Fenofibrate: uses, appearance and warnings

Fenofibrate tablets are peroxisome proliferator-activated receptors (PPARα) 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 145 mg of fenofibrate tablets 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) ].

48 mg yellow, film coated, oval tablets, debossed “V3650” on one side and plain on the reverse side. 145 mg white, film coated, modified capsule shaped tablets, debossed “V3651” on one side and plain on the reverse side. Oral Tablets: 48 mg and 145 mg ( 3 ).

Fenofibrate Tablets, USP are available in two strengths: 48 mg Yellow, film coated, oval tablets, debossed “V3650” on one side and plain on the reverse side, available in bottles of 30 (NDC 35561-249-10), 90 (NDC 35561-249-11) and 500 (NDC 35561-249-13) tablets. 145 mg White, film coated, modified capsule shaped tablets, debossed “V3651” on one side and plain on the reverse side, available in bottles of 30 (NDC 35561-250-10), 90 (NDC 35561-250-11) and 500 (NDC 35561-250-13). Storage Store at 20° to 25°C (68° to 77°F) with excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep out of the reach of children. Protect from moisture.

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 , 5.2 ) . Gallbladder disease ( 4 , 5.5 ) . Known hypersensitivity to fenofibrate ( 4 ) . Nursing mothers ( 4 , 8.2 ) .

Hepatotoxicity: Serious drug-induce liver injury, including liver transplantation and death, has been reported with fenofibrate. 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. Risk are increased during co-administered 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: Use caution in concomitant treatment with oral coumarin anticoagulants. Adjust the dosage of coumarin anticoagulant 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 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 5518 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 9795 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 tablets, clofibrate, and gemfibrozil, the adverse findings in 4 large randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to fenofibrate. 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 (3.0% vs. 1.8%). In a study conducted by the World Health Organization (WHO), 5000 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 (5.70% 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. 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=4081) 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 = .91 - 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). 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 - 5.05). …

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 Bostal LLC at 1-844-375-5410 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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) ] 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 …

Coumarin anticoagulants: ( 7.1 ). Immunosuppressants: ( 7.2 ). Bile acid resins: ( 7.3 ). 7.1 Coumarin Anticoagulants Potentiation of coumarin-type anticoagulant effects has been observed with prolongation of the PT/INR. Caution should be exercised when coumarin anticoagulants are given in conjunction with fenofibrate. 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 [see Warnings and Precautions (5.6) ] . …