Initial Therapy: Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal before instituting fenofibrate therapy. Every attempt should be made to control serum lipids with appropriate diet, exercise, weight loss in obese patients. Secondary causes of hypercholesterolemia, such as uncontrolled type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemia, obstructive liver disease, pharmacological treatment (e.g., diuretics, beta-blockers, estrogens, progestogens, immunosuppresants, protease inhibitors) and excessive alcohol intake should be adequately treated before fenofibrate therapy is considered.
Liver Function: Abnormal liver function tests have been observed during fenofibrate administration, including elevations of serum transaminases [e.g., alanine aminotransferase (ALT), aspartate aminotransferase (AST)], and decreases or, rarely, increases in alkaline phosphatase.
Perform regular periodic monitoring of liver function, including ALT, for the duration of fenofibrate therapy. Discontinue treatment if enzyme levels persist above three times the upper limit of normal (ULN).
Cholelithiasis: Fenofibrate may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Discontinue fenofibrate therapy if gallstones are found.
Pancreatitis: Pancreatitis has been reported in patients taking fenofibrate. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.
Mortality and Coronary Heart Disease Morbidity: The effects of fenofibrate on coronary heart disease morbidity and mortality and noncardiovascular mortality has not been established. Fenofibrate was not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus.
Venothromboembolic Disease: In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, pulmonary embolus and deep vein thrombosis were observed at higher rates in the fenofibrate-treated group compared with the placebo-treated group.
Hematologic Changes: After initiation of fenofibrate therapy, mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been reported. However, these levels stabilize during long-term administration. Thrombocytopenia and agranulocytosis have been reported in patients treated with fenofibrate. Periodic blood counts are recommended during the first 12 months of fenofibrate therapy.
Skeletal Muscle Effects: Muscle toxicity, including rare cases of rhabdomyolysis, with or without renal failure, has been observed with the use of fibrates and other lipid-lowering agents. The incidence of this disorder increases in cases of hypoalbuminemia and previous renal insufficiency. Muscle toxicity should be suspected in patients with diffuse myalgia, myositis, muscular cramps and weakness, and/or marked increases in creatinine phosphokinase (CPK) levels (> 5 times ULN). Discontinue fenofibrate in such cases.
Patients with predisposing factors for myopathy/rhabdomyolysis, including elderly (age >70 years), personal or familial history of hereditary muscular disorders, renal impairment, hypothyroidism and high alcohol intake, may be at increased risk of developing rhabdomyolysis. In such cases, the risk of treatment should be considered in relation to possible benefit, and clinical monitoring is recommended.
The risk of muscle toxicity may be increased if the drug is administered with another fibrate or an HMG-CoA reductase inhibitor, particularly in cases of preexisting muscular disease. Thus, the coadministration of fenofibrate with a statin should be reserved to patients with severe combined dyslipidemia and high cardiovascular risk without any history of muscular disease. This combination should be used with caution and patients should be closely monitored for signs of muscle toxicity.
Renal Function: Monitor creatinine levels during the first three months after initiation of treatment. Discontinue fenofibrate therapy in case of an increase in creatinine levels >50% ULN. Renal monitoring should also be considered in patients at risk for renal insufficiency such as the elderly and patients with diabetes.
Hypersensitivity Reactions: Fenofibrate therapy has been associated with acute hypersensitivity reactions including severe skin rashes requiring patient hospitalization and treatment with steroids, including reports of Stevens-Johnson syndrome and toxic epidermal necrolysis. Urticaria was also reported in controlled studies.
Paradoxical Decreases in HDL-C Levels: There have been reports of severe decreases in HDL-C levels (as low as 2 mg/dL) occurring in diabetic and non-diabetic patients initiated on fibrate therapy. The reduction was accompanied by a decrease in apo A-I concentrations, and occurred within two weeks to years after initiation of fibrate therapy. Upon discontinuance of therapy, HDL-C concentrations rapidly returned to baseline and remained at normal levels.
The clinical significance of this paradoxical decrease in HDL-C is unknown. It is recommended that HDL-C levels be checked within the first few months after initiation of fibrate therapy. If a severely depressed HDL-C level is detected, fibrate therapy should be withdrawn and the HDL-C level monitored until it has returned to baseline, and fibrate therapy should not be re-initiated.
Use in Children: The safety and efficacy in pediatric patients have not been established.
Use in Elderly: Fenofibric acid is known to be substantially excreted by the kidney, and the risk of adverse reactions to fenofibrate may be greater in patients with renal impairment. Care should be taken in dose selection since elderly patients are more likely to have decreased renal function (see also Precautions).