Fenofibrate

1 INDICATIONS AND USAGE Fenofibrate tablets are 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. Fenofibrate Tablets, USP are a peroxisome proliferator-activated 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 TG (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 ). Limitations of Use Markedly elevated levels of serum TG (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) ] .

2 DOSAGE AND ADMINISTRATION Severe hypertriglyceridemia : 54 to 160 mg orally once daily; the dosage should be adjusted according to patient response ( 2.2 ). Primary hyperlipidemia :160 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 fenofibrate tablets. Discontinue fenofibrate tablets in patients who do not have an adequate response after 2 months of treatment ( 2.2 ). Renal impairment : Initial dosage of 54 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 Fenofibrate Tablets Assess lipid levels before initiating therapy. Identify other causes (e.g., diabetes mellitus, hypothyroidism, or medications) of high TG levels and manage as appropriate. Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibrate tablets, and should continue this diet during treatment with fenofibrate tablets. In patients with diabetes and fasting chylomicronemia, improve glycemic control prior to considering starting fenofibrate tablets. 2.2 Recommended Dosage and Administration Severe hypertriglyceridemia: The recommended dosage of fenofibrate tablets is 54 mg or 160 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 fenofibrate tablets is 160 mg orally once daily. Administer fenofibrate tablets as a single dose at any time of day, with or without food. Advise patients to swallow fenofibrate tablets whole. Do not crush, break, dissolve, or chew tablets. Assess TG when clinically appropriate, as early as 4 to 8 weeks after initiating fenofibrate tablets. Discontinue fenofibrate tablets in patients who do not have an adequate response after 2 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 fenofibrate tablets 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 fenofibrate tablets and periodically thereafter [see Warnings and Precautions (5.4) ] . Treatment with fenofibrate tablets should be initiated at a dosage of 54 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 dosage. Fenofibrate tablets are 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 Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . 2.4 Recommended Dosage in Geriatric Patients Dosage selection for geriatric patients should be made on the basis of renal function [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] .

5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Serious drug-induced liver injury, including liver transplantation and death, has been reported with fenofibrates, including 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 fenofibrates. Risks are increased during co-administration with a statin, in geriatric patients, and in patients with renal impairment or hypothyroidism. Discontinue fenofibrate tablets if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Temporarily discontinue fenofibrate tablets 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 fenofibrate tablets dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever ( 5.3 ). Increases in Serum Creatinine : Monitor renal function in patients with renal impairment taking fenofibrate tablets. Consider monitoring renal function in patients at risk for renal impairment ( 5.4 ). Cholelithiasis : Fenofibrate may increase cholesterol excretion into the bile, leading to 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 tablets and treat 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 fenofibrates, including fenofibrate tablets; pemafibrate; clofibrate; and gemfibrozil; the findings in 5 large randomized, placebo-controlled clinical trials with these other fibrate drugs may also apply to fenofibrate tablets. 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 1 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…

4 CONTRAINDICATIONS Fenofibrate tablets are contraindicated in patients with: 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 fenofibrate, fenofibric acid, or any of the excipients in fenofibrate tablets. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with fenofibrate [see Warnings and Precautions (5.9) ] . 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 fenofibrate tablets ( 4 ).

7 DRUG INTERACTIONS Table 2 presents clinically important drug interactions with fenofibrate tablets. Table 2. Clinically Important Drug Interactions with Fenofibrate Tablets 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 fenofibrate tablets 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 dosage 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 fenofibrate tablets 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 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 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 fenofibrate tablets, there is a risk that an interaction will lead to deterioration of renal function. Intervention: The benefits and risks of using fenofibrate tablets 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 fenofibrate tablets 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 fenofibrate tablets at least 1 hour before or 4 to 6 hours after a bile acid resin to avoid impeding its absorption ( 7 ).

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 dosage of 160 mg of fenofibrate tablets 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 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 160 mg fenofibrate 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 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.

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) ] Paradoxical Decreases in HDL Cholesterol Levels [see Warnings and Precautions (5.11) ] Adverse reactions (≥ 2% and greater than placebo): abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Rhodes Pharmaceuticals LLC at 1-888-873-5329; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of fenofibrate tablets 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 fenofibrate tablets 145 mg per day [see Clinical Pharmacology (12.3) ]. Adverse reactions reported by 2% or more of patients treated with fenofibrate (and greater than placebo) during the 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 either an intermediate or the maximum recommended daily dosage of fenofibrate versus 1.1% of patients treated with placebo. In an 8-week trial, the incidence of ALT or AST elevations ≥ 3 times the upper limit of normal was 13% in patients receiving an intermediate daily dosage or the maximum recommended daily dosage of fenofibrate and was 0% in those receiving the lowest recommended daily dosage of fenofibrate or placebo [see Warnings and Precautions (5.2) ] . 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 : Anemia, white blood cell decreases Gastrointestinal : Pancreatitis General : Asthenia Hepatobiliary : Increased total bilirubin, hepatitis, cirrhosis Immune System : Anaphylaxis…