FENOFIBRATE

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

2 DOSAGE AND ADMINISTRATION Primary hypercholesterolemia or mixed dyslipidemia: 120 mg per day. ( 2.2 ) Severe hypertriglyceridemia: 40 to 120 mg per day; the dose should be adjusted according to patient response. ( 2.3 ) Renally impaired patients: Initial dose of 40 mg per day; the dose should be increased according to the effect on renal function and lipid levels. ( 2.4 ) Geriatric patients: Select dose on the basis of renal function. ( 2.5 ) To increase absorption of fenofibrate tablets, take with food. ( 2.1 ) 2.1 General Considerations Fenofibrate tablets should be given with food to optimize the absorption of the medicine. Patients should be advised to swallow fenofibrate tablets whole. Do not crush, dissolve or chew tablets. The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality. Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be an important ancillary measure. Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus should be looked for and adequately treated. Estrogen therapy, thiazide diuretics and beta-blockers, are sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia. Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of fenofibrate tablets if lipid levels fall significantly below the targeted range. Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 120 mg once daily. 2.2 Primary Hypercholesterolemia or Mixed Dyslipidemia The initial dose of fenofibrate tablets is 120 mg per day. 2.3 Severe Hypertriglyceridemia The initial dose is 40 to 120 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 120 mg per day. 2.4 Impaired Renal Function Treatment with fenofibrate tablets should be initiated at a dose of 40 mg per day in patients with mild to moderately impaired renal function, and increased only after evaluation of the effects on renal function and lipid levels at this dose. The use of fenofibrate tablets should be avoided in patients with severe renal impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . 2.5 Geriatric Patients Dose selection for the elderly should be made on the basis of renal function [see Use in Specific Populations (8.5) ] .

5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Serious drug-induced liver injury, including liver transplantation and death, has been reported with fenofibrate tablets. 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 (with a significantly higher rate observed for gemfibrozil), particularly in elderly patients and patients with diabetes, renal failure, or hypothyroidism. ( 5.3 ) Serum Creatinine: Fenofibrate can reversibly increase serum creatinine levels. ( 5.4 ) Monitor renal function periodically in patients with renal impairment. ( 8.6 ) Cholelithiasis: Fenofibrate increases cholesterol excretion into the bile, leading to risk of cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. ( 5.5 ) Coumarin Anticoagulants: Exercise caution in concomitant treatment with coumarin anticoagulants. Adjust the dosage of coumarin to maintain the prothrombin time/INR at the desired level to prevent bleeding complications. ( 5.6 ) 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 The effect of fenofibrate tablets on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established. The Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) trial was a randomized placebo-controlled study of 5,518 patients with type 2 diabetes mellitus on background statin therapy treated with fenofibrate. The mean duration of follow-up was 4.7 years. Fenofibrate plus statin combination therapy showed a non-significant 8% relative risk reduction in the primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular disease death (hazard ratio [HR] 0.92, 95% CI 0.79-1.08) (p = 0.32) as compared to statin monotherapy. In a gender subgroup analysis, the hazard ratio for MACE in men receiving combination therapy versus statin monotherapy was 0.82 (95% CI 0.69-0.99), and the hazard ratio for MACE in women receiving combination therapy versus statin monotherapy was 1.38 (95% CI 0.98-1.94) (interaction p = 0.01). The clinical significance of this subgroup finding is unclear. 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 0.75-1.05, p = 0.16) and a significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.80-0.99], p = 0.04). There was a non-significant 11% (HR 1.11 [0.95, 1.29], p = 0.18) and 19% (HR 1.19 [0.90, 1.57], p = 0.22) increase in total and coronary heart disease mortality, respectively, with fenofibrate as compared to placebo. Because of chemical, pharmacological, and clinical similarities between fenofibrate, clofibrate, and gemfibrozil, the adverse findings in 4 large, randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to fenofibrate tablets. 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…

4 CONTRAINDICATIONS Fenofibrate tablets are contraindicated in: patients with severe renal dysfunction, including those receiving dialysis [see Clinical Pharmacology (12.3) ] . patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities [see Warnings and Precautions (5.2) ] . patients with pre-existing gallbladder disease [see Warnings and Precautions (5.5) ] . patients with a known hypersensitivity to fenofibrate [see Warnings and Precautions (5.9) ] . nursing mothers [see Use in Specific Populations (8.2) ] . Severe renal dysfunction, including patients receiving dialysis ( 4 , 8.6 , 12.3 ) Active liver disease ( 4 , 5.3 ) Gallbladder disease ( 4 , 5.5 ) Nursing mothers ( 4 , 8.2 ) Known hypersensitivity to fenofibrate ( 4 )

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

8.1 Pregnancy Risk Summary Limited available data with fenofibrate use in pregnant women are insufficient to determine a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no evidence of embryo-fetal toxicity was observed with oral administration of fenofibrate in rats and rabbits during organogenesis at doses less than or equivalent to the maximum recommended clinical dose of 120 mg daily, based on body surface area (mg/m 2 ). Adverse reproductive outcomes occurred at higher doses in the presence of maternal toxicity [see Data] . Fenofibrate tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In pregnant rats given oral dietary doses of 14, 127, and 361 mg/kg/day from gestation day 6-15 during the period of organogenesis, no adverse developmental findings were observed at 14 mg/kg/day (less than the clinical exposure at the maximum recommended human dose [MRHD] of 300 mg fenofibrate daily, equivalent to 120 mg fenofibrates tablets daily, based on body surface area comparisons). Increased fetal skeletal malformations were observed at maternally toxic doses (361 mg/kg/day, corresponding to 12 times the clinical exposure at the MRHD) that significantly suppressed maternal body weight gain. In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 6-18 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, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), no adverse developmental effects were observed at 15 mg/kg/day (less than the clinical exposure at the MRHD, based on body surface area comparisons), despite maternal toxicity (decreased weight gain). Post-implantation loss was observed at ≥ 75 mg/kg/day (≥ 2 times the clinical exposure at the MRHD) in the presence of maternal toxicity (decreased weight gain). Decreased pup survival was noted at 300 mg/kg/day (10 times the clinical exposure at the MRHD), which was associated with decreased maternal body weight gain/maternal neglect.

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) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Pancreatitis [see Warnings and Precautions (5.7) ] Hypersensitivity Reactions [see Warnings and Precautions (5.9) ] Venothromboembolic Disease [see Warnings and Precautions (5.10) ] The most common adverse reactions (> 2% and at least 1% greater than placebo) are abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Creekwood Pharmaceuticals LLC. at 1-732-344-0220 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect rates observed in clinical practice. Adverse reactions 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 5.0% of patients treated with fenofibrate and in 3.0% treated with placebo. Increases in liver function tests were the most frequent events, causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials. Table 1. Adverse Reactions Reported by 2% or More of Patients Treated with Fenofibrate and Greater than Placebo During the Double-Blind, Placebo-Controlled Trials * Dosage equivalent to 130 mg fenofibrate 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 Nausea 2.3% 1.9% Constipation 2.1% 1.4% METABOLIC AND NUTRITIONAL DISORDERS Abnormal Liver Tests 7.5% 1.4% Increased AST 3.4% 0.5% Increased ALT 3.0% 1.6% Increased Creatine Phosphokinase 3.0% 1.4% RESPIRATORY Respiratory Disorder 6.2% 5.5% Rhinitis 2.3% 1.1% Urticaria was seen in 1.1 vs. 0% and rash in 1.4 vs. 0.8% of fenofibrate and placebo patients respectively in controlled trials. 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 equivalent to 87 mg to 130 mg fenofibrate daily (at the highest dose, comparable to fenofibrate tablets, 120 mg) 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 87 mg to 130 mg fenofibrate daily and was 0% in those receiving dosages equivalent to 43 mg or less fenofibrate 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: myalgia, rhabdomyolysis, pancreatitis, acute renal failure, muscle spasms, hepatitis, cirrhosis, increased total bilirubin, anemia, arthralgia, decreases in hematocrit, white blood cell decreases, asthenia, severely depressed HDL cholesterol levels, and interstitial lung disease. Photosensitivity reactions have occurred days to months after initiation; in some of these cases, patients reported a prior photosensitivity reaction to ketoprofen.