FENOFIBRATE

Product Type: HUMAN PRESCRIPTION DRUG

Route: ORAL

Dosage Form:

NDC: 50090-6974

Application: ANDA076509

Effective: 20231227

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 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 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 160 mg of fenofibrate tablet 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 160 mg once daily. ( 2.2 ) Severe hypertriglyceridemia: Initial dose of 54 mg to 160 mg once daily. Maximum dose is 160 mg. ( 2.3 ) Renally impaired patients: Initial dose of 54 mg once daily. ( 2.4 ) Geriatric patients: Select the dose on the basis of renal function. ( 2.5 ) Should be given with meals. ( 2.1 ) 2.1 General Considerations Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibrate tablets and should continue this diet during treatment with fenofibrate tablets. Fenofibrate tablets should be given with meals, thereby optimizing the bioavailability of the medication. The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality. Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be an important ancillary measure. Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus should be looked for and adequately treated. Estrogen therapy, thiazide diuretics and beta-blockers, are sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia. Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of fenofibrate 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 160 mg once daily. 2.2 Primary Hypercholesterolemia or Mixed Dyslipidemia The initial dose of fenofibrate tablet is 160 mg once daily. 2.3 Severe Hypertriglyceridemia The initial dose is 54 mg per day to 160 mg per day. Dosage should be individualized according to patient response and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals. The maximum dose is 160 mg once daily. 2.4 Impaired Renal Function Treatment with fenofibrate tablets should be initiated at a dose of 54 mg per day in patients having mild to moderately impaired renal function and increased only after evaluation of the effects on renal function and lipid levels at this dose. The use of fenofibrate 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) ].

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

Not available.

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) ] 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 Amneal Pharmaceuticals at 1-877-835-5472 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% 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 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 Function Tests 7.5% ** 1.4% 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 160 mg fenofibrate. ** Significantly different from Placebo. 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 107 mg to 160 mg fenofibrate 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 equivalent to 107 mg to 160 mg fenofibrate daily and was 0% in those receiving dosages equivalent to 54 mg or less fenofibrate daily or placebo. 6.2 Post-marketing 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 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.