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1 INDICATIONS AND USAGE Antara is indicated as adjunctive therapy to diet: To reduce triglyceride (TG) levels in adults with severe hypertriglyceridemia (TG greater than or equal to 500 mg/dL). To reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia when use of recommended LDL-C lowering therapy is not possible. Limitations of Use 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 determined [see Warnings and Precautions ( 5.7 )] . Fenofibrate did not reduce coronary heart disease morbidity and mortality in two large, randomized controlled trials of patients with type 2 diabetes mellitus [see Warnings and Precautions ( 5.1 ) and Clinical Studies ( 14.4 ) ]. Antara is a peroxisome proliferator receptor (PPAR) alpha agonist indicated as an adjunct to diet: To reduce triglyceride (TG) levels in adults with severe hypertriglyceridemia (TG greater than or equal to 500 mg/dL). (1). To reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia when use of recommended LDL-C lowering therapy is not possible (1). Limitations of Use: 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 determined. (1) Fenofibrate did not reduce coronary heart disease morbidity and mortality in two large, randomized controlled trials of patients with type 2 diabetes mellitus. (1)

2 DOSAGE AND ADMINISTRATION Severe Hypertriglyceridemia : 30 mg to 90 mg orally once daily; the dose should be adjusted according to patient response ( 2.2 ). Primary hyperlipidemia : 90 mg orally once daily ( 2.2 ). Administer as a single dose, at any time of day, with or without food ( 2.2 ). Assess TG when clinically appropriate, as early as 4 to 8 weeks after initiating Antara. Discontinue Antara in patients who do not have an adequate response after two months of treatment ( 2.2 ). Renal impairment : Initial dosage of 30 mg orally once daily ( 2.3 ). Geriatric patients : Select the dosage on the basis of renal function ( 2.4 ). 2.1 Prior to Initiation of Antara Assess lipid levels before initiating therapy. Identify other causes (e.g., diabetes mellitus, hypothyroidism, or medications) of high triglyceride levels and manage as appropriate. Patients should be placed on an appropriate lipid-lowering diet before receiving Antara and should continue this diet during treatment with Antara. In patients with diabetes and fasting chylomicronemia, improve glycemic control prior to considering starting Antara. 2.2 Recommended Dosage and Administration • Severe hypertriglyceridemia : ○ The recommended dosage of Antara is 30 mg or 90 mg orally once daily. ○ Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals. • Primary hyperlipidemia : ○ The recommended dosage of Antara is 90 mg orally once daily. • Administer Antara as a single dose at any time of day, with or without food. • Advise patients to swallow Antara capsules whole. Do not crush, break, dissolve, or chew capsules. • Assess TG when clinically appropriate, as early as 4 to 8 weeks after initiating Antara. Discontinue Antara in patients who do not have an adequate response after two months of treatment. • If a dose is missed, advise patients not to take an extra dose. Resume treatment with the next dose. • Advise patients to take Antara at least 1 hour before or 4 hours to 6 hours after a bile acid binding resin to avoid impeding its absorption. 2.3 Recommended Dosage in Patients with Renal Impairment Assess renal function prior to initiation of Antara and periodically thereafter [see Warnings and Precautions ( 5.4 )]. Treatment with Antara should be initiated at a dosage of 30 mg orally once daily in patients with mild to moderately impaired renal function (eGFR 30 to <60 mL/min/1.73m 2 ), and increased only after evaluation of the effects on renal function and TG levels at this dose. Antara is contraindicated in patients with severe renal impairment (eGFR <30 mL/min/ 1.73m 2 ), including those with end-stage renal disease (ESRD) and those receiving dialysis [see Contraindications ( 4 ), Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 ) ] 2.4 Recommended Dosage in Geriatric Patients Dosage 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 ) ].

3 DOSAGE FORMS AND STRENGTHS Capsules: 30 mg and 90 mg ( 3 ) Antara capsules: 30 mg; size '4' capsules with opaque light green cap and opaque light green body, imprinted with LUPIN logo and "ANTARA" in black ink on body, and "30" in black ink on cap, containing white to off-white pellets. 90 mg; size '3' capsules with opaque dark green cap and opaque white body, imprinted with LUPIN logo and "ANTARA" in black ink on body, and "90" in black ink on cap, containing white to off-white pellets.

4 CONTRAINDICATIONS Severe renal impairment, including those with end-stage renal disease (ESRD) and those receiving dialysis ( 4 ) Active liver disease, including those with unexplained persistent liver function abnormalities ( 4 ) Pre-existing gallbladder disease ( 4 ) Hypersensitivity to fenofibrate fenofibric acid, or any of the excipients in Antara ( 4 ) Antara is contraindicated in the following conditions: Severe renal impairment, including those with end-stage renal disease (ESRD) and those receiving dialysis [see Clinical Pharmacology ( 12.3 ) ]. Active liver disease, including those with unexplained persistent liver function abnormalities [see Warnings and Precautions ( 5.2 ) ]. Pre-existing gallbladder disease [see Warnings and Precautions ( 5.5 ) ]. Hypersensitivity to fenofibric acid, fenofibrate, or any of the excipients in Antara. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with fenofibrate [see Warnings and Precautions ( 5.9 ) ].

5 WARNINGS AND PRECAUTIONS Hepatotoxicity : Serious drug-induced liver injury, including liver transplantation and death, has been reported with Antara. Monitor patient's liver function, including serum ALT, AST, and total bilirubin, at baseline and periodically for the duration of therapy. Discontinue if signs or symptoms of liver injury develop or if elevated enzyme levels persist ( 5.2 ). Myopathy and rhabdomyolysis : Have been reported in patients taking fenofibrate. Risks are increased during co-administration with a statin, particularly in elderly patients and patients with diabetes, renal failure, or uncontrolled hypothyroidism. Discontinue Antara if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Temporarily discontinue Antara in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis. Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the Antara dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever ( 5.3 ). Serum creatinine: Increases in serum creatinine have been reported in patients on Antara. Monitor renal function in patients with renal impairment taking Antara. Consider monitoring renal function in patients at risk for renal impairment ( 5.4 ). Cholelithiasis: Fenofibrate increases cholesterol excretion into the bile, leading to risk of cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. ( 5.5 ). Hypersensitivity Reactions: Acute hypersensitivity reactions, including anaphylaxis and angioedema, and delayed hypersensitivity reactions, including severe cutaneous adverse drug reactions have been reported postmarketing. Some cases were life-threatening and required emergency treatment. Discontinue fenofibrate and treat patients appropriately if reactions occur ( 5.9 ). 5.1 Mortality and Coronary Heart Disease Morbidity Fenofibrate did not reduce cardiovascular disease morbidity or mortality in two large, randomized controlled trials of patients with type 2 diabetes mellitus [see Clinical Studies ( 14.4 )] . Because of chemical, pharmacological, and clinical similarities between Antara, pemafibrate, clofibrate, and gemfibrozil, findings in 5 large randomized, placebo-controlled clinical trials with these other fibrate drugs may also apply to Antara. Pemafibrate did not reduce cardiovascular disease morbidity or mortality in a large, randomized, placebo-controlled trial of patients with type 2 diabetes mellitus on background statin therapy [see Clinical Studies ( 14.4 )] . In the Coronary Drug Project, a large trial conducted from 1965 to 1985 in men post myocardial infarction, there was no difference in mortality or nonfatal myocardial infarction between the clofibrate group and the placebo group after 5 years of treatment (NCT00000482). In a trial conducted by the World Health Organization (WHO) from 1965 to 1976, men without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional one year. There was a statistically significant, higher age-adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs. 3.96%, p≤0.01). Excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis.

one year. There was a statistically significant, higher age-adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs. 3.96%, p≤0.01). Excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis. The Helsinki Heart Study, conducted from 1982 to 1987, was a large (n=4,081) trial of middle-aged men without a history of coronary artery disease. Subjects received either placebo or gemfibrozil for 5 years, with a 3.5 year open extension afterward. Total mortality was numerically but not statistically higher in the gemfibrozil randomization group versus placebo [95% confidence interval (CI) of the hazard ratio (HR) 0.91 to 1.64]. A secondary prevention component of the Helsinki Heart Study treated middle-aged men with gemfibrozil or placebo for 5 years. The HR for cardiac deaths was 2.2, 95% CI, 0.94 to 5.05. 5.2 Hepatotoxicity Serious drug-induced liver injury (DILI), including liver transplantation and death, has been reported postmarketing with Antara. DILI has been reported within the first few weeks of treatment or after several months of therapy and in some cases has reversed with discontinuation of Antara treatment. Patients with DILI have experienced signs and symptoms including dark urine, abnormal stool, jaundice, malaise, abdominal pain, myalgia, weight loss, pruritus, and nausea. Many patients had concurrent elevations of total bilirubin, serum alanine transaminase (ALT), and aspartate transaminase (AST). DILI has been characterized as hepatocellular, chronic active, and cholestatic hepatitis, and cirrhosis has occurred in association with chronic active hepatitis. In clinical trials, fenofibrate at dosages comparable to 30 mg or 90 mg of Antara per day has been associated with increases in serum AST or ALT. The incidence of increases in transaminases may be dose related [see Adverse Reactions ( 6.1 )] . Antara is contraindicated in patients with active liver disease, including those with unexplained persistent liver function abnormalities [see Contraindications ( 4 )]. Monitor patient's liver function, including serum ALT, AST, and total bilirubin, at baseline and periodically for the duration of therapy with Antara. Discontinue Antara if signs or symptoms of liver injury develop or if elevated enzyme levels persist (ALT or AST > 3 times the upper limit of normal, or if accompanied by elevation of bilirubin). Do not restart Antara in these patients if there is no alternative explanation for the liver injury. 5.3 Myopathy and Rhabdomyolysis Antara may cause myopathy [muscle pain, tenderness, or weakness associated with elevated creatine kinase (CK)] and rhabdomyolysis. Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, and concomitant use with certain other drugs [see Drug Interaction ( 7 ) and Uses in Specific Populations ( 8.6 )] . Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis Data from observational studies indicate that the risk for rhabdomyolysis is increased when fibrates are co-administered with a statin. Avoid concomitant use unless the benefit of further alterations in TG levels is likely to outweigh the increased risk of this drug combination [see Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.3 ) ]. Cases of myopathy, including rhabdomyolysis, have been reported with Antara co-administered with colchicine. Consider whether the benefit of using colchicine concomitantly with Antara outweighs the increased risk of myopathy [see Drug Interactions ( 7 ) ]. Discontinue Antara if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected.

is, have been reported with Antara co-administered with colchicine. Consider whether the benefit of using colchicine concomitantly with Antara outweighs the increased risk of myopathy [see Drug Interactions ( 7 ) ]. Discontinue Antara if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if Antara is discontinued. Temporarily discontinue Antara in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy). Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the Antara dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. 5.4 Increases in Serum Creatinine Increases in serum creatinine have been reported in patients on Antara. These increases tend to return to baseline following discontinuation of Antara. The clinical significance of this finding is unknown. Monitor renal function in patients with renal impairment taking Antara. Renal monitoring should also be considered for patients taking Antara at risk for renal insufficiency such as the elderly and patients with diabetes. Antara is contraindicated in patients with severe renal impairment, including those with end-stage renal disease (ESRD) and those receiving dialysis [ see Dosage and Administration ( 2.3 ), Contraindications ( 4 ), Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 )] . 5.5 Cholelithiasis Fenofibrate may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Antara therapy should be discontinued if gallstones are found. Antara is contraindicated in patients with pre-existing gallbladder disease. 5.6 Increased Bleeding Risk with Coumarin Anticoagulants Caution should be exercised when anticoagulants are given in conjunction with Antara because of the potentiation of coumarin-type anti-coagulants in prolonging the prothrombin time/International Normalized Ratio (PT/INR). To prevent bleeding complications, frequent monitoring of PT/INR and dosage adjustment of the anticoagulant are recommended until PT/INR has stabilized [see Drug Interactions ( 7 ) ]. 5.7 Pancreatitis Pancreatitis has been reported in patients taking Antara. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct. 5.8 Hematologic Changes Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of Antara. However, these levels stabilize during long-term administration. Thrombocytopenia and agranulocytosis have been reported in individuals treated with Antara. Periodic monitoring of red and white blood cell counts is recommended during the first 12 months of Antara administration. 5.9 Hypersensitivity Reactions Acute Hypersensitivity Anaphylaxis and angioedema have been reported postmarketing with fenofibrate. In some cases, reactions were life-threatening and required emergency treatment. If a patient develops signs or symptoms of an acute hypersensitivity reaction, advise them to seek immediate medical attention and discontinue Antara. Antara is contraindicated in patients with a hypersensitivity to fenofibrate, fenofibric acid, or any of the ingredients in Antara.

ing and required emergency treatment. If a patient develops signs or symptoms of an acute hypersensitivity reaction, advise them to seek immediate medical attention and discontinue Antara. Antara is contraindicated in patients with a hypersensitivity to fenofibrate, fenofibric acid, or any of the ingredients in Antara. Delayed Hypersensitivity Severe cutaneous adverse drug reactions (SCAR), including Stevens-Johnson syndrome, Toxic Epidermal Necrolysis, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported postmarketing, occurring days to weeks after initiation of Antara. The cases of DRESS were associated with cutaneous reactions (such as rash or exfoliative dermatitis) and a combination of eosinophilia, fever, systemic organ involvement (renal, hepatic, or respiratory). Discontinue fenofibrate and treat patients appropriately if SCAR is suspected. 5.10 Venothromboembolic Disease In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, pulmonary embolus (PE) and deep vein thrombosis (DVT) were observed at higher rates in the fenofibrate than the placebo-treated group. Of 9,795 patients enrolled in FIELD, there were 4,900 in the placebo group and 4,895 in the fenofibrate group. For DVT, there were 48 events (1%) in the placebo group and 67 (1.4%) in the fenofibrate group (p = 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1.1%) in the fenofibrate group (p = 0.022). In the Coronary Drug Project, a higher proportion of the clofibrate group experienced definite or suspected fatal or nonfatal pulmonary embolism or thrombophlebitis than the placebo group (5.2% vs. 3.3% at five years; p < 0.01). In the cardiovascular outcome trial with pemafibrate, pulmonary embolism was reported for 37 (0.7%) subjects in the pemafibrate group and 16 (0.3%) subjects in the placebo group. Deep vein thrombosis was reported for 36 (0.7%) subjects in the pemafibrate group and 13 (0.2%) subjects in the placebo group. 5.11 Paradoxical Decrease in HDL Cholesterol Levels There have been postmarketing and clinical trial reports of severe decreases in HDL cholesterol levels (as low as 2 mg/dL) occurring in patients with and without diabetes initiated on fibrate therapy. The decrease in HDL-C is mirrored by a decrease in apolipoprotein A1. This decrease has been reported to occur within 2 weeks to years after initiation of fibrate therapy. The HDL-C levels remain depressed until fibrate therapy has been withdrawn; the response to withdrawal of fibrate therapy is rapid and sustained. The clinical significance of this decrease in HDL-C is unknown. Check HDL-C levels within the first few months after initiation of Antara. If a severely depressed HDL-C level is detected, discontinue Antara and monitor HDL-C until it has returned to baseline. Antara should not be re-initiated.

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Mortality and coronary heart disease morbidity [see Warnings and Precautions ( 5.1 )] Hepatoxicity [see Warnings and Precautions ( 5.2 )] Myopathy and Rhabdomyolysis [see Warnings and Precautions ( 5.3 )] Increases in Serum Creatinine [see Warnings and Precautions ( 5.4 )] Cholelithiasis [see Warnings and Precautions ( 5.5 )] Increased Bleeding Risk with Coumarin Anticoagulants [see Warnings and Precautions ( 5.6 )] Pancreatitis [see Warnings and Precautions ( 5.7 )] Hematologic Changes [see Warnings and Precautions ( 5.8 )] Hypersensitivity reactions [see Warnings and Precautions ( 5.9 )] Venothromboembolic disease [see Warnings and Precautions ( 5.10 )] 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. The Safety of Antara has been established in adults with hypertriglyceridemia or primary hyperlipidemia based on adequate and well-controlled trials of other formulations of fenofibrate, referenced below as "fenofibrate" [see Clinical Studies ( 14 )]. Dosages of fenofibrate used in these trials were comparable to Antara 90 mg per day [see Clinical Pharmacology ( 12.3 )]. Adverse events reported by 2% or more of patients treated with fenofibrate (and greater than placebo) during double-blind, placebo-controlled trials are listed in Table 1. Adverse reactions led to discontinuation of treatment in 5% of patients treated with fenofibrate and in 3% 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 Adverse Reaction Placebo (N=365) Fenofibrate (N=439) Abnormal Liver Tests 1% 8% Abdominal Pain 4% 5% Increased ALT 2% 3% Increased AST 1% 3% Increased Creatine Phosphokinase 1% 3% Constipation 1% 2% Rhinitis 1% 2% Other Adverse Reactions Urticaria Urticaria was seen in 1.1 vs. 0%, and rash in 1.4 vs. 0.8% of fenofibrate and placebo patients, respectively, in controlled trials. Increases in Liver Enzymes In a pooled analysis of 10 placebo-controlled trials, increases to >3 times the upper limit of normal in ALT occurred in 5.3% of patients taking fenofibrate at doses comparable to 90 mg Antara daily versus 1.1% of patients treated with placebo. In an 8-week study, the incidence of ALT or AST elevations ≥ 3 times the upper limit of normal was 13% in patients receiving dosages comparable to 60 mg to 90 mg Antara daily and was 0% in those receiving dosages comparable to 30 mg or less Antara daily or placebo. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of fenofibrate.

the upper limit of normal was 13% in patients receiving dosages comparable to 60 mg to 90 mg Antara daily and was 0% in those receiving dosages comparable to 30 mg or less Antara daily or placebo. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of fenofibrate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood Disorders: Anemia Gastrointestinal Disorders: Pancreatitis General Disorder: Asthenia Hepatobiliary Disorders: Increased total bilirubin, hepatitis, cirrhosis Immune System Disorders: Anaphylaxis, angioedema Lipid Disorders: Severely depressed HDL-cholesterol levels Musculoskeletal Disorders: Myalgia, muscle spasms, rhabdomyolysis, arthralgia Renal and Urinary Disorders: Acute renal failure Respiratory Disorders: Interstitial lung disease Skin and Subcutaneous Tissue Disorders: Photosensitivity reactions. This may occur in patients who report a prior photosensitivity reaction to ketoprofen.

<table ID="ID189" width="94%" styleCode="Noautorules"><caption> 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 </caption><col width="52%"/><col width="23%"/><col width="23%"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"><content styleCode="bold"> Adverse Reaction </content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> Placebo </content> <content styleCode="bold"> (N=365)</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> Fenofibrate (N=439) </content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Abnormal Liver Tests </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 8% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Abdominal Pain </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 4% </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 5% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Increased ALT </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 3% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Increased AST </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 3% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Increased Creatine Phosphokinase </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 3% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Constipation </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 2% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Rhinitis </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 2% </td></tr></tbody></table>

7 DRUG INTERACTIONS Table 2. Clinically Important Drug Interactions with Antara Statins Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with statins. Intervention: Consider if the benefit of using Antara concomitantly with statin therapy outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of statin therapy. Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with fenofibrates. Intervention: Consider if the benefit of using colchicine concomitantly with Antara outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dosage titration of colchicine. Coumarin Anticoagulants Clinical Impact: Fibrates may cause potentiation of coumarin-type anticoagulant effects with prolongation of the PT/INR. Intervention: Caution should be exercised when coumarin anticoagulants are given in conjunction with Antara. 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 Immunosuppressants Clinical Impact: Immunosuppressants such as cyclosporine and tacrolimus can produce nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine, and because renal excretion is the primary elimination route of fibrate drugs including Antara, there is a risk that an interaction will lead to deterioration of renal function. Intervention: The benefits and risks of using Antara with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dosage employed and renal function monitored. Bile-Acid Binding Resins Clinical Impact: Bile-acid binding resins may bind other drugs given concurrently. Intervention: In patients taking a bile acid resin, administer Antara at least 1 hour before or 4 to 6 hours after the bile acid resin to avoid impeding its absorption. Consider if the benefit of concomitant use of statins or colchicine outweighs the increased risk of myopathy and rhabdomyolysis. Monitor patients for signs and symptoms of myopathy ( 7 ) Exercise caution in concomitant treatment with coumarin anticoagulants. Reduce the dosage of coumarin to maintain the PT/INR at the desired level to prevent bleeding complications ( 7 ). Consider the benefits and risks of concomitant use with immunosuppressants and other potentially nephrotoxic agents. Use the lowest effective dosage and monitor renal function ( 7 ). Administer Antara at least 1 hour before or 4 to 6 hours after the bile acid resins to avoid impeding its absorption ( 7 ).

<table ID="ID292" width="616" styleCode="Noautorules"><caption> Table 2. Clinically Important Drug Interactions with Antara </caption><col width="160"/><col width="456"/><tbody><tr><td colspan="2" valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"><content styleCode="bold"> Statins</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Clinical Impact:</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with statins. </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Intervention:</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Consider if the benefit of using Antara concomitantly with statin therapy outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of statin therapy. </td></tr><tr><td colspan="2" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Colchicine</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Clinical Impact:</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with fenofibrates. </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Intervention:</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Consider if the benefit of using colchicine concomitantly with Antara outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dosage titration of colchicine. </td></tr><tr><td colspan="2" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Coumarin Anticoagulants</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Clinical Impact:</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Fibrates may cause potentiation of coumarin-type anticoagulant effects with prolongation of the PT/INR. </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Intervention:</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Caution should be exercised when coumarin anticoagulants are given in conjunction with Antara. The dosage of the anticoagulants should be reduced to maintain the PT/INR at the desired level to prevent bleeding complications.

italics">Intervention:</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Caution should be exercised when coumarin anticoagulants are given in conjunction with Antara. 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 </td></tr><tr><td colspan="2" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Immunosuppressants</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Clinical Impact:</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Immunosuppressants such as cyclosporine and tacrolimus can produce nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine, and because renal excretion is the primary elimination route of fibrate drugs including Antara, there is a risk that an interaction will lead to deterioration of renal function. </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Intervention:</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> The benefits and risks of using Antara with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dosage employed and renal function monitored. </td></tr><tr><td colspan="2" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Bile-Acid Binding Resins</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Clinical Impact:</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Bile-acid binding resins may bind other drugs given concurrently. </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Intervention:</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> In patients taking a bile acid resin, administer Antara at least 1 hour before or 4 to 6 hours after the bile acid resin to avoid impeding its absorption. </td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Limited available data with fenofibrate use in pregnant women are insufficient to determine a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no evidence of embryo-fetal toxicity was observed with oral administration of fenofibrate in rats and rabbits during organogenesis at doses less than or comparable to the maximum recommended clinical dose of 90 mg of Antara daily, based on body surface area (mg/m 2 ). Adverse reproductive outcomes occurred at higher doses in the presence of maternal toxicity (see Data). Antara should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In pregnant rats given oral dietary doses of 14 mg/kg/day, 127 mg/kg/day, and 361 mg/kg/day from gestation day 6 to 15 during the period of organogenesis, no adverse developmental findings were observed at 14 mg/kg/day (less than the clinical exposure at the maximum recommended human dose [MRHD] of 300 mg fenofibrate daily, comparable to 90 mg Antara daily, based on body surface area comparisons). Increased fetal skeletal malformations were observed at maternally toxic doses (361 mg/kg/day, corresponding to 12 times the clinical exposure at the MRHD) that significantly suppressed maternal body weight gain. In pregnant rabbits given oral gavage doses of 15 mg/kg/day, 150 mg/kg/day, and 300 mg/kg/day from gestation day 6 to 18 during the period of organogenesis and allowed to deliver, no adverse developmental findings were observed at 15 mg/kg/day (a dose that approximates the clinical exposure at the MRHD, based on body surface area comparisons). Aborted litters were observed at maternally toxic doses (≥ 150 mg/kg/day, corresponding to ≥ 10 times the clinical exposure at the MRHD) that suppressed maternal body weight gain. In pregnant rats given oral dietary doses of 15 mg/kg/day, 75 mg/kg/day, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), no adverse developmental effects were observed at 15 mg/kg/day (less than the clinical exposure at the MRHD, based on body surface area comparisons), despite maternal toxicity (decreased weight gain). Post-implantation loss was observed at ≥ 75 mg/kg/day (≥ 2 times the clinical exposure at the MRHD) in the presence of maternal toxicity (decreased weight gain). Decreased pup survival was noted at 300 mg/kg/day (10 times the clinical exposure at the MRHD), which was associated with decreased maternal body weight gain/maternal neglect. 8.2 Lactation Risk Summary There is no available information on the presence of fenofibrate in human milk, effects of the drug on the breastfed infant, or the effects on milk production. Fenofibrate is present in the milk of rats, and is therefore likely to be present in human milk. Because of the potential for serious adverse reactions in breastfed infants, such as disruption of infant lipid metabolism, women should not breastfeed during treatment with Antara and for 5 days after the final dose [see Contraindications ( 4 ) ].

the milk of rats, and is therefore likely to be present in human milk. Because of the potential for serious adverse reactions in breastfed infants, such as disruption of infant lipid metabolism, women should not breastfeed during treatment with Antara and for 5 days after the final dose [see Contraindications ( 4 ) ]. 8.4 Pediatric Use The safety and effectiveness of Antara have not been established in pediatric patients with severe hypertriglyceridemia or primary hyperlipidemia. 8.5 Geriatric Use Assess renal function in elderly patients and follow contraindications and dosing recommendations for patients with renal impairment [ see Contraindications ( 4 ), Warnings and Precautions ( 5.3 , 5.4 ), and Use in Specific Populations ( 8.6 ) ]. While fenofibric acid exposure is not influenced by age, elderly patients are more likely to have renal impairment, and fenofibric acid is substantially excreted by the kidney [ see Clinical Pharmacology ( 12.3 ) ]. Consider monitoring renal function in elderly patients taking Antara. 8.6 Renal Impairment Antara is contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73m 2 ), including those with end-stage renal disease (ESRD) and those receiving dialysis [see Contraindications ( 4 ) ]. Dose reduction is required in patients with mild to moderate renal impairment [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 ) ]. Patients with severe renal impairment have 2.7-fold higher exposure of fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared with healthy volunteers. Renal impairment is a risk factor for myopathy and rhabdomyolysis [ see Warnings and Precautions ( 5.3 , 5.4 ), and Clinical Pharmacology ( 12.3 ) ]. 8.7 Hepatic Impairment The use of Antara has not been evaluated in subjects with hepatic impairment. Antara is contraindicated in patients with active liver disease, including those with unexplained persistent liver function abnormalities [see Contraindications ( 4 ) and Clinical Pharmacology ( 12.3 ) ].

8.1 Pregnancy Risk Summary Limited available data with fenofibrate use in pregnant women are insufficient to determine a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no evidence of embryo-fetal toxicity was observed with oral administration of fenofibrate in rats and rabbits during organogenesis at doses less than or comparable to the maximum recommended clinical dose of 90 mg of Antara daily, based on body surface area (mg/m 2 ). Adverse reproductive outcomes occurred at higher doses in the presence of maternal toxicity (see Data). Antara should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In pregnant rats given oral dietary doses of 14 mg/kg/day, 127 mg/kg/day, and 361 mg/kg/day from gestation day 6 to 15 during the period of organogenesis, no adverse developmental findings were observed at 14 mg/kg/day (less than the clinical exposure at the maximum recommended human dose [MRHD] of 300 mg fenofibrate daily, comparable to 90 mg Antara daily, based on body surface area comparisons). Increased fetal skeletal malformations were observed at maternally toxic doses (361 mg/kg/day, corresponding to 12 times the clinical exposure at the MRHD) that significantly suppressed maternal body weight gain. In pregnant rabbits given oral gavage doses of 15 mg/kg/day, 150 mg/kg/day, and 300 mg/kg/day from gestation day 6 to 18 during the period of organogenesis and allowed to deliver, no adverse developmental findings were observed at 15 mg/kg/day (a dose that approximates the clinical exposure at the MRHD, based on body surface area comparisons). Aborted litters were observed at maternally toxic doses (≥ 150 mg/kg/day, corresponding to ≥ 10 times the clinical exposure at the MRHD) that suppressed maternal body weight gain. In pregnant rats given oral dietary doses of 15 mg/kg/day, 75 mg/kg/day, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), no adverse developmental effects were observed at 15 mg/kg/day (less than the clinical exposure at the MRHD, based on body surface area comparisons), despite maternal toxicity (decreased weight gain). Post-implantation loss was observed at ≥ 75 mg/kg/day (≥ 2 times the clinical exposure at the MRHD) in the presence of maternal toxicity (decreased weight gain). Decreased pup survival was noted at 300 mg/kg/day (10 times the clinical exposure at the MRHD), which was associated with decreased maternal body weight gain/maternal neglect.

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

8.5 Geriatric Use Assess renal function in elderly patients and follow contraindications and dosing recommendations for patients with renal impairment [ see Contraindications ( 4 ), Warnings and Precautions ( 5.3 , 5.4 ), and Use in Specific Populations ( 8.6 ) ]. While fenofibric acid exposure is not influenced by age, elderly patients are more likely to have renal impairment, and fenofibric acid is substantially excreted by the kidney [ see Clinical Pharmacology ( 12.3 ) ]. Consider monitoring renal function in elderly patients taking Antara.

10 OVERDOSAGE In the event of an overdose of Antara, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. There is no specific treatment for overdose with Antara. 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.

11 DESCRIPTION Antara (fenofibrate) Capsule, is a peroxisome proliferator-activated receptor (PPAR) alpha agonist available as capsules for oral administration. Each capsule contains 30 mg or 90 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°C to 82°C. Fenofibrate is a white solid which is stable under ordinary conditions. Inactive Ingredients : Each gelatin capsule contains hypromellose, simethicone emulsion, sodium lauryl sulphate, sugar spheres and talc. The capsule shell contains the following inactive ingredients: black iron oxide, D & C Yellow 10, potassium hydroxide, propylene glycol, gelatin, shellac, sodium lauryl sulphate, titanium dioxide. The 30 mg capsule shell contains following additional inactive ingredients: FD & C Blue 2, yellow iron oxide. The 90 mg capsule shell contains following additional inactive ingredients: FD & C Blue 1, FD & C Yellow 6. Fenofibrate

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The active moiety of Antara is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been 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 PPAR alpha receptor. 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). 12.2 Pharmacodynamics Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total cholesterol, total triglycerides, and triglyceride-rich lipoprotein (VLDL) in treated patients with severe hypertriglyceridemia. 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. Fenofibrate is insoluble in water and its bioavailability is optimized when taken with meals. However, after fenofibrate is dissolved, 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 Antara capsules 90 mg occur within 2 to 6 hours after administration. Effect of Food The extent of absorption of fenofibric acid was unaffected when Antara was taken either in fasted state or with a low-fat meal. However, the C max of Antara 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 26.7% increase in AUC and 15.35% increase in Cmax of fenofibric acid from Antara capsule 30mg 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. Elimination 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. Excretion: After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radio-labelled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces.

a significant extent. Excretion: After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radio-labelled 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 23 hours, allowing once daily dosing. Specific Populations Geriatric Patients: In elderly volunteers aged 77 to 87 years, 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 ) ] . Pediatric Patients: Pharmacokinetics of Antara has not been studied in pediatric patients. Male and Female Patients: No pharmacokinetic difference between males and females has been observed for fenofibrate. Racial and Ethnic Groups : 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. Patients with 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 renal impairment (CrCl 30 mL/min to 80 mL/min or eGFR 30 mL/min/1.73m 2 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 Antara is contraindicated in patients with severe renal impairment, including end-stage renal disease (ESRD) or those receiving dialysis. Dose reduction is required in patients having mild to moderate renal impairment [see Dosage and Administration ( 2.4 ) ]. Patients with Hepatic Impairment: No pharmacokinetic studies have been conducted in patients having hepatic impairment. Drug-Drug Interaction Studies: 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 3 describes the effects of co-administered drugs on fenofibric acid systemic exposure. Table 4 describes the effects of co-administered fenofibric acid on exposure to other drugs.

YP1A2. They are weak inhibitor of CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations. Table 3 describes the effects of co-administered drugs on fenofibric acid systemic exposure. Table 4 describes the effects of co-administered fenofibric acid on exposure to other drugs. Table 3 Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Antara or Fenofibrate Administration 1 TriCor (fenofibrate) oral tablet 2 TriCor (fenofibrate) oral micronized capsule Co-Administered Drug Dosage Regimen of Co-Administered Drug Dosage Regimen of Fenofibrate Changes in Fenofibric Acid Exposure AUC C max Lipid-lowing 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 4 Effects of Antara or Fenofibrate on Systemic Exposure of Co-Administered Drugs 1 TriCor (fenofibrate) oral tablet 2 TriCor (fenofibrate) oral micronized capsule Dosage Regimen of Fenofibrate Dosage Regimen of Co- Administered Drug Changes in Co-Administered Drug Exposure Analyte AUC C max 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 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 Antara is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been 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 PPAR alpha receptor. 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).

12.2 Pharmacodynamics Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total cholesterol, total triglycerides, and triglyceride-rich lipoprotein (VLDL) in treated patients with severe hypertriglyceridemia.

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. Fenofibrate is insoluble in water and its bioavailability is optimized when taken with meals. However, after fenofibrate is dissolved, 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 Antara capsules 90 mg occur within 2 to 6 hours after administration. Effect of Food The extent of absorption of fenofibric acid was unaffected when Antara was taken either in fasted state or with a low-fat meal. However, the C max of Antara 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 26.7% increase in AUC and 15.35% increase in Cmax of fenofibric acid from Antara capsule 30mg 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. Elimination 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. Excretion: After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radio-labelled 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 23 hours, allowing once daily dosing. Specific Populations Geriatric Patients: In elderly volunteers aged 77 to 87 years, 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 ) ] . Pediatric Patients: Pharmacokinetics of Antara has not been studied in pediatric patients. Male and Female Patients: No pharmacokinetic difference between males and females has been observed for fenofibrate.

ion of the drug or metabolites [see Dosage and Administration ( 2.4 ) and Use in Special Populations ( 8.5 ) ] . Pediatric Patients: Pharmacokinetics of Antara has not been studied in pediatric patients. Male and Female Patients: No pharmacokinetic difference between males and females has been observed for fenofibrate. Racial and Ethnic Groups : 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. Patients with 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 renal impairment (CrCl 30 mL/min to 80 mL/min or eGFR 30 mL/min/1.73m 2 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 Antara is contraindicated in patients with severe renal impairment, including end-stage renal disease (ESRD) or those receiving dialysis. Dose reduction is required in patients having mild to moderate renal impairment [see Dosage and Administration ( 2.4 ) ]. Patients with Hepatic Impairment: No pharmacokinetic studies have been conducted in patients having hepatic impairment. Drug-Drug Interaction Studies: 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 3 describes the effects of co-administered drugs on fenofibric acid systemic exposure. Table 4 describes the effects of co-administered fenofibric acid on exposure to other drugs.

<table ID="ID231" width="100%" styleCode="Noautorules"><caption> Table 3 Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Antara or Fenofibrate Administration</caption><col width="22%"/><col width="21%"/><col width="35%"/><col width="10%"/><col width="11%"/><tfoot><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">¹TriCor (fenofibrate) oral tablet </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">²TriCor (fenofibrate) oral micronized capsule</paragraph></td></tr></tfoot><tbody><tr><td styleCode="Lrule Toprule Rrule" align="left"><content styleCode="bold"> Co-Administered Drug</content> </td><td valign="top" styleCode=" Toprule Rrule" align="left"><content styleCode="bold"> Dosage Regimen of Co-Administered Drug</content> </td><td styleCode=" Toprule Rrule" align="left"><content styleCode="bold"> Dosage Regimen of Fenofibrate </content> </td><td colspan="2" valign="top" styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> Changes in Fenofibric Acid Exposure </content> </td></tr><tr><td styleCode="Lrule Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule"/><td styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule" align="left"><content styleCode="bold"> AUC </content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> C_max</content> </td></tr><tr><td colspan="5" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Lipid-lowing agents </content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Atorvastatin </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 20 mg once daily for 10 days </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Fenofibrate 160 mg¹ once daily for 10 days </td><td valign="top" styleCode=" Botrule Rrule" align="left"> &#x2193;2% </td><td valign="top" styleCode=" Botrule Rrule" align="left"> &#x2193;4% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Pravastatin </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 40 mg as a single dose </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Fenofibrate 3 x 67 mg² as a single dose </td><td valign="top" styleCode=" Botrule Rrule" align="left"> &#x2193;1% </td><td valign="top" styleCode=" Botrule Rrule" align="left"> &#x2193;2% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Fluvastatin </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 40 mg as a single dose </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Fenofibrate 160 mg¹ as a single dose </td><td valign="top" styleCode=" Botrule Rrule" align="left"> &#x2193;2% </td><td valign="top" styleCode=" Botrule Rrule" align="left"> &#x2193;10% </td></tr><tr><td colspan="5" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Anti-diabetic agents </content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Glimepiride </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 1 mg as a single dose </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Fenofibrate 145 mg¹ once daily for 10 days </td><td valign="top" styleCode=" Botrule Rrule" align="left"> &#x2191;1% </td><td valign="top" styleCode=" Botrule Rrule" align="left"> &#x2193;1% </td></tr><tr><td styleCode="Lrule Botrule R

ingle dose </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Fenofibrate 145 mg¹ once daily for 10 days </td><td valign="top" styleCode=" Botrule Rrule" align="left"> &#x2191;1% </td><td valign="top" styleCode=" Botrule Rrule" align="left"> &#x2193;1% </td></tr><tr><td styleCode="Lrule Botrule R rule" align="left"> Metformin </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 850 mg three times daily for 10 days </td><td styleCode=" Botrule Rrule" align="left"> Fenofibrate 54 mg¹ three times daily for 10 days </td><td valign="top" styleCode=" Botrule Rrule" align="left"> &#x2193;9% </td><td valign="top" styleCode=" Botrule Rrule" align="left"> &#x2193;6% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Rosiglitazone </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 8 mg once daily for 5 days </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Fenofibrate 145 mg¹ once daily for 14 days </td><td valign="top" styleCode=" Botrule Rrule" align="left"> &#x2191;10% </td><td valign="top" styleCode=" Botrule Rrule" align="left"> &#x2191;3% </td></tr></tbody></table>

8 mg once daily for 5 days </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Fenofibrate 145 mg¹ once daily for 14 days </td><td valign="top" styleCode=" Botrule Rrule" align="left"> &#x2191;10% </td><td valign="top" styleCode=" Botrule Rrule" align="left"> &#x2191;3% </td></tr></tbody></table> <table ID="ID258" width="100%" styleCode="Noautorules"><caption> Table 4 Effects of Antara or Fenofibrate on Systemic Exposure of Co-Administered Drugs</caption><col/><col/><col width="20%"/><col width="13%"/><col width="13%"/><tfoot><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">¹TriCor (fenofibrate) oral tablet </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">²TriCor (fenofibrate) oral micronized capsule</paragraph></td></tr></tfoot><tbody><tr><td styleCode="Lrule Toprule Rrule" align="left"><content styleCode="bold"> Dosage Regimen of Fenofibrate</content> </td><td valign="top" styleCode=" Toprule Rrule" align="left"><content styleCode="bold"> Dosage Regimen of Co- Administered Drug</content> </td><td colspan="3" valign="top" styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> Changes in Co-Administered Drug Exposure </content> </td></tr><tr><td styleCode="Lrule Botrule Rrule"/><td styleCode=" Botrule Rrule"/><td styleCode=" Botrule Rrule" align="left"><content styleCode="bold"> Analyte </content> </td><td styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> AUC </content> </td><td styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> C_max</content> </td></tr><tr><td colspan="5" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Lipid-lowing agents </content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Fenofibrate 160 mg¹ once daily for 10 days </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Atorvastatin, 20 mg once daily for 10 days </td><td styleCode=" Botrule Rrule" align="left"> Atorvastatin </td><td styleCode=" Botrule Rrule" align="left"> &#x2193;17% </td><td styleCode=" Botrule Rrule" align="left"> 0% </td></tr><tr><td styleCode=" Lrule Rrule" align="left"> Fenofibrate 3 x 67 mg² as a single dose </td><td styleCode=" Rrule" align="left"> Pravastatin, 40 mg as a single dose </td><td styleCode=" Botrule Rrule" align="left"> Pravastatin </td><td styleCode=" Botrule Rrule" align="left"> &#x2191;13% </td><td styleCode=" Botrule Rrule" align="left"> &#x2191;13% </td></tr><tr><td styleCode="Lrule Botrule Rrule"/><td styleCode=" Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule" align="left"> 3&#x3B1;-Hydroxyl-iso-pravastatin </td><td styleCode=" Botrule Rrule" align="left"> &#x2191;26% </td><td styleCode=" Botrule Rrule" align="left"> &#x2191;29% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Fenofibrate 160 mg¹ as a single dose </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Fluvastatin, 40 mg as a single dose </td><td valign="top" styleCode=" Botrule Rrule" align="left"> (+)-3R, 5S Fluvastatin </td><td styleCode=" Botrule Rrule" align="left"> &#x2191;15% </td><td styleCode=" Botrule Rrule" align="left"> &#x2191;16% </td></tr><tr><td colspan="5" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Anti-diabetic agents </content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Fenofibrate 145 mg¹ once daily for 10 days </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Glimepiride, 1 mg once daily as a single dose </td><td styleCode=" Botrule Rrule" align="left"> Glimepiride </td><td styleCode=" Botrule Rrule" align="left"> &#x2191;35% </td><td styleCode=" Botrule Rrule" align="le

145 mg¹ once daily for 10 days </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Glimepiride, 1 mg once daily as a single dose </td><td styleCode=" Botrule Rrule" align="left"> Glimepiride </td><td styleCode=" Botrule Rrule" align="left"> &#x2191;35% </td><td styleCode=" Botrule Rrule" align="le ft"> &#x2191;18% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Fenofibrate 54 mg¹ three times daily for 10 days </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Metformin, 850 mg three times daily for 10 days </td><td styleCode=" Botrule Rrule" align="left"> Metformin </td><td styleCode=" Botrule Rrule" align="left"> &#x2191;3% </td><td styleCode=" Botrule Rrule" align="left"> &#x2191;6% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Fenofibrate 145 mg¹ once daily for 14 days </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Rosiglitazone, 8 mg once daily for 5 days </td><td styleCode=" Botrule Rrule" align="left"> Rosiglitazone </td><td styleCode=" Botrule Rrule" align="left"> &#x2191;6% </td><td styleCode=" Botrule Rrule" align="left"> &#x2193;1% </td></tr></tbody></table>

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: 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 mg/kg/day, 45 mg/kg/day, and 200 mg/kg/day, approximately 0.3 times, 1 times, 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 carcinoma 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 in males at 6 times the MRHD. In a second 24-month study in a different strain of rats (Sprague-Dawley), doses of 10 mg/kg/day 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 mg/kg/day 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 carcinomas 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 mg/kg/day, 45 mg/kg/day, and 200 mg/kg/day (approximately 0.2 times, 1 times, 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 mg/kg/day, 60 mg/kg/day, 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 (approximately 10 times the MRHD, based on mg/m 2 surface area comparisons).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: 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 mg/kg/day, 45 mg/kg/day, and 200 mg/kg/day, approximately 0.3 times, 1 times, 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 carcinoma 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 in males at 6 times the MRHD. In a second 24-month study in a different strain of rats (Sprague-Dawley), doses of 10 mg/kg/day 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 mg/kg/day 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 carcinomas 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 mg/kg/day, 45 mg/kg/day, and 200 mg/kg/day (approximately 0.2 times, 1 times, 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 mg/kg/day, 60 mg/kg/day, 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 (approximately 10 times the MRHD, based on mg/m 2 surface area comparisons).

14 CLINICAL STUDIES 14.1 Overview of Clinical Trials The effectiveness of Antara has been established in adults with hypertriglyceridemia or primary hyperlipidemia based on adequate and well-controlled trials of other formulations of fenofibrate, referenced below as "fenofibrate." Dosages of fenofibrate used in these trials were comparable to Antara 90 mg per day [see Clinical Pharmacology ( 12.3 )] . 14.2 Clinical Trials in Adults with Hypertriglyceridemia The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials of 147 patients with hypertriglyceridemia. Patients were treated for eight weeks under protocols that differed only in that one entered patients with baseline TG levels of 500 to 1,500 mg/dL, and the other TG levels of 350 to 499 mg/dL. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia, treatment with fenofibrate 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 48 30 36 22.9 * LDL Cholesterol 42 100 90 -4.2 45 103 131 45* VLDL Cholesterol 42 137 142 11 45 126 54 -49.4 * The effect of Antara on serum triglycerides was studied in a double-blind, randomized, 3 arm parallel-group trial of 146 patients. 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 a formulation of Antara comparable to 90 mg taken once daily with meals, a formulation of Antara comparable to 90 mg taken once daily between meals, or placebo. Antara, whether taken with meals or between meals, had comparable effects on TG and all lipid parameters (See Table 6).

ere treated for eight weeks with either a formulation of Antara comparable to 90 mg taken once daily with meals, a formulation of Antara comparable to 90 mg taken once daily between meals, or placebo. Antara, whether taken with meals or between meals, had comparable effects on TG and all lipid parameters (See Table 6). Table 6 Antara Treatment in Patients with Hypertriglyceridemia *p ≤ 0.05 vs placebo **p ≤ 0.05 vs placebo (log transformed data) Placebo (n =50) Antara with meals (n=54) Antara 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* 14.3 Clinical Trials in Adults with Primary Hyperlipidemia The effects of fenofibrate were assessed in four randomized, placebo-controlled, double-blind, parallel group trials in patients with hyperlipidemia and mixed dyslipidemia. Fenofibrate therapy reduced LDL-C, Total-C, and triglycerides, and increased HDL-C (See Table 7). Table 7. 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 Mean baseline lipid values (N=646) 306.9 mg/dL 213.8 mg/dL 52.3 mg/dL 191mg/dL All fenofibrate (n=361) -18.7% * -20.6% * +11% * -28.9% * Placebo (n=285) -0.4% -2.2% +0.7% +7.7% 14.4 Lack of Efficacy in Cardiovascular Outcomes Trials Fenofibrate did not reduce cardiovascular disease morbidity or mortality in two large, randomized controlled trials of patients with type 2 diabetes mellitus. The Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) (NCT00000620) trial was a randomized placebo-controlled trial of 5,518 patients (2,765 assigned to receive fenofibrate) with type 2 diabetes mellitus on background statin therapy treated with fenofibrate. The mean age at baseline was 62 years and 31% were female. Overall, 68% were White, 15% were Black or African American; 7% identified as Hispanic or Latino. The mean duration of follow-up was 4.7 years. The primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular disease death was a HR of 0.92 (95% CI, 0.79 to 1.08) for fenofibrate plus statin combination therapy as compared to statin monotherapy. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial was a 5-year randomized, placebo-controlled trial of 9,795 patients (4,895 assigned to receive fenofibrate) with type 2 diabetes mellitus treated with fenofibrate. The mean age at baseline was 62 years, 37% were female, and 93% were White. The primary outcome of coronary heart disease events was a HR of 0.89, (95% CI 0.75 to 1.05) with fenofibrate compared to placebo. The HR for total and coronary heart disease mortality, respectively, was 1.11 (95% CI, 0.95 to 1.29) and 1.19 (95% CI, 0.90 to 1.57) with fenofibrate as compared to placebo. Because of chemical, pharmacological, and clinical similarities between fenofibrate and pemafibrate, findings in a large randomized, placebo-controlled clinical trial with pemafibrate are relevant for Antara. Pemafibrate did not reduce cardiovascular disease morbidity or mortality in a large, randomized, placebo-controlled trial of patients with type 2 diabetes mellitus on background statin therapy (NCT03071692).

ate, findings in a large randomized, placebo-controlled clinical trial with pemafibrate are relevant for Antara. Pemafibrate did not reduce cardiovascular disease morbidity or mortality in a large, randomized, placebo-controlled trial of patients with type 2 diabetes mellitus on background statin therapy (NCT03071692). The trial was a randomized placebo-controlled trial of 10,497 patients (5,240 assigned to receive pemafibrate) with type 2 diabetes mellitus on background lipid-lowering therapy. The median age at baseline was 64 years and 28% were female. Overall, 86% were White, 5% were Asian, 3% were Black or African American; 19% identified as Hispanic or Latino. The median duration of follow-up was 3.4 years. The primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non-fatal ischemic stroke, coronary revascularization, and death from cardiovascular causes, was a HR of 1.03 (95% CI, 0.91 to 1.15) for pemafibrate plus statin combination therapy as compared to statin monotherapy.

<table ID="ID243" width="105%" styleCode="Noautorules"><caption> Table 5 Effects of Fenofibrate in Patients with Hypertriglyceridemia</caption><col width="19%"/><col width="5%"/><col width="11%"/><col width="12%"/><col width="10%"/><col width="5%"/><col width="11%"/><col width="12%"/><col width="10%"/><tfoot><tr><td align="left" colspan="9"><paragraph styleCode="Footnote">*p &lt; 0.05 vs.

5 Effects of Fenofibrate in Patients with Hypertriglyceridemia</caption><col width="19%"/><col width="5%"/><col width="11%"/><col width="12%"/><col width="10%"/><col width="5%"/><col width="11%"/><col width="12%"/><col width="10%"/><tfoot><tr><td align="left" colspan="9"><paragraph styleCode="Footnote">*p &lt; 0.05 vs. placebo</paragraph></td></tr></tfoot><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"><content styleCode="bold"> Study 1</content> </td><td colspan="4" valign="top" styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> Placebo </content> </td><td colspan="4" valign="top" styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> Fenofibrate</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Baseline TG levels 350 to 499 mg/dL </td><td valign="top" styleCode=" Botrule Rrule" align="center"> N </td><td valign="top" styleCode=" Botrule Rrule" align="center"> Baseline (mean) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> Endpoint (mean) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> % Change (mean) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> N </td><td valign="top" styleCode=" Botrule Rrule" align="center"> Baseline (mean) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> Endpoint (mean) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> % Change (mean) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Triglycerides </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 28 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 449 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 450 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -0.5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 27 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 432 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 223 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -46.2 * </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> VLDL Triglycerides </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 19 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 367 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 350 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2.7 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 19 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 350 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 178 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -44.1 * </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Total Cholesterol </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 28 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 255 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 261 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2.8 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 27 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 252 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 227 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -9.1 * </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> HDL Cholesterol </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 28 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 35 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 36 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 </td><td valign="top" styleCode=" Bot

Cholesterol </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 28 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 35 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 36 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 </td><td valign="top" styleCode=" Bot rule Rrule" align="center"> 27 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 34 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 40 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 19.6 * </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> LDL Cholesterol </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 28 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 120 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 129 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1.2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 27 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 128 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 137 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 14.5 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> VLDL Cholesterol </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 27 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 99 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 99 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5.8 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 27 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 92 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 46 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -44.7 * </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Study 2 </content> </td><td colspan="4" valign="top" styleCode=" Botrule Rrule" align="left"><content styleCode="bold"> Placebo </content> </td><td colspan="4" valign="top" styleCode=" Botrule Rrule" align="left"><content styleCode="bold"> Fenofibrate</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Baseline TG levels 500 to 1500 mg/dL </td><td valign="top" styleCode=" Botrule Rrule" align="center"> N </td><td valign="top" styleCode=" Botrule Rrule" align="center"> Baseline (mean) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> Endpoint (mean) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> % Change (mean) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> N </td><td valign="top" styleCode=" Botrule Rrule" align="center"> Baseline (mean) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> Endpoint (mean) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> % Change (mean) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Triglycerides </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 44 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 710 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 750 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7.2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 48 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 726 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 308 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -54.5 * </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> VLDL Triglycerides </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 29 </td><td valign="top" styleCode=" Botrule Rrule" align="center">

ign="center"> 308 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -54.5 * </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> VLDL Triglycerides </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 29 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 537 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 571 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 18.7 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 33 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 543 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 205 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -50.6 * </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Total Cholesterol </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 44 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 272 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 271 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.4 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 48 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 261 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 223 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -13.8 * </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> HDL Cholesterol </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 44 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 27 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 28 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 48 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 30 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 36 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 22.9 * </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> LDL Cholesterol </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 42 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 100 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 90 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -4.2 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 45 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 103 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 131 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 45* </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> VLDL Cholesterol </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 42 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 137 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 142 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 11 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 45 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 126 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 54 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -49.4 * </td></tr></tbody></table>

gn="center"> 11 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 45 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 126 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 54 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -49.4 * </td></tr></tbody></table> <table ID="ID245" width="99%" styleCode="Noautorules"><caption> Table 6 Antara Treatment in Patients with Hypertriglyceridemia </caption><col width="16%"/><col width="13%"/><col width="12%"/><col width="14%"/><col width="13%"/><col width="13%"/><col width="16%"/><tfoot><tr><td align="left" colspan="7"><paragraph styleCode="Footnote">*p &#x2264; 0.05 vs placebo</paragraph></td></tr><tr><td align="left" colspan="7"><paragraph styleCode="Footnote">**p &#x2264; 0.05 vs placebo (log transformed data)</paragraph></td></tr></tfoot><tbody><tr><td styleCode="Lrule Toprule Botrule Rrule"/><td colspan="2" styleCode="Lrule Toprule Botrule Rrule" align="left"><content styleCode="bold"> Placebo (n =50)</content> </td><td colspan="2" styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> Antara with meals (n=54)</content> </td><td colspan="2" styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> Antara between meals (n=42)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule"/><td valign="top" styleCode=" Botrule Rrule" align="center"> Baseline mg/dL (mean) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> % Change at endpoint (mean) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> Baseline mg/dL (mean) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> % Change at endpoint (mean) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> Baseline mg/dL (mean) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> % Change at endpoint (mean) </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Triglycerides </td><td styleCode=" Botrule Rrule" align="center"> 479 </td><td styleCode=" Botrule Rrule" align="center"> +0.7 </td><td styleCode=" Botrule Rrule" align="center"> 475 </td><td styleCode=" Botrule Rrule" align="center"> -36.7* </td><td styleCode=" Botrule Rrule" align="center"> 487 </td><td styleCode=" Botrule Rrule" align="center"> -36.6* </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Total Cholesterol </td><td styleCode=" Botrule Rrule" align="center"> 237 </td><td styleCode=" Botrule Rrule" align="center"> -0.8 </td><td styleCode=" Botrule Rrule" align="center"> 248 </td><td styleCode=" Botrule Rrule" align="center"> -5.1 </td><td styleCode=" Botrule Rrule" align="center"> 241 </td><td styleCode=" Botrule Rrule" align="center"> -3.4 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> HDL Cholesterol </td><td styleCode=" Botrule Rrule" align="center"> 35 </td><td styleCode=" Botrule Rrule" align="center"> +0.8 </td><td styleCode=" Botrule Rrule" align="center"> 36 </td><td styleCode=" Botrule Rrule" align="center"> +13.7* </td><td styleCode=" Botrule Rrule" align="center"> 36 </td><td styleCode=" Botrule Rrule" align="center"> +14.3* </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Non-HDL Cholesterol </td><td styleCode=" Botrule Rrule" align="center"> 202 </td><td styleCode=" Botrule Rrule" align="center"> -1.1 </td><td styleCode=" Botrule Rrule" align="center"> 212 </td><td styleCode=" Botrule Rrule" align="center"> -8.2** </td><td styleCode=" Botrule Rrule" align="center"> 205 </td><td styleCode=" Botrule Rrule" align="center"> -6.6** </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> LDL Cholesterol </td><td styleCode=" Botrule Rrule" align="center"> 115 </td><td styleCode=" Botrule Rrule" align="center">

.2** </td><td styleCode=" Botrule Rrule" align="center"> 205 </td><td styleCode=" Botrule Rrule" align="center"> -6.6** </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> LDL Cholesterol </td><td styleCode=" Botrule Rrule" align="center"> 115 </td><td styleCode=" Botrule Rrule" align="center"> +3.2 </td><td styleCode=" Botrule Rrule" align="center"> 120 </td><td styleCode=" Botrule Rrule" align="center"> +15.4* </td><td styleCode=" Botrule Rrule" align="center"> 122 </td><td styleCode=" Botrule Rrule" align="center"> +14.5 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> VLDL Cholesterol </td><td styleCode=" Botrule Rrule" align="center"> 87 </td><td styleCode=" Botrule Rrule" align="center"> -1.6 </td><td styleCode=" Botrule Rrule" align="center"> 92 </td><td styleCode=" Botrule Rrule" align="center"> -34.4* </td><td styleCode=" Botrule Rrule" align="center"> 83 </td><td styleCode=" Botrule Rrule" align="center"> -30.4* </td></tr></tbody></table>

ter"> 87 </td><td styleCode=" Botrule Rrule" align="center"> -1.6 </td><td styleCode=" Botrule Rrule" align="center"> 92 </td><td styleCode=" Botrule Rrule" align="center"> -34.4* </td><td styleCode=" Botrule Rrule" align="center"> 83 </td><td styleCode=" Botrule Rrule" align="center"> -30.4* </td></tr></tbody></table> <table ID="ID299" width="100%" styleCode="Noautorules"><caption> Table 7. Mean Percent Change in Lipid Parameters at End of Treatment^&#x2020;</caption><col width="39%"/><col width="16%"/><col width="16%"/><col width="14%"/><col width="13%"/><tfoot><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">&#x2020; Duration of study treatment was 3 to 6 months.</paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">* p=&lt;0.05 vs. placebo.</paragraph></td></tr></tfoot><tbody><tr><td styleCode="Lrule Toprule Botrule Rrule" align="left"><content styleCode="bold"> Treatment Group </content> </td><td styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> Total-C </content> </td><td styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> LDL-C </content> </td><td styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> HDL-C </content> </td><td styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> TG </content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Mean baseline lipid values (N=646) </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 306.9 mg/dL </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 213.8 mg/dL </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 52.3 mg/dL </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 191mg/dL </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> All fenofibrate (n=361) </td><td styleCode=" Botrule Rrule" align="left"> -18.7% * </td><td styleCode=" Botrule Rrule" align="left"> -20.6% * </td><td styleCode=" Botrule Rrule" align="left"> +11% * </td><td styleCode=" Botrule Rrule" align="left"> -28.9% * </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Placebo (n=285) </td><td styleCode=" Botrule Rrule" align="left"> -0.4% </td><td styleCode=" Botrule Rrule" align="left"> -2.2% </td><td styleCode=" Botrule Rrule" align="left"> +0.7% </td><td styleCode=" Botrule Rrule" align="left"> +7.7% </td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING Antara capsules are supplied as follows: Strength Description NDC Package Size (capsules per bottle) 30 mg size '4', with opaque light green cap and opaque light green body, imprinted with LUPIN logo and "ANTARA" in black ink on body, and "30" in black ink on cap, containing white to off-white pellets. NDC 27437 - 107 – 06 30 90 mg size '3' with opaque dark green cap and opaque white body, imprinted with LUPIN logo and "ANTARA" in black ink on body, and "90" in black ink on cap, containing white to off-white pellets. NDC 27437 - 108 - 06 30 NDC 27437 - 108 - 09 90 NDC 27437 - 108 - 01 100 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.

<table ID="ID293" width="0" styleCode="Noautorules"><col width="74"/><col width="239"/><col width="161"/><col width="162"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="center"><content styleCode="bold"> Strength</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Description</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> NDC</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Package Size (capsules per bottle)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> 30 mg </td><td valign="top" styleCode=" Botrule Rrule" align="left"> size &apos;4&apos;, with opaque light green cap and opaque light green body, imprinted with LUPIN logo and &quot;ANTARA&quot; in black ink on body, and &quot;30&quot; in black ink on cap, containing white to off-white pellets. </td><td valign="top" styleCode=" Botrule Rrule" align="left"> NDC 27437 - 107 &#x2013; 06 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 30 </td></tr><tr><td rowspan="3" valign="top" styleCode="Lrule Botrule Rrule" align="left"> 90 mg </td><td rowspan="3" valign="top" styleCode=" Botrule Rrule" align="left"> size &apos;3&apos; with opaque dark green cap and opaque white body, imprinted with LUPIN logo and &quot;ANTARA&quot; in black ink on body, and &quot;90&quot; in black ink on cap, containing white to off-white pellets. </td><td valign="top" styleCode=" Botrule Rrule" align="left"> NDC 27437 - 108 - 06 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 30 </td></tr><tr><td valign="top" styleCode=" Botrule Rrule" align="left"> NDC 27437 - 108 - 09 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 90 </td></tr><tr><td valign="top" styleCode=" Botrule Rrule" align="left"> NDC 27437 - 108 - 01 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 100 </td></tr></tbody></table>

17 PATIENT COUNSELING INFORMATION Hepatotoxicity Inform patients that Antara may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 )] . Myopathy and Rhabdomyolysis Advise patients that Antara may cause myopathy and rhabdomyolysis. Inform patients that the risk is also increased when taking certain types of medication and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to inform other healthcare providers prescribing a new medication or increasing the dosage of an existing medication that they are taking Antara. Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever [see Warnings and Precautions ( 5.3 ) and Drug Interactions ( 7 )] . Hypersensitivity Reactions Inform patients that serious hypersensitivity reactions, such as anaphylaxis and angioedema, have been reported with fibrates. Advise patients to report immediately any signs or symptoms suggesting allergic reaction, and to discontinue drug until they have consulted prescribing physicians [see Warnings and Precautions ( 5.9 )] . Pregnancy Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if Antara should be discontinued [see Use in Specific Populations ( 8.1 )] . Lactation Advise patients that breastfeeding during treatment with Antara is not recommended [see Use in Specific Populations ( 8.2 )]. Missed Doses If a dose is missed, advise patients not take an extra dose and to resume treatment with the next dose. Manufactured for: Lupin Pharmaceuticals, Inc Baltimore, Maryland 21202 United States. Manufactured by: Lupin Limited Goa - 403 722 India Or Lupin Limited Pithampur (M.P.) - 454 775 India Or Lupin Limited Nagpur - 441 108 India For medical inquiries, call Lupin Pharmaceuticals, Inc. at 1-800-399-2561. ID: XXXXX

DESCRIPTION Fenofibrate, USP (micronized), is a lipid regulating agent available as capsules for oral administration. Each capsule contains 67 mg, 134 mg or 200 mg of micronized fenofibrate, USP. The chemical name for fenofibrate, USP 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 O 4 Cl and the molecular weight is 360.83; fenofibrate, USP is very soluble in methylene chloride; slightly soluble in alcohol; practically insoluble in water. The melting point is 79° to 82°C. Fenofibrate, USP is a white or almost white crystalline powder which is stable under ordinary conditions. Each 67 mg fenofibrate capsule, USP (micronized) contains the following inactive ingredients: sodium lauryl sulfate, croscarmellose sodium, pregelatinized starch, microcrystalline cellulose, colloidal silicon dioxide, sodium stearyl fumarate, titanium dioxide and gelatin. The capsule shell imprinting ink contains the following inactive ingredients: shellac, black iron oxide and potassium hydroxide. Each 134 mg fenofibrate capsule, USP (micronized) contains the following inactive ingredients: sodium lauryl sulfate, croscarmellose sodium, pregelatinized starch, microcrystalline cellulose, colloidal silicon dioxide, sodium stearyl fumarate, titanium dioxide, FD&C Yellow 6, D&C Yellow 10 and gelatin. The capsule shell imprinting ink contains the following inactive ingredients: shellac, black iron oxide and potassium hydroxide. Each 200 mg fenofibrate capsule, USP (micronized) contains the following inactive ingredients: sodium lauryl sulfate, croscarmellose sodium, pregelatinized starch, microcrystalline cellulose, colloidal silicon dioxide, sodium stearyl fumarate, titanium dioxide, FD&C Yellow 6, D&C Yellow 10 and gelatin. The capsule shell imprinting ink contains the following inactive ingredients: shellac, black iron oxide and potassium hydroxide. structure-fenofibrate

CLINICAL PHARMACOLOGY A variety of clinical studies have demonstrated that elevated levels of total cholesterol (total-C), low density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apo B), an LDL membrane complex, are associated with human atherosclerosis. Similarly, decreased levels of high density lipoprotein cholesterol (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 triglycerides, 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 apoproteins apo AI and apo AII. The 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 apoproteins C-III (an inhibitor of lipoprotein lipase activity). The resulting fall 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. Pharmacokinetics/Metabolism Clinical experience has been obtained with two different formulations of fenofibrate: a “micronized” and “non-micronized” formulation, which have been demonstrated to be bioequivalent. Comparisons of blood levels following oral administration of both formulations in healthy volunteers demonstrate that a single capsule containing 67 mg of the “micronized” formulation is bioequivalent to 100 mg of the “non-micronized” formulation. Three capsules containing 67 mg fenofibrate (micronized) are bioequivalent to a single 200 mg fenofibrate (micronized) capsule. 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.

0% 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 micronized fenofibrate, the absorption is increased by approximately 35% under fed as compared to fasting conditions. Distribution In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within 5 days of dosing with single oral doses equivalent to 67 mg of fenofibrate 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 (e.g., cytochrome P450) to a significant extent. Excretion 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 administration in a clinical setting. 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 the elderly, without increasing accumulation of the drug or metabolites. Pediatrics Fenofibrate has not been investigated in adequate and well-controlled trials in pediatric patients. 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. Therefore, inter-ethnic pharmacokinetic differences are very unlikely. Renal Insufficiency 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) showed 2.7-fold increase in exposure for fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared to that of healthy subjects. Patients with mild to moderate renal impairment (CrCl 30 to 80 mL/min) 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. Hepatic Insufficiency No pharmacokinetic studies have been conducted in patients having hepatic insufficiency. 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 inhibitors of CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.

g-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 CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations. Potentiation of coumarin-type anti-coagulants has been observed with prolongation of the prothrombin time/INR. Bile acid sequestrants have been shown to bind other drugs given concurrently. Therefore, fenofibrate should be taken at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption. (see WARNINGS and PRECAUTIONS). Concomitant administration of a single dose of fenofibrate (administered as 3 x 67 mg fenofibrate capsules) with a single dose of pravastatin (40 mg) in 23 healthy subjects increased the mean C max and mean AUC for pravastatin by 13%. The C max and AUC of fenofibrate decreased by 2% and 1%, respectively, after concomitant administration of fenofibrate and pravastatin. The mean C max and AUC for 3α-hydroxy-iso-pravastatin increased by 29% and 26%, respectively. Concomitant administration of a single dose of fenofibrate (equivalent to 145 mg fenofibrate) and a single dose of fluvastatin (40 mg) resulted in a small increase (approximately 15% to 16%) in exposure to (+)3R,5S-fluvastatin, the active enantiomer of fluvastatin. A single dose of either pravastatin or fluvastatin had no clinically important effect on the pharmacokinetics of fenofibric acid. Concomitant administration of fenofibrate (equivalent to fenofibrate 200 mg) with atorvastatin (20 mg) once daily for 10 days resulted in approximately 17% decrease (range from 67% decrease to 44% increase) in atorvastatin AUC values in 22 healthy males. The atorvastatin C max values were not significantly affected by fenofibrate. The pharmacokinetics of fenofibric acid were not significantly affected by atorvastatin. Concomitant administration of fenofibrate (equivalent to fenofibrate 200 mg) once daily for 10 days with glimepiride (1 mg tablet) single dose simultaneously with the last dose of fenofibrate resulted in a 35% increase in mean AUC of glimepiride in healthy subjects. Glimepiride C max was not significantly affected by fenofibrate coadministration. There was no statistically significant effect of multiple doses of fenofibrate on glucose nadir or AUC with the baseline glucose concentration as the covariate after glimepiride administration in healthy volunteers. However, glucose concentrations at 24 hours remained statistically significantly lower after pretreatment with fenofibrate than with glimepiride alone. Glimepiride had no significant effect on the pharmacokinetics of fenofibric acid. Concomitant administration of fenofibrate (54 mg) and metformin (850 mg) three times a day for 10 days resulted in no significant changes in the pharmacokinetics of fenofibric acid and metformin when compared with the two drugs administered alone in healthy subjects. Concomitant administration of fenofibrate (equivalent to fenofibrate 200 mg) once daily for 14 days with rosiglitazone tablet (rosiglitazone maleate) (8 mg) once daily for 5 days, Day 10 through Day 14, resulted in no significant changes in the pharmacokinetics of fenofibric acid and rosiglitazone when compared with the two drugs administered alone in healthy subjects.

nt to fenofibrate 200 mg) once daily for 14 days with rosiglitazone tablet (rosiglitazone maleate) (8 mg) once daily for 5 days, Day 10 through Day 14, resulted in no significant changes in the pharmacokinetics of fenofibric acid and rosiglitazone when compared with the two drugs administered alone in healthy subjects. Clinical Trials Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb) The effects of fenofibrate at a dose equivalent to 200 mg fenofibrate capsules 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 mg/dL. Fenofibrate capsules therapy lowered LDL-C, total-C, and the LDL-C/HDL-C ratio. Fenofibrate capsules therapy also lowered triglycerides and raised HDL-C (see Table 1). Table 1. Mean Percent Change in Lipid Parameters at End of Treatment a Treatment Group Total-C LCL-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 mg/dL All FEN (n=361) -18.7% b -20.6% b +11% b -28.9% b 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% b -31.4% b +9.8% -23.5% b 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=646) 312.8 mg/dL 219.8 mg/dL 46.7 mg/dL 231.9 mg/dL All FEN (n=126) -16.8% b -20.1% b +14.6% b -35.9% b Placebo (n=116) -3% -6.6% +2.3% +0.9% a Duration of study treatment was 3 to 6 months b p = <0.05 vs. Placebo In a subset of the subjects, measurements of apo B were conducted. Fenofibrate treatment significantly reduced apo B from baseline to endpoint as compared with placebo (-25.1% vs. 2.4%, p<0.0001, n=213 and 143 respectively). Hypertriglyceridemia (Fredrickson Type IV and V) The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials1 of 147 hypertriglyceridemia patients (Fredrickson Type IV and V). Patients were treated for eight weeks under protocols that differed only in that one entered patients with baseline triglyceride (TG) levels of 500 to 1,500 mg/dL, and the other TG levels of 350 to 500 mg/dL. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia (Type IV/V hyperlipidemia), treatment with fenofibrate at dosages equivalent to 200 mg fenofibrate per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol. Treatment of patients with Type IV hyperlipoproteinemia and elevated triglycerides often results in an increase of low density lipoprotein (LDL) cholesterol (see Table 2).

rate at dosages equivalent to 200 mg fenofibrate per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol. Treatment of patients with Type IV hyperlipoproteinemia and elevated triglycerides often results in an increase of low density lipoprotein (LDL) cholesterol (see Table 2). Table 2: Effects of Fenofibrate Capsules in Patients with Fredrickson Type IV/V Hyperlipidemia Study 1 Baseline TG levels 350 to 499 mg/dL Placebo Fenofibrate Capsules 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 12 27 128 137 14.5 VLDL Cholesterol 27 99 99 5.8 27 92 46 -44.7* Study 2 Baseline TG levels 500 to 1500 mg/dL Placebo Fenofibrate Capsules 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 48 30 36 22.9* LDL Cholesterol 42 100 90 -4.2 45 103 131 45* VLDL Cholesterol 42 137 142 11 45 126 54 -49.4* * = p <0.05 vs. Placebo The effect of fenofibrate on cardiovascular morbidity and mortality has not been determined.

INDICATIONS AND USAGE Treatment of Hypercholesterolemia Fenofibrate capsules are indicated as adjunctive therapy to diet for the reduction of LDL-C, Total-C, Triglycerides and Apo B in adult patients with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson Types IIa and IIb). Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate (see National Cholesterol Education Program [NCEP] Treatment Guidelines, below). Treatment of Hypertriglyceridemia Fenofibrate capsules are also indicated as adjunctive therapy to diet for treatment of adult patients with hypertriglyceridemia (Fredrickson Types IV and V hyperlipidemia). 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. Drug therapy is not indicated for patients with Type I hyperlipoproteinemia, who have elevations of chylomicrons and plasma triglycerides, but who have normal levels of very low density lipoprotein (VLDL). Inspection of plasma refrigerated for 14 hours is helpful in distinguishing Types I, IV and V hyperlipoproteinemia 2 . 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, like thiazide diuretics and beta-blockers, is 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. The use of drugs should be considered only when reasonable attempts have been made to obtain satisfactory results with non-drug methods. If the decision is made to use drugs, the patient should be instructed that this does not reduce the importance of adhering to diet (See WARNINGS and PRECAUTIONS ). Fredrickson Classification of Hyperlipoproteinemias Type Lipoprotein Elevated Lipid Elevation Major Minor C = cholesterol TG = triglycerides LDL = low density lipoprotein VLDL = very low density lipoprotein IDL = intermediate density lipoprotein I (rare) Chylomicrons TG ↑↔C IIa LDL C — IIb LDL, VLDL C TG III (rare) IDL C, TG — IV VLDL TG ↑↔C V (rare) Chylomicrons, VLDL TG ↑↔ The NCEP Treatment Guidelines Definite Athlerosclerotic Disease* Two or More Other Risk Factors† LDL-Cholesterol mg/dL (mmol/L) Initiation Level Goal No No ≥ 190 (≥ 4.9) < 160 (< 4.1) No Yes ≥ 160 (≥ 4.1) < 130 (< 3.4) Yes Yes or No ≥ 130‡ (≥ 3.4) < 100 (< 2.6)

<table width="90%"><caption>Fredrickson Classification of Hyperlipoproteinemias</caption><col width="15%" align="center" valign="bottom"/><col width="35%" align="center" valign="bottom"/><col width="25%" align="center" valign="bottom"/><col width="25%" align="center" valign="bottom"/><thead><tr><th rowspan="2" align="center">Type</th><th rowspan="2" align="center">Lipoprotein Elevated</th><th colspan="2" align="center">Lipid Elevation</th></tr><tr><th align="center">Major</th><th align="center">Minor</th></tr></thead><tfoot><tr styleCode="First Last"><td colspan="4" align="left" valign="top">C = cholesterol TG = triglycerides LDL = low density lipoprotein VLDL = very low density lipoprotein IDL = intermediate density lipoprotein </td></tr></tfoot><tbody><tr><td align="center">I (rare)</td><td align="center">Chylomicrons</td><td align="center">TG</td><td align="center">&#x2191;&#x2194;C</td></tr><tr><td align="center">IIa</td><td align="center">LDL</td><td align="center">C</td><td align="center">&#x2014;</td></tr><tr><td align="center">IIb</td><td align="center">LDL, VLDL</td><td align="center">C</td><td align="center">TG</td></tr><tr><td align="center">III (rare)</td><td align="center">IDL</td><td align="center">C, TG</td><td align="center">&#x2014;</td></tr><tr><td align="center">IV</td><td align="center">VLDL</td><td align="center">TG</td><td align="center">&#x2191;&#x2194;C</td></tr><tr><td align="center">V (rare)</td><td align="center">Chylomicrons, VLDL</td><td align="center">TG</td><td align="center">&#x2191;&#x2194;</td></tr></tbody></table>

enter">&#x2014;</td></tr><tr><td align="center">IV</td><td align="center">VLDL</td><td align="center">TG</td><td align="center">&#x2191;&#x2194;C</td></tr><tr><td align="center">V (rare)</td><td align="center">Chylomicrons, VLDL</td><td align="center">TG</td><td align="center">&#x2191;&#x2194;</td></tr></tbody></table> <table width="90%"><caption>The NCEP Treatment Guidelines</caption><col width="25%" align="center" valign="bottom"/><col width="25%" align="center" valign="bottom"/><col width="25%" align="center" valign="bottom"/><col width="25%" align="center" valign="bottom"/><thead><tr><th rowspan="2" align="center" styleCode="Lrule">Definite Athlerosclerotic Disease*</th><th rowspan="2" align="center">Two or More Other Risk Factors&#x2020;</th><th colspan="2" align="center" styleCode="Rrule">LDL-Cholesterol mg/dL (mmol/L)</th></tr><tr><th align="center">Initiation Level</th><th align="center" styleCode="Rrule">Goal</th></tr></thead><tbody><tr><td align="center" styleCode="Lrule">No</td><td align="center">No</td><td align="center">&#x2265; 190 (&#x2265; 4.9)</td><td align="center" styleCode="Rrule">&lt; 160 (&lt; 4.1)</td></tr><tr><td align="center" styleCode="Lrule">No</td><td align="center">Yes</td><td align="center">&#x2265; 160 (&#x2265; 4.1)</td><td align="center" styleCode="Rrule">&lt; 130 (&lt; 3.4)</td></tr><tr><td align="center" styleCode="Lrule">Yes</td><td align="center">Yes or No</td><td align="center">&#x2265; 130&#x2021; (&#x2265; 3.4)</td><td align="center" styleCode="Rrule">&lt; 100 (&lt; 2.6)</td></tr></tbody></table>

CONTRAINDICATIONS Fenofibrate capsules are contraindicated in patients who exhibit hypersensitivity to fenofibrate. Fenofibrate capsules are contraindicated in patients with hepatic or severe renal dysfunction, including primary biliary cirrhosis, and patients with unexplained persistent liver function abnormality. Fenofibrate capsules are contraindicated in patients with preexisting gallbladder disease (see WARNINGS).

WARNINGS Hepatotoxicity: Serious drug-induced liver injury (DILI), including liver transplantation and death, have been reported postmarketing with fenofibrate. DILI has been reported within the first few weeks of treatment or after several months of therapy and in some cases has reversed with discontinuation of fenofibrate treatment. Patients with DILI have experienced signs and symptoms including dark urine, abnormal stool, jaundice, malaise, abdominal pain, myalgia, weight loss, pruritus, and nausea. Many patients had concurrent elevations of total bilirubin, serum alanine transaminase (ALT), and aspartate transaminase (AST). DILI has been characterized as hepatocellular, chronic active, and cholestatic hepatitis, and cirrhosis has occurred in association with chronic active hepatitis. In clinical trials, fenofibrate at doses equivalent to 134 mg to 200 mg fenofibrate daily has been associated with increases in serum AST orALT. The incidence of increases in transaminases may be dose-related. Fenofibrate is contraindicated in patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities [see Contraindications (4)] . Monitor patient’s liver function, including serum ALT, AST, and total bilirubin, at baseline and periodically for the duration of therapy with fenofibrate. Discontinue fenofibrate if signs or symptoms of liver injury develop or if elevated enzyme levels persist (ALT or AST > 3 times the upper limit of normal, or if accompanied by elevation of bilirubin). Do not restart fenofibrate in these patients if there is no alternative explanation for the liver injury. Cholelithiasis: Fenofibrate, like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Fenofibrate therapy should be discontinued if gallstones are found. Concomitant Oral Anticoagulants: Caution should be exercised when anticoagulants are given in conjunction with fenofibrate because of the potentiation of coumarin-type anticoagulants in prolonging the prothrombin time/INR. The dosage of the anticoagulant should be reduced to maintain the prothrombin time/lNR at the desired level to prevent bleeding complications. Frequent prothrombin time/INR determinations are advisable until it has been definitely determined that the prothrombin time/INR has stabilized. Concomitant HMG-CoA Reductase Inhibitors: The combined use of fenofibrate and HMG-CoA reductase inhibitors should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination. Concomitant administration of fenofibrate (equivalent to fenofibrate 200 mg) and pravastatin (40 mg) once daily for 10 days increased the mean C max and AUC values for pravastatin by 36% (range from 69% decrease to 321% increase) and 28% (range from 54% decrease to 128% increase), respectively, and for 3α-hydroxy-iso-pravastatin by 55% (range from 32% decrease to 314% increase) and 39% (range from 24% decrease to 261% increase), respectively.

creased the mean C max and AUC values for pravastatin by 36% (range from 69% decrease to 321% increase) and 28% (range from 54% decrease to 128% increase), respectively, and for 3α-hydroxy-iso-pravastatin by 55% (range from 32% decrease to 314% increase) and 39% (range from 24% decrease to 261% increase), respectively. (See also CLINICAL PHARMACOLOGY , Drug-drug interactions .) The combined use of fibric acid derivatives and HMG-CoA reductase inhibitors has been associated, in the absences of a marked pharmacokinetic interaction, in numerous case reports, with rhabdomyolysis, markedly elevated creatine kinase (CK) levels and myoglobinuria, leading in a high proportion of cases to acute renal failure. The use of fibrates alone, including fenofibrate capsules may occasionally be associated with myositis, myopathy, or rhabdomyolysis. Patients receiving fenofibrate and complaining of muscle pain, tenderness, or weakness should have prompt medical evaluation for myopathy, including serum creatine kinase level determination. If myopathy/myositis is suspected or diagnosed, fenofibrate therapy should be stopped. Mortality: The effect of fenofibrate on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established. Other Considerations: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a 5-year randomized, placebo-controlled study of 9,795 patients with type 2 diabetes mellitus treated with fenofibrate. Fenofibrate demonstrated a non-significant 11% relative reduction in the primary outcome of coronary heart disease events (hazard ratio [HR] 0.89, 95% CI 0.75 to 1.05, p=0.16) and a significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.8 to 0.99], p=0.04). There was a non-significant 11% (HR 1.11 [0.95, 1.29], p=0.18) and 19% (HR 1.19 [0.9, 1.57], p=0.22) increase in total and coronary heart disease mortality, respectively, with fenofibrate as compared to placebo. In the Coronary Drug Project, a large study of post myocardial infarction of patients treated for 5 years with clofibrate, there was no difference in mortality seen between the clofibrate group and the placebo group. There was however, a difference in the rate of cholelithiasis and cholecystitis requiring surgery between the two groups (3% vs. 1.8%). Because of chemical, pharmacological, and clinical similarities between fenofibrate micronized. Atromid-S (clofibrate), and Lopid (gemfibrozil), the adverse findings in 4 large randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to fenofibrate. In a study conducted by the World Health Organization (WHO), 5,000 subjects without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional one year. There was a statistically significant, higher age-adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.7% vs. 3.96%, p=<0.01). Excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis. This appeared to confirm the higher risk of gallbladder disease seen in clofibrate-treated patients studied in the Coronary Drug Project. The Helsinki Heart Study was a large (n=4,081) study of middle-aged men without a history of coronary artery disease. Subjects received either placebo or gemfibrozil for 5 years, with a 3.5-year open extension afterward. Total mortality was numerically higher in the gemfibrozil randomization group but did not achieve statistical significance (p=0.19, 95% confidence interval for relative risk G:P=0.91 to 1.64).

coronary artery disease. Subjects received either placebo or gemfibrozil for 5 years, with a 3.5-year open extension afterward. Total mortality was numerically higher in the gemfibrozil randomization group but did not achieve statistical significance (p=0.19, 95% confidence interval for relative risk G:P=0.91 to 1.64). Although cancer deaths trended higher in the gemfibrozil group (p=0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups. Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the 9 year follow-up data from World Health Organization study (RR=1.29). Similarly, the numerical excess of gallbladder surgeries in the gemfibrozil group did not differ statistically from that observed in the WHO study. A secondary prevention component of the Helsinki Heart Study enrolled middle-aged men excluded from the primary prevention study because of known or suspected coronary heart disease. Subjects received gemfibrozil or placebo for 5 years. Although cardiac deaths trended higher in the gemfibrozil group, this was not statistically significant (hazard ratio 2.2, 95% confidence interval: 0.94 to 5.05). The rate of gallbladder surgery was not statistically significant between study groups, but did trend higher in the gemfibrozil group, (1.9% vs. 0.3%, p=0.07). There was a statistically significant difference in the number of appendectomies in the gemfibrozil group (6/311 vs. 0/317, p=0.029).

PRECAUTIONS Initial Therapy: Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal before instituting fenofibrate therapy. Every attempt should be made to control serum lipids with appropriate diet, exercise, weight loss in obese patients, and control of any medical problems such as diabetes mellitus and hypothyroidism that are contributing to the lipid abnormalities. Medications known to exacerbate hypertriglyceridemia (beta-blockers, thiazides, estrogens) should be discontinued or changed if possible prior to consideration of triglyceride-lowering drug therapy. Continued Therapy: Periodic determination of serum lipids should be obtained during initial therapy in order to establish the lowest effective dose of fenofibrate capsules. Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 200 mg per day. Pancreatitis: Pancreatitis has been reported in patients taking fenofibrate, gemfibrozil, and clofibrate. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct. Hypersensitivity Reactions: Acute Hypersensitivity: Anaphylaxis and angioedema have been reported postmarketing with fenofibrate. In some cases, reactions were life-threatening and required emergency treatment. If a patient develops signs or symptoms of an acute hypersensitivity reaction, advise them to seek immediate medical attention and discontinue fenofibrate. Delayed Hypersensitivity: Severe cutaneous adverse drug reactions (SCAR), including Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported postmarketing, occurring days to weeks after initiation of fenofibrate. The cases of DRESS were associated with cutaneous reactions (such as rash or exfoliative dermatitis) and a combination of eosinophilia, fever, systemic organ involvement (renal, hepatic, or respiratory). Discontinue fenofibrate and treat patients appropriately if SCAR is suspected. Hematologic Changes: Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of fenofibrate therapy. However, these levels stabilize during long-term administration. Extremely rare spontaneous reports of thrombocytopenia and agranulocytosis have been received during post-marketing surveillance outside of the U.S. Periodic blood counts are recommended during the first 12 months of fenofibrate administration. Myopathy and Rhabdomyolysis: The use of fibrates alone, including fenofibrate, may occasionally be associated with myopathy. Treatment with drugs of the fibrate class has been associated on rare occasions with rhabdomyolysis, usually in patients with impaired renal function. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevations of creatine phosphokinase levels. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. CPK levels should be assessed in patients reporting these symptoms and fenofibrate therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed.

atients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. CPK levels should be assessed in patients reporting these symptoms and fenofibrate therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed. Venothromboembolic Disease: In the FIELD trial, pulmonary embolus (PE) and deep vein thrombosis (DVT) were observed at higher rates in the fenofibrate- than the placebo-treated group. Of 9,795 patients enrolled in FIELD, there were 4,900 in the placebo group and 4,895 in the fenofibrate group. For DVT, there were 48 events (1%) in the placebo group and 67 (1%) in the fenofibrate group (p = 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1%) in the fenofibrate group (p = 0.022). In the Coronary Drug Project, a higher proportion of the clofibrate group experienced definite or suspected fatal or nonfatal pulmonary embolism or thrombophlebitis than the placebo group (5.2% vs. 3.3% at 5 years; p < 0.01). Serum Creatinine: Elevations in serum creatinine have been reported in patients on fenofibrate. These elevations tend to return to baseline following discontinuation of fenofibrate. The clinical significance of these observations is unknown. Drug Interactions Oral Anticoagulants: CAUTION SHOULD BE EXERCISED WHEN COUMARIN ANTICOAGULANTS ARE GIVEN IN CONJUNCTION WITH FENOFIBRATE CAPSULES. THE DOSAGE OF THE ANTICOAGULANTS SHOULD BE REDUCED TO MAINTAIN THE PROTHROMBIN TIME/INR AT THE DESIRED LEVEL TO PREVENT BLEEDING COMPLICATIONS. FREQUENT PROTHROMBIN TIME/INR DETERMINATIONS ARE ADVISABLE UNTIL IT HAS BEEN DEFINITELY DETERMINED THAT THE PROTHROMBIN TIME/INR HAS STABILIZED. HMG-CoA Reductase Inhibitors: The combined use of fenofibrate and HMG-CoA reductase inhibitors should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination (see WARNINGS). Resins: Since bile acid sequestrants may bind other drugs given concurrently, patients should take fenofibrate capsules at least one hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption. Cyclosporine: Because cyclosporine 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. The benefits and risks of using fenofibrate with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed. Carcinogenesis, Mutagenesis, Impairment of Fertility: Two dietary carcinogenicity studies have been conducted in rats with fenofibrate. In the first 24-month study, 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, 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.

D in males. In a second 24-month rat carcinogenicity study in a different strain of rats, 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 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. Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and unscheduled DNA synthesis in primary rat hepatocytes. In fertility studies rats were given oral dietary doses of fenofibrate, males received 61 days prior to mating and females 15 days prior to mating through weaning which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (~ 10 times the MRHD, based on mg/m 2 surface area comparisons). Teratogenic Effects: 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 MRHD, based on body surface area comparisons: mg/m 2 .

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 . Nursing Mothers: It is not known whether fenofibrate is excreted into milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from fenofibrate, a decision should be made whether to discontinue nursing or administration of fenofibrate taking into account the importance of the drug to the lactating woman. Pediatric Use: Safety and efficacy in pediatric patients have not been established. 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. However, elderly patients have a higher incidence of renal impairment, such that dose selection for the elderly should be made on the basis of renal function (see CLINICAL PHARMACOLOGY , Special Populations, Renal Insufficiency ). Elderly patients with normal renal function should require no dose modifications.

Drug Interactions Oral Anticoagulants: CAUTION SHOULD BE EXERCISED WHEN COUMARIN ANTICOAGULANTS ARE GIVEN IN CONJUNCTION WITH FENOFIBRATE CAPSULES. THE DOSAGE OF THE ANTICOAGULANTS SHOULD BE REDUCED TO MAINTAIN THE PROTHROMBIN TIME/INR AT THE DESIRED LEVEL TO PREVENT BLEEDING COMPLICATIONS. FREQUENT PROTHROMBIN TIME/INR DETERMINATIONS ARE ADVISABLE UNTIL IT HAS BEEN DEFINITELY DETERMINED THAT THE PROTHROMBIN TIME/INR HAS STABILIZED. HMG-CoA Reductase Inhibitors: The combined use of fenofibrate and HMG-CoA reductase inhibitors should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination (see WARNINGS). Resins: Since bile acid sequestrants may bind other drugs given concurrently, patients should take fenofibrate capsules at least one hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption. Cyclosporine: Because cyclosporine 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. The benefits and risks of using fenofibrate with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Two dietary carcinogenicity studies have been conducted in rats with fenofibrate. In the first 24-month study, 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, 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 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. Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and unscheduled DNA synthesis in primary rat hepatocytes. In fertility studies rats were given oral dietary doses of fenofibrate, males received 61 days prior to mating and females 15 days prior to mating through weaning which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (~ 10 times the MRHD, based on mg/m 2 surface area comparisons).

Teratogenic Effects: 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 MRHD, based on body surface area comparisons: mg/m 2 .

Nursing Mothers: It is not known whether fenofibrate is excreted into milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from fenofibrate, a decision should be made whether to discontinue nursing or administration of fenofibrate taking into account the importance of the drug to the lactating woman.

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. However, elderly patients have a higher incidence of renal impairment, such that dose selection for the elderly should be made on the basis of renal function (see CLINICAL PHARMACOLOGY , Special Populations, Renal Insufficiency ). Elderly patients with normal renal function should require no dose modifications.

ADVERSE REACTIONS Clinical Studies 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 3 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. Photosensitivity reactions have occurred days to months after initiation; in some of these cases, patients reported a prior photosensitivity reaction to ketoprofen. Table 3. Adverse Reactions Reported by 2% or More of Patients Treated withFenofibrate and Greater than Placebo During the Double-Blind, Placebo-Controlled Trials BODY SYSTEM Adverse Reaction 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%† 1.4% Nausea 2.3% 1.9% Constipation 2.1% 1.4% METABOLIC AND NUTRITIONAL DISORDERS Increased ALT 3% 1.6% Increased CPK 3% 1.4% Increased AST 3.4%† 0.5% RESPIRATORY Respiratory Disorder 6.2% 5.5% Rhinitis 2.3% 1.1% * Dosage equivalent to 145 mg fenofibrate. † Significantly different from Placebo. Increases in Liver Enzymes: In a pooled analysis of 10 placebo-controlled trials, increases to >3 times the upper limit of normal in ALT occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated with placebo. In an 8-week study, the incidence of ALT or AST elevations ≥ 3 times the upper limit of normal was 13% in patients receiving dosages equivalent to 134 mg to 200 mg fenofibrate daily and was 0% in those receiving dosages equivalent to 34 mg to 67 mg fenofibrate daily or placebo. Post-Marketing Experience: The following adverse reactions have been identified during post-approval use of fenofibrate: myalgia, rhabdomyolysis, pancreatitis, acute renal failure, muscle spasm, hepatitis, cirrhosis, increased total bilirubin, anemia, arthralgia, decreases in hemoglobin, decreases in hematocrit, white blood cell decreases, asthenia and interstitial lung disease. 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. To report SUSPECTED ADVERSE REACTIONS, contact AustarPharma, LLC at 1-844-375-5410 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

<table width="80%"><col width="40%" align="left" valign="top"/><col width="30%" align="center" valign="top"/><col width="30%" align="center" valign="top"/><thead><tr styleCode="First Last"><th align="left">BODY SYSTEM Adverse Reaction </th><th align="center">Fenofibrate* (N=439) </th><th align="center">PLACEBO (N=365) </th></tr></thead><tbody><tr><td colspan="3" align="left"><content styleCode="bold">BODY AS A WHOLE</content></td></tr><tr><td align="left"> Abdominal Pain</td><td align="center">4.6%</td><td align="center">4.4%</td></tr><tr><td align="left"> Back Pain</td><td align="center">3.4%</td><td align="center">2.5%</td></tr><tr><td align="left"> Headache</td><td align="center">3.2%</td><td align="center">2.7%</td></tr><tr><td colspan="3" align="left"><content styleCode="bold">DIGESTIVE</content></td></tr><tr><td align="left"> Abnormal Liver Function Tests</td><td align="center">7.5%&#x2020;</td><td align="center">1.4%</td></tr><tr><td align="left"> Nausea</td><td align="center">2.3%</td><td align="center">1.9%</td></tr><tr><td align="left"> Constipation</td><td align="center">2.1%</td><td align="center">1.4%</td></tr><tr><td colspan="3" align="left"><content styleCode="bold">METABOLIC AND NUTRITIONAL DISORDERS</content></td></tr><tr><td align="left"> Increased ALT</td><td align="center">3%</td><td align="center">1.6%</td></tr><tr><td align="left"> Increased CPK</td><td align="center">3%</td><td align="center">1.4%</td></tr><tr><td align="left"> Increased AST</td><td align="center">3.4%&#x2020;</td><td align="center">0.5%</td></tr><tr><td colspan="3" align="left"><content styleCode="bold">RESPIRATORY</content></td></tr><tr><td align="left"> Respiratory Disorder</td><td align="center">6.2%</td><td align="center">5.5%</td></tr><tr><td align="left"> Rhinitis</td><td align="center">2.3%</td><td align="center">1.1%</td></tr></tbody></table>

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.

DOSAGE AND ADMINISTRATION Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibrate capsules, and should continue this diet during treatment with fenofibrate capsules. Fenofibrate capsules should be given with meals, thereby optimizing the bioavailability of the medication. For the treatment of adult patients with primary hypercholesterolemia or mixed hyperlipidemia, the initial dose of fenofibrate capsules is 200 mg per day. For adult patients with hypertriglyceridemia, the initial dose is 67 mg to 200 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 200 mg per day. Treatment with fenofibrate capsules, should be initiated at a dose of 67 mg/day in patients having impaired renal function, and increased only after evaluation of the effects on renal function and lipid levels at this dose. In the elderly, the initial dose should likewise be limited to 67 mg/day. Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of fenofibrate capsules if lipid levels fall significantly below the targeted range.

HOW SUPPLIED Fenofibrate capsules, USP (micronized) 67 mg are opaque white cap and body, hard gelatin capsules, printed in black ink “CL” and “22” on opposing cap and body portions of the capsule. They are supplied as follows: NDC 35561-345-11 Bottles of 90 capsules NDC 35561-345-12 Bottles of 100 capsules NDC 35561-345-13 Bottles of 500 capsules Fenofibrate capsules, USP (micronized) 134 mg are opaque white cap and opaque yellow body, hard gelatin capsules, printed in black ink “CL” and “23” on opposing cap and body portions of the capsule. They are supplied as follows: NDC 35561-346-11 Bottles of 90 capsules NDC 35561-346-12 Bottles of 100 capsules NDC 35561-346-13 Bottles of 500 capsules Fenofibrate capsules, USP (micronized) 200 mg are opaque yellow cap and body, hard gelatin capsules, printed in black ink “CL” and “24” on opposing cap and body portions of the capsule. They are supplied as follows: NDC 35561-347-11 Bottles of 90 capsules NDC 35561-347-12 Bottles of 100 capsules NDC 35561-347-13 Bottles of 500 capsules Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep out of the reach of children. Protect from moisture.

REFERENCES GOLDBERG AC, et al. Fenofibrate for the Treatment of Type IV and V Hyperlipoproteinemias: A Double-Blind, Placebo-Controlled Multicenter US Study. Clinical Therapeutic s, 11, pp. 69-83, 1989. NIKKILA EA. Familial Lipoprotein Lipase Deficiency and Related Disorders of Chylomicron Metabolism. In Stanbury J.B., et al. (eds.): The Metabolic Basis of Inherited Disease , 5th edition, McGraw-Hill, 1983, Chap. 30, pp. 622-642. BROWN WV, et al. Effects of Fenofibrate on Plasma Lipids: Double-Blind, Multicenter Study In Patients with Type IIA or IIB Hyperlipidemia. Arteriosclerosis . 6, pp. 670-678, 1986.