What are the risks of taking fenofibrate (fibric acid derivative)?

Risks of Taking Fenofibrate

Fenofibrate carries significant risks including hepatotoxicity, myopathy, rhabdomyolysis, increased serum creatinine, and cholelithiasis, and should be used cautiously in patients with renal impairment or when combined with statins. 1

Major Safety Concerns

Hepatotoxicity

• Serious drug-induced liver injury, including liver transplantation and death, has been reported with fenofibrate 1
• Regular monitoring of liver function is required:
  • Baseline and periodic measurement of ALT, AST, and total bilirubin
  • Discontinue if signs or symptoms of liver injury develop or if elevated enzyme levels persist 1

Myopathy and Rhabdomyolysis

• Risk factors for myopathy/rhabdomyolysis with fenofibrate include:
  • Combination with statins (particularly higher doses) 2, 1
  • Elderly patients 1
  • Diabetes 1
  • Renal impairment 1, 3
  • Hypothyroidism 1, 3
• The risk of rhabdomyolysis is higher when statins are combined with gemfibrozil compared to fenofibrate 2, 4
• Symptoms include proximal myalgias, stiffness, weakness, and dark urine 3

Renal Effects

• Fenofibrate can reversibly increase serum creatinine levels 1
• Dosing considerations based on renal function:
  • Avoid use in severe renal impairment (GFR <30 mL/min/1.73 m²) 5, 1
  • Dose reduction required in mild to moderate renal impairment 1
  • For moderate CKD (stage 3): 48 mg/day 5
  • For eGFR 30-59 mL/min/1.73 m²: ≤54 mg/day 5

Gallbladder Disease

• Fenofibrate increases cholesterol excretion into the bile, leading to risk of cholelithiasis 1
• Contraindicated in patients with preexisting gallbladder disease 1
• If cholelithiasis is suspected, gallbladder studies are indicated 1

Drug Interactions

• Coumarin anticoagulants: Fenofibrate may potentiate anticoagulant effects, requiring careful monitoring and dose adjustment of anticoagulants 1
• Cytochrome P450 inhibitors: May increase risk of myopathy 3
• Combination therapy with statins: Increased risk of myopathy, particularly with gemfibrozil rather than fenofibrate 4

Special Population Considerations

Pregnancy

• Limited data on use during pregnancy
• Should be used only if potential benefit justifies potential risk to the fetus 1

Breastfeeding

• Contraindicated during breastfeeding due to potential for serious adverse reactions in infants 1
• Women should not breastfeed during treatment and for 5 days after the final dose 1

Elderly Patients

• Dose selection should be based on renal function rather than age 5, 1
• Higher incidence of adverse effects in elderly patients, particularly when combined with statins 1

Efficacy vs. Risk Considerations

• Fenofibrate was not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus 1
• Statin plus fibrate combination therapy has not been shown to improve atherosclerotic cardiovascular disease outcomes and is generally not recommended 2
• In the ACCORD study, fenofibrate plus simvastatin did not reduce cardiovascular events compared to simvastatin alone 2
• Potential benefit may exist for men with both high triglycerides (≥204 mg/dL) and low HDL cholesterol (≤34 mg/dL) 2

Monitoring Recommendations

1. Baseline assessment of:

   • Liver function (ALT, AST, bilirubin)
   • Renal function
   • Lipid profile

2. Regular monitoring:

   • Liver function tests
   • Renal function, particularly in patients with renal impairment
   • Signs and symptoms of myopathy (muscle pain, tenderness, weakness)

3. Discontinue fenofibrate if:

   • Signs or symptoms of liver injury develop
   • Elevated liver enzymes persist
   • Severe muscle pain, tenderness, or weakness occurs, especially if accompanied by malaise or fever
   • Hypersensitivity reactions occur

By understanding these risks and implementing appropriate monitoring, the safety profile of fenofibrate can be optimized when its use is clinically indicated.