fenofibrate micronized (Rx)

1-10%

Abdominal pain (4.6%)

Back pain (3.4%)

Increased AST (3.4%)

Headache (3.2%)

Increased ALT (3%)

Increased CPK (3%)

Nausea (2.3%)

Constipation (2.1%)

Postmarketing Reports

Myalgia, rhabdomyolysis, muscle spasms, arthralgia

Pancreatitis

Renal failure

Hepatitis, cirrhosis

Anemia

Severely depressed HDL levels

Photosensitivity reactions (may occur days to months after initiating therapy)

Interstitial lung disease

Increase total bilirubin

Asthenia

Contraindications

Hypersensitivity

Severe renal impairment (including dialysis)

Active liver disease, including primary biliary cirrhosis and unexplained persistent liver function abnormalities

Pre-existing gallbladder disease

Breastfeeding women

Cautions

Effect on coronary heart disease morbidity and mortality not established

Increases risk of myositis or myopathy, and has been associated with rhabdomyolysis; risk may increase when coadministered with statins

Higher doses or coadministration with statins associated with increased serum transaminases

May increase serum creatinine; monitor renal function periodically in patients with renal impairment

May increase cholesterol excretion in bile, potentially leading to cholelithiasis

Coadministration with warfarin may increase anticoagulant effects resulting in PT/INR prolongation

Pancreatitis reported; may be a failure of efficacy with severe hypertriglyceridemia, a direct drug effect, or secondary effect via biliary stone or sludge formation

May decrease hemoglobin, hematocrit, and leukocytes; thrombocytopenia and agranulocytosis reported; monitoring of blood counts recommended during first year of therapy

Anaphylaxis and angioedema reported; if patient develops signs or symptoms of acute hypersensitivity reaction, advise them to seek immediate medical attention and discontinue therapy Severe cutaneous adverse drug reactions (SCAR), including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS), reported postmarketing, occurring days to weeks after initiation of therapy; cases of DRESS associated with cutaneous reactions (such as rash exfoliative dermatitis) and a combination of eosinophilia, fever, systemic organ involvement (renal, hepatic, or respiratory); discontinue therapy and treat patients appropriately if SCAR is suspected

PE and DVT reported; use caution in patients with risk factors for VTE

Paradoxical decreases in HDL cholesterol reported; monitor HDL-C within few months of initiating therapy; discontinue of HDL-C becomes severely depressed; do not restart therapy

Hepatotoxicity

• Serious drug-induced liver injury (DILI), including liver transplantation and death, reported; DILI reported within first few weeks of treatment or after several months of therapy and in some cases has reversed with discontinuation of treatment
• Patients with DILI have experienced signs and symptoms including dark urine, abnormal stool, jaundice, malaise, abdominal pain, myalgia, weight loss, pruritus, and nausea
• Many patients had concurrent elevations of total bilirubin, serum alanine transaminase (ALT), and aspartate transaminase (AST)
• DILI has been characterized as hepatocellular, chronic active, and cholestatic hepatitis, and cirrhosis has occurred in association with chronic active hepatitis
• In clinical trials, fenofibrate at doses equivalent to 90 mg daily associated with increases in serum AST or ALT; the incidence of increases in transaminases may be dose-related
• Monitor patient’s liver function, including serum ALT, AST, and total bilirubin, at baseline and periodically for duration of therapy
• Discontinue therapy if signs or symptoms of liver injury develop or if elevated enzyme levels persist (ALT or AST > 3 times the upper limit of normal, or if accompanied by elevation of bilirubin); do not restart therapy in these patients if there is no alternative explanation for the liver injury

Pregnancy Category: C

Lactation: Contraindicated

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Fenofibrate is a prodrug that is metabolized to the active moiety, fenofibric acid

Activates peroxisome proliferator activated receptor-alpha (PPAR-alpha); increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reduces Apo CIII production (lipoprotein lipase inhibitor)

Reduces TC, LDL-C, Apo B, TG, and VLDL; increases HDL-C, Apo AI, and Apo AII

Absorption

Peak Plasma Time: 4-8 hr (fenofibric acid)

Distribution

Time to steady-state: within 7 days (Antara); within 5 days (Lofibra capsules)

Protein Bound: 99%

Metabolism

Fenofibrate converted by ester hydrolysis to fenofibric acid (active moiety)

Fenofibric acid is primarily conjugated with glucuronic acid; a small amount is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid

Elimination

Half-life: 20-23 hr

Excretion: 66% in urine, primarily as fenofibric acid and fenofibric acid glucuronide; 25% feces

Pharmacogenomics

Genotyping patients with atherogenic dyslipidemia might establish who will benefit most from therapy with fenofibric to increase HDL-C

Three single-nucleotide polymorphisms (SNPs) in the APOA5 region have been associated with increases in HDL-C