 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 tablets USP are available as: Fenofibrate tablets USP, 160 mg are white to off-white oval shaped, biconvex film coated tablets, debossed with "LU" on one side and "J42" on the other side. They are available as follows: Bottles of 30 NDC 63187-681-30 Bottles of 60 NDC 63187-681-60 Bottles of 90 NDC 63187-681-90 Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from moisture. Keep out of reach of children.