Choline fenofibrate

Fenofibric acid delayed-release capsules is indicated as adjunctive therapy to diet: • to reduce triglyceride (TG) levels in adults with severe hypertriglyceridemia (TG greater than or equal to 500 mg/dL). • to reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia when use of recommended LDL-C lowering therapy is not possible. Limitations of Use • Markedly elevated levels of serum TG (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 determined. • Fenofibrate did not reduce coronary heart disease morbidity and mortality in two large, randomized controlled trials of patients with type 2 diabetes mellitus.

The active moiety of fenofibric acid delayed-release capsules is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been 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 PPAR alpha receptor. Through this mechanism, fenofibric acid 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).

• Severe hypertriglyceridemia: 45 to 135 mg orally once daily, the dosage should be adjusted according to patient response. • Primary hyperlipidemia: 135 mg orally once daily. • Administer as a single dose, at any time of day, with or without food. • Assess TG when clinically appropriate, as early as 4 to 8 weeks after initiating fenofibric acid delayed-release capsules. Discontinue fenofibric acid delayed-release capsules in patients who do not have an adequate response after 2 months of treatment. • Swallow capsules whole. Do not crush, break, dissolve, or chew. • Renal impairment: Initial dosage of 45 mg orally once daily. • Geriatric patients: Select the dosage on the basis of renal function.

Fenofibric acid delayed-release capsules are contraindicated in patients with: • Severe renal impairment, including those with end-stage renal disease (ESRD) and those receiving dialysis. • Active liver disease, including those with unexplained persistent liver function abnormalities. • Pre-existing gallbladder disease. • Hypersensitivity to fenofibric acid, fenofibrate, or any of the excipients in fenofibric acid delayed-release capsules. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with fenofibrate. • Severe renal impairment, including those with end-stage renal disease (ESRD) and those receiving dialysis.

• Hepatotoxicity: Serious drug-induced liver injury, including liver transplantation and death, has been reported with fenofibrates, including fenofibric acid delayed-release capsules. 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. • Myopathy and Rhabdomyolysis: Have been reported in patients taking fenofibrates. Risks are increased during co-administration with a statin, in geriatric patients, and in patients with renal impairment or hypothyroidism. Discontinue fenofibric acid delayed-release capsules if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected.

The following serious adverse reactions are described below and elsewhere in the labeling: • Mortality and coronary heart disease morbidity • Hepatoxicity • Myopathy and Rhabdomyolysis • Increases in Serum Creatinine • Cholelithiasis • Increased Bleeding Risk with Coumarin Anticoagulants • Pancreatitis • Hematologic Changes • Hypersensitivity reactions • Venothromboembolic disease • Paradoxical Decreases in HDL Cholesterol Levels Adverse reactions (≥ 2% and greater than placebo): abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis.

Table 2 presents clinically important drug interactions with fenofibric acid. Table 2. Clinically Important Drug Interactions with fenofibric acid delayed-release capsules 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 fenofibric acid 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.

Store at room temperature 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture.