FENOFIBRATE

Warnings and Precautions, Heptatotoxicity (5.2) 03/2021 Warnings and Precautions, Myopathy and rhabdomyolysis (5.3) 03/2021 Warnings and Precautions, Hepatotoxicity ( 5.2 ) 03/2021 Warnings and Precautions, Myopathy and Rhabdomyolysis ( 5.3 ) 03/2021

1 INDICATIONS AND USAGE Fenofibrate is a peroxisome proliferator-activated receptor (PPAR) alpha agonist indicated as an adjunct to diet: To reduce elevated LDL-C, Total-C, TG and Apo B, and to increase HDL-C in adult patients with primary hypercholesterolemia or mixed dyslipidemia ( 1.1 ). For treatment of adult patients with severe hypertriglyceridemia ( 1.2 ). Limitations of Use: Fenofibrate was not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus ( 5.1 ). 1.1 Primary Hypercholesterolemia or Mixed Dyslipidemia Fenofibrate tablets USP are indicated as adjunctive therapy to diet to reduce elevated low-density lipoprotein cholesterol (LDL-C), total cholesterol (Total-C), Triglycerides and apolipoprotein B (Apo B), and to increase high-density lipoprotein cholesterol (HDL-C) in adult patients with primary hypercholesterolemia or mixed dyslipidemia. 1.2 Severe Hypertriglyceridemia Fenofibrate tablets USP 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 obviate the need for pharmacologic intervention. Markedly elevated levels of serum triglycerides (e.g. >2,000 mg/dL) may increase the risk of developing pancreatitis. The effect of fenofibrate therapy on reducing this risk has not been adequately studied. 1.3 Important Limitations of Use Fenofibrate at a dose equivalent to 145 mg of fenofibrate tablets USP was not shown to reduce coronary heart disease morbidity and mortality in a large, randomized controlled trial of patients with type 2 diabetes mellitus [see Warnings and Precautions (5.1) ].

1.1 Primary Hypercholesterolemia or Mixed Dyslipidemia Fenofibrate tablets USP are indicated as adjunctive therapy to diet to reduce elevated low-density lipoprotein cholesterol (LDL-C), total cholesterol (Total-C), Triglycerides and apolipoprotein B (Apo B), and to increase high-density lipoprotein cholesterol (HDL-C) in adult patients with primary hypercholesterolemia or mixed dyslipidemia.

1.2 Severe Hypertriglyceridemia Fenofibrate tablets USP 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 obviate the need for pharmacologic intervention. Markedly elevated levels of serum triglycerides (e.g. >2,000 mg/dL) may increase the risk of developing pancreatitis. The effect of fenofibrate therapy on reducing this risk has not been adequately studied.

1.3 Important Limitations of Use Fenofibrate at a dose equivalent to 145 mg of fenofibrate tablets USP was not shown to reduce coronary heart disease morbidity and mortality in a large, randomized controlled trial of patients with type 2 diabetes mellitus [see Warnings and Precautions (5.1) ].

2 DOSAGE AND ADMINISTRATION Primary hypercholesterolemia or mixed dyslipidemia: Initial dose of 145 mg once daily ( 2.2 ). Severe hypertriglyceridemia: Initial dose of 48 to 145 mg once daily. Maximum dose is 145 mg ( 2.3 ). Renally impaired patients: Initial dose of 48 mg once daily ( 2.4 ). Geriatric patients: Select the dose on the basis of renal function ( 2.5 ) May be taken without regard to meals ( 2.1 ). 2.1 General Considerations Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibrate, and should continue this diet during treatment with fenofibrate. Fenofibrate tablets can be given without regard to meals. The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality. Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be an important ancillary measure. Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus should be looked for and adequately treated. Estrogen therapy, thiazide diuretics and beta-blockers, are sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia. Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of fenofibrate if lipid levels fall significantly below the targeted range. Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 145 mg once daily. 2.2 Primary Hypercholesterolemia or Mixed Dyslipidemia The initial dose of fenofibrate is 145 mg once daily. 2.3 Severe Hypertriglyceridemia The initial dose is 48 to 145 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 145 mg once daily. 2.4 Impaired Renal Function Treatment with fenofibrate should be initiated at a dose of 48 mg per day in patients having mild to moderately impaired renal function, and increased only after evaluation of the effects on renal function and lipid levels at this dose. The use of fenofibrate should be avoided in patients with severe renal impairment [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 ) ] 2.5 Geriatric Patients Dose selection for the elderly should be made on the basis of renal function [see Use in Specific Populations ( 8.5 ) ].

2.1 General Considerations Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibrate, and should continue this diet during treatment with fenofibrate. Fenofibrate tablets can be given without regard to meals. The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality. Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be an important ancillary measure. Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus should be looked for and adequately treated. Estrogen therapy, thiazide diuretics and beta-blockers, are sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia. Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of fenofibrate if lipid levels fall significantly below the targeted range. Therapy should be withdrawn in patients who do not have an adequate response after two months of tr …

3 DOSAGE FORMS AND STRENGTHS Fenofibrate tablets, USP are available as film-coated tablets containing 48 mg or 145 mg of fenofibrate. • 48 mg yellow colored tablets, oval shaped, biconvex film coated tablets, debossed with “C50” on one side and plain on other side. • 145 mg white colored, oval shaped, biconvex film coated tablets, debossed with “C49” on one side and plain surface on the other side. Tablets: 48 mg and 145 mg ( 3 ).

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 ).

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 ) ] Pancreatitis [see Warnings and Precautions ( 5.7 ) ] Hypersensitivity reactions [see Warnings and Precautions ( 5.9 ) ] Venothromboembolic disease [see Warnings and Precautions ( 5.10 ) ] Adverse reactions > 2% and at least 1% greater than placebo: Abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis ( 6) . To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adverse events reported by 2% or more of patients treated with fenofibrate (and greater than placebo) during the double-blind, placebo-controlled trials, regardless of causality, are listed in Table 1 below. Adverse events led to discontinuation of treatment in 5.0% of patients treated with fenofibrate and in 3.0% treated with placebo. Increases in liver function tests were the most frequent events, causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials. Table 1: Adverse Reactions Reported by 2% or More of Patients Treated with Fenofibrate and Greater than Placebo During the Double-Blind, Placebo-Controlled Trials BODY SYSTEM Adverse Reaction Fenofibrate Dosage equivalent to 145 mg fenofibrate. (N=439) Placebo (N=365) BODY AS A WHOLE Abdominal Pain 4.6% 4.4% Back Pain 3.4% 2.5% Headache 3.2% 2.7% DIGESTIVE Nausea 2.3% 1.9% Constipation 2.1% 1.4% METABOLIC AND NUTRITIONAL DISORDERS Abnormal Liver Function Tests 7.5% Significantly different from Placebo. 1.4% Increased ALT 3.0% 1.6% Increased CPK 3.0% 1.4% Increased AST 3.4% 0.5% 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 96 mg to 145 mg fenofibrate daily versus 1.1% of patients treated with placebo [see Warnings and Precautions ( 5.2 ) ]. In an 8-week study, the incidence of ALT or AST elevations ≥ 3times the upper limit of normal was 13% in patients receiving dosages equivalent to 96 mg to 145 mg fenofibrate daily and was 0% in those receiving dosages equivalent to 48 mg or less fenofibrate daily or placebo. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval 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 spasm, hepatitis, cirrhosis, increased total bilirubin, anemia, arthralgia, decreases in hemoglobin, 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. To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com; 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 …

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 USE IN SPECIFIC POPULATIONS Geriatric Use: Determine dose selection based on renal function ( 8.5 ). Renal Impairment: Avoid use in severe renal impairment patients. Dose reduction is required in mild to moderate renal impairment patients ( 8.6 ). 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 145 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 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, 127, 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, equivalent to 145 mg fenofibrate tablet 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 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, 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. 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 fenofibrate and for 5 days after the final dose [see Contraindications ( 4 ) ]. 8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients. 8.5 Geriatric Use Fenofibric acid is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Fenofibric acid exposure is not influenced by age. Since elderly patients have a higher incidence of renal impair …

12.1 Mechanism of Action The active moiety of fenofibrate tablets, is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been extensively studied through oral administration of fenofibrate. The lipid-modifying effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor α (PPARα). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting decrease in TG produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARα also induces an increase in the synthesis of apolipoproteins A-I, A-II and HDL-cholesterol. Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid.

11 DESCRIPTION Fenofibrate tablets, USP, are a lipid regulating agent available as tablets for oral administration. Each tablet contains 54 mg or 160 mg of 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 CI and the molecular weight is 360.83; fenofibrate, USP is insoluble in water. The melting point is 79°C to 82°C. Fenofibrate, USP is a white solid which is stable under ordinary conditions. Inactive Ingredients Each 54 mg fenofibrate tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, crospovidone, iron oxide yellow, lactose monohydrate, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium lauryl sulfate, sodium starch glycolate, sodium stearyl fumarate, talc, titanium dioxide, glyceryl mono and dicaprylocaprate, and D&C yellow #10 lake. Each 160 mg fenofibrate tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, crospovidone, lactose monohydrate, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium lauryl sulfate, sodium starch glycolate, sodium stearyl fumarate, talc, titanium dioxide, and glyceryl mono and dicaprylocaprate. Fenofibrate tablet meets USP Dissolution Test 3. structure

10 OVERDOSAGE In the event of an overdose of fenofibrate tablets, 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 fenofibrate tablets. General supportive care of the patient is indicated, including monitoring of vital signs and observation of clinical status, should an overdose occur. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. Because fenofibric acid is highly bound to plasma proteins, hemodialysis should not be considered.

16 HOW SUPPLIED/STORAGE AND HANDLING 54 mg Yellow, circular, biconvex film coated tablets, debossed with "T31" on one side and plain surface on the other side. Bottles of 90 tablets (NDC 33342-347-10). Package of 126 tablets (9 x 14 unit-dose) (NDC33342-347-47) Package of 100 tablets (10 x 10 unit-dose) (NDC33342-347-12) 160 mg White, oval, bevel edged biconvex film coated tablets, debossed with "T32" on one side and plain surface on the other side. Bottles of 90 tablets (NDC33342-348-10) Bottles of 500 tablets (NDC33342-348-15) Package of 100 tablets (10 x 10 unit-dose) (NDC33342-348-12) Storage Store at 20o to 25oC (68o to 77oF); excursions permitted to 15° to 30oC (59° to 86oF). [See USP Controlled Room Temperature]. Keep this and all medication out of reach of children. Protect from moisture. Dispense in tightly-closed, light-resistant container as defined in the USP, with a child-resistant closure, as required.