What are the side effects of Fenofibrate (fibric acid derivative)?

Fenofibrate Side Effects

Fenofibrate causes several important adverse effects that require monitoring, most notably increased serum creatinine (average increase 0.113-0.136 mg/dL), elevated liver enzymes, increased risk of pancreatitis and pulmonary embolism, gallstone formation, and myopathy risk when combined with statins. 1, 2

Renal Effects

• Fenofibrate consistently increases serum creatinine levels by approximately 0.113-0.136 mg/dL (10-12 mmol/L), which typically reverses after discontinuation 1, 2
• The drug is absolutely contraindicated when eGFR falls below 30 mL/min/1.73m² 3, 2
• In moderate renal impairment (eGFR 30-59 mL/min/1.73m²), dose must be reduced to maximum 54 mg/day with intensive monitoring 3
• Monitor renal function before initiation, within 3 months of starting, and every 6 months thereafter 4, 3

Hepatobiliary Effects

• Fenofibrate increases cholesterol saturation in bile, raising gallstone risk 4, 5
• The American Association for the Study of Liver Diseases recommends using fibrates with caution in patients with gallstone history 4
• Obtain baseline ultrasound imaging before initiating therapy to document absence of stones 4
• Transient elevations in liver transaminases commonly occur and are usually asymptomatic 6, 7
• Discontinue fenofibrate if persistent ALT elevations ≥3 times upper limit of normal occur 3
• Monitor hepatic transaminases before initiation and as clinically indicated during treatment 3

Cardiovascular and Thrombotic Effects

• Fenofibrate increases the risk of pancreatitis and pulmonary embolism compared to placebo 1
• Increased risk of atrial fibrillation has been documented 2
• Increased bleeding risk occurs, particularly relevant for patients on anticoagulants 2, 8
• In women with well-controlled diabetes without dyslipidemia, fenofibrate may paradoxically increase cardiovascular event risk 1, 2

Musculoskeletal Effects

• The risk of myopathy increases significantly when fenofibrate is combined with statins, though fenofibrate has lower risk than gemfibrozil 4, 2
• Gemfibrozil plus statin is absolutely contraindicated due to markedly increased rhabdomyolysis risk 3
• Fenofibrate plus statin combination showed no significant increase in myopathy, myositis, or rhabdomyolysis in the ACCORD trial, but did increase ALT >5 times upper limit of normal 1
• Common musculoskeletal reactions include muscle pain, tenderness, and weakness 8, 5
• In primary biliary cholangitis, 5-10% of patients develop musculoskeletal pain 2

Metabolic Effects

• Fenofibrate increases uric acid levels and can precipitate gout 2
• Despite raising uric acid, fenofibrate has modest uricosuric effects that may benefit some patients with gout and hyperlipidemia 2
• May cause new-onset diabetes or disturb diabetes management in some patients 2

Gastrointestinal Effects

• Common gastrointestinal disturbances include nausea, abdominal pain, and other GI symptoms 8, 5, 6
• Patients should report onset of abdominal pain immediately 8

Dermatologic and Other Effects

• Skin reactions including rash, pruritus, and sweating occur in approximately 6% of patients 5, 6
• Neurologic effects including headache and dizziness are reported 5, 6
• Weight loss may occur 5
• Rare autoimmune adverse effects including thrombocytopenia and hepatitis have been reported, requiring caution in patients with rheumatoid arthritis 4

Critical Monitoring Requirements

• Assess serum creatinine and eGFR before starting, within 3 months, and every 6 months thereafter 3
• Monitor liver function tests before initiation and as clinically indicated 3
• Patients on coumarin anticoagulants require increased monitoring as fenofibrate potentiates anticoagulant effects 8
• Extreme caution is necessary in elderly patients, particularly with combination statin therapy 4

Important Drug Interactions

• Fenofibrate should not be initiated in patients already on statin therapy; if combination is necessary, use only with low or moderate-intensity statins 2
• The American Diabetes Association states statin-fibrate combination has not shown cardiovascular benefit and is generally not recommended 3
• Fenofibrate must be taken at least 4 hours apart from cholestyramine to avoid interaction 4

Contraindications in Special Populations

• Contraindicated in severe renal impairment (eGFR <30 mL/min/1.73m²) including dialysis patients 3, 2
• Should not be used in kidney transplant recipients 3
• Patients should not breastfeed during treatment and for 5 days after the final dose 8