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

Fenofibrate Side Effects

Fenofibrate is generally well tolerated, but clinicians must monitor for gastrointestinal disturbances, elevated liver transaminases, increased serum creatinine, musculoskeletal symptoms, and increased uric acid levels, with specific attention to renal function and potential drug interactions, particularly with statins. 1

Common Adverse Effects

Gastrointestinal Effects

• Gastrointestinal disturbances are among the most frequently reported side effects, including nausea, abdominal pain, and general GI discomfort 2, 3, 4
• These symptoms typically occur in approximately 6% of patients in clinical trials 3

Musculoskeletal Effects

• Muscle pain, tenderness, weakness, and cramps occur commonly and require immediate physician notification 1, 2
• The risk of myopathy increases when fenofibrate is combined with statins, though adverse musculoskeletal events were not significantly increased in the ACCORD trial with fenofibrate plus simvastatin 5
• Gemfibrozil (not fenofibrate) carries the highest risk of rhabdomyolysis when combined with statins, particularly simvastatin, and this combination is contraindicated 5

Hepatic Effects

• Transient elevations in transaminase levels commonly occur and are usually minor and asymptomatic 2, 4, 6
• Isolated cases of hepatitis with substantially elevated transaminase levels have been reported 2
• Patients must be monitored for symptoms of liver injury including jaundice, abdominal pain, nausea, malaise, dark urine, abnormal stool, and pruritus 1

Metabolic and Laboratory Abnormalities

Renal Effects

• Fenofibrate increases serum creatinine levels, which typically return to baseline after discontinuation 5
• The drug is contraindicated in severe renal impairment (eGFR <30 mL/min/1.73m²) and requires dose reduction to maximum 54 mg/day in moderate renal impairment (eGFR 30-59 mL/min/1.73m²) 7
• Renal function must be evaluated before initiation, within 3 months after starting, and every 6 months thereafter 7
• If eGFR decreases persistently to <30 mL/min/1.73m², fenofibrate must be discontinued 7

Uric Acid and Gout

• Fenofibrate increases uric acid levels and can precipitate gout 5
• Despite this, fenofibrate has modest uricosuric effects that may be beneficial in some patients with gout and hyperlipidemia 5

Glucose Metabolism

• Fenofibrate may cause new-onset diabetes or disturb diabetes management in some patients 5
• However, it does not adversely affect glycemic control in diabetic patients with hyperlipoproteinemia 2

Cardiovascular and Hematologic Effects

Cardiovascular Concerns

• In women without dyslipidemia, fenofibrate may increase the risk of cardiovascular events 5
• Increased risk of atrial fibrillation has been reported 5
• Increased bleeding risk has been documented 5

Hematologic Effects

• Mild abnormalities in leukocytes and hemoglobin may occur 3

Other Notable Side Effects

Dermatologic

• Skin reactions including rash, pruritus, and sweating occur in some patients 2, 3

Neurologic

• Headache and dizziness are reported 2, 3

Biliary Effects

• Fenofibrate increases the biliary lithogenic index (cholesterol saturation), though gallstones have seldom been associated with fenofibrate use 2, 3
• In primary biliary cholangitis, 5-10% of patients (mostly with bezafibrate) develop musculoskeletal pain 5

Critical Monitoring Requirements

Patients must inform their physician immediately of: 1

• Any muscle pain, tenderness, or weakness
• Symptoms of liver injury (jaundice, abdominal pain, nausea, malaise, dark urine, abnormal stool, pruritus)
• Onset of abdominal pain
• Any new symptoms

Drug Interactions and Contraindications

• Fenofibrate potentiates coumarin anticoagulants, requiring increased monitoring of anticoagulation 1
• Patients should not breastfeed during treatment and for 5 days after the final dose 1
• Fenofibrate should not be initiated in patients already on statin therapy due to increased risk of muscle symptoms and rhabdomyolysis; if combination therapy is necessary, use only with low or moderate-intensity statins 7

Long-Term Safety Profile

• The safety profile remains consistent during long-term treatment (2-7 years) 2
• European postmarketing surveillance over 10 years with 6 million patient-years of exposure showed a low reaction rate of approximately 0.3% incidence 3
• Carcinogenicity was evident in rodents at doses 12-40 times the human dose, but cancer has not been associated with fenofibrate in over 10 years of clinical use 3