Fenofibrate

May cause cholelithiasis; discontinue if gallstones are found upon gallbladder studies.

A paradoxical, severe, and reversible decrease in HDL-C (as low as 2 mg/dL) with a simultaneous decrease in apolipoprotein A1 has been reported within 2 weeks to years after initiation of fibrate therapy; clinical significance unknown. Monitor HDL-C within a few months of initiation of therapy and discontinue if HDL-C becomes severely depressed; do not restart therapy.

May cause mild-to-moderate decreases in hemoglobin, hematocrit and WBC upon initiation of therapy which usually stabilizes with long-term therapy. Agranulocytosis and thrombocytopenia have been reported. Periodic monitoring of blood counts is recommended during the first year of therapy.

Hepatic transaminases can become significantly elevated (dose-related); hepatocellular, chronic active, and cholestatic hepatitis have been reported after weeks to several years of therapy. Baseline and regular monitoring of liver function tests is required; discontinue therapy in patients whose enzyme levels persist above 3 times the upper limit of normal.

Acute hypersensitivity reactions (eg, severe skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported.

Has been associated with rare myositis, myopathy, or rhabdomyolysis; monitor patients closely. Risk increased in the elderly, those receiving concomitant HMG-CoA reductase inhibitors or colchicine, and patients with diabetes mellitus, renal insufficiency, or hypothyroidism. Instruct patients to report unexplained muscle pain, tenderness, weakness, especially if accompanied with malaise or fever; or brown urine. Discontinue therapy in patients who develop markedly elevated CPK concentrations or if myopathy/myositis is suspected or diagnosed.

Pancreatitis has been reported with fenofibrate use; may be secondary to a failure of efficacy in patients with severe hypertriglyceridemia, medication side effect, or due to biliary tract stone or sludge formation from bile duct obstruction.

Increases in serum creatinine (>2 mg/dL) have been observed with use; clinical significance unknown. These elevations tend to return to baseline following discontinuation of fenofibrate. Fenofibrate has been shown to increase creatinine production (unknown mechanism) resulting in an equal increase of creatinuria thereby demonstrating that the increase does not reflect a reduction in creatinine clearance (Hottelart 2002). Monitor renal function in patients with renal impairment; consider monitoring renal function in patients with increased risk for developing renal impairment (eg, elderly and patients with diabetes).

Use has been associated with pulmonary embolism (PE) and deep vein thrombosis (DVT). Use with caution in patients with risk factors for VTE. Disease-related concerns:

Fibric acid derivatives have not demonstrated significant efficacy in altering cardiovascular disease mortality in major clinical studies. In two large randomized controlled clinical trials, neither fenofibrate monotherapy (Keech 2005) nor the addition of fenofibrate to simvastatin (ACCORD Study Group 2010) compared to placebo were shown to reduce cardiovascular disease morbidity and mortality in patients with type 2 diabetes.

Contraindicated in patients with active liver disease, including primary biliary cirrhosis and unexplained persistent liver function abnormalities.

Use with caution in patients with mild to moderate renal impairment; dosage adjustment required. Contraindicated in patients with severe renal impairment including those receiving dialysis. Avoid use of Triglide in patients with mild or moderate renal impairment. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Use caution with HMG-CoA reductase inhibitors; may lead to myopathy, rhabdomyolysis. No incremental benefit of combination therapy on cardiovascular morbidity and mortality over statin monotherapy has been established. In combination with HMG-CoA reductase inhibitors, fenofibrate is generally regarded as safer than gemfibrozil due to limited pharmacokinetic interaction with statins. Fenofibrate may be considered in patients on low- or moderate-intensity statin therapy (ie, statin therapy intended to lower LDL-C by 500 mg/dL, outweigh the potential risk for adverse effects (ACC/AHA [Stone 2013]). Special populations:

Use with caution in the elderly; dosage adjustment may be required. Dosage form specific issues:

Some products may contain peanut or arachis oil; use is contraindicated in patients with a peanut or arachis allergy for applicable formulations.

Some products may contain soya lecithin; use is contraindicated in patients with a soya lecithin allergy for applicable formulations. Other warnings/precautions:

Fenofibrate is not a first- or second-line choice in patients with hypercholesterolemia; other agents may be more suitable (ACC/AHA [Stone 2013]). Secondary causes of hyperlipidemia should be ruled out prior to therapy.

Therapy should be withdrawn if an adequate response is not obtained after 2 to 3 months of therapy at the maximal daily dose. In patients with severe hypertriglyceridemia, the occurrence of pancreatitis may represent a failure of efficacy, a direct effect of the drug, or obstruction of the common bile duct due to biliary tract stone or sludge formation.