What are the contraindications, precautions, dosing, monitoring, drug interactions, and special considerations for fenofibrate therapy?

Fenofibrate: Comprehensive Safety, Dosing, and Monitoring Guide

Absolute Contraindications

Fenofibrate is absolutely contraindicated in patients with severe renal dysfunction (eGFR <30 mL/min/1.73 m²), active liver disease, gallbladder disease, known hypersensitivity to fenofibrate, and in nursing mothers. 1

• Dialysis patients must not receive fenofibrate under any circumstances 1
• Active hepatic disease represents an absolute contraindication due to risk of serious drug-induced liver injury, including cases requiring liver transplantation and death 1
• Pre-existing gallbladder disease contraindicates use because fenofibrate increases cholesterol excretion into bile, raising cholelithiasis risk 1

Dosing by Renal Function

Renal function determines fenofibrate dosing more than any other factor, and failure to adjust for renal impairment is the most common prescribing error. 2

Normal Renal Function (eGFR ≥60 mL/min/1.73 m²)

• Primary hypercholesterolemia or mixed dyslipidemia: 160 mg once daily with meals 1
• Severe hypertriglyceridemia: 54–160 mg once daily with meals, maximum 160 mg 1

Mild-to-Moderate Renal Impairment (eGFR 30–59 mL/min/1.73 m²)

• Initial and maximum dose: 54 mg once daily 2, 3
• Do not exceed 54 mg in this population; dose escalation is contraindicated 2
• The most frequent prescribing error is giving 160 mg to patients with eGFR 30–59 mL/min/1.73 m²—always start at 54 mg and only consider increases after confirming renal safety 2

Severe Renal Impairment (eGFR <30 mL/min/1.73 m²)

• Fenofibrate is contraindicated 2, 1
• High risk of renal toxicity and rhabdomyolysis in this population 4

Geriatric Patients

• Select dose based entirely on renal function using the algorithm above 1
• Elderly patients, particularly thin or frail older women, face increased myopathy risk when fenofibrate is combined with statins 5

Pre-Treatment Assessment

Before initiating fenofibrate, obtain the following baseline studies:

• Serum creatinine and calculated eGFR to confirm renal function and guide dosing 2
• Fasting lipid panel to verify triglycerides ≥200 mg/dL (moderate hypertriglyceridemia) or document other lipid abnormalities 2
• Liver function tests: ALT, AST, and total bilirubin 2, 1
• Creatine kinase (CK) if planning combination with a statin 5

Ongoing Monitoring Schedule

Renal function monitoring is mandatory and non-negotiable throughout fenofibrate therapy. 2

• At 3 months: Recheck serum creatinine and eGFR 2
• Every 6 months thereafter: Monitor renal function (creatinine, eGFR) while patient remains on therapy 2, 3
• Discontinue immediately if eGFR persistently declines to <30 mL/min/1.73 m² during treatment 2

Hepatic Monitoring

• Monitor ALT, AST, and total bilirubin at baseline and periodically throughout therapy 1
• Discontinue fenofibrate if signs or symptoms of liver injury develop or if elevated enzyme levels persist 1

Lipid Response Monitoring

• Recheck fasting lipid panel at 4–12 weeks after initiation, then every 6–12 months once goals are achieved 5

When Combined with Statins

• Evaluate muscle symptoms and CK before starting combination therapy 5
• Reassess muscle symptoms 6–12 weeks after initiation, then at each follow-up visit 5
• Obtain CK measurement immediately if muscle soreness, tenderness, or pain develops 5
• Exercise particular caution during perioperative periods; consider withholding statins during major surgery 5

Drug Interactions

Critical: Gemfibrozil Combination is Prohibited

Never combine fenofibrate with gemfibrozil—this combination markedly increases rhabdomyolysis risk. 2

• Gemfibrozil increases myopathy risk approximately 15-fold compared to fenofibrate when combined with statins (8.6 vs 0.58 cases per million prescriptions) 5

Statin Combinations: Fenofibrate is Preferred

When combining a fibrate with any statin, fenofibrate is the only acceptable choice. 5

• Fenofibrate can be safely combined with all statins without specific dose restrictions 5
• Use only low- or moderate-intensity statins when combining with fenofibrate to minimize myopathy risk 5, 2
• Avoid atorvastatin 80 mg when combined with fenofibrate 5
• Hydrophilic statins (pravastatin, fluvastatin) are preferred because they are not metabolized by cytochrome P450 3A4, unlike lipophilic statins (atorvastatin, lovastatin, simvastatin) 6
• The FIELD trial reported zero cases of rhabdomyolysis among ~1,000 patients on fenofibrate-statin combination, demonstrating a favorable safety profile 5

Coumarin Anticoagulants

• Use caution when combining fenofibrate with warfarin or other coumarin anticoagulants 1
• Adjust anticoagulant dosage to maintain prothrombin time/INR at desired level to prevent bleeding complications 1
• Monitor INR more frequently after initiating or discontinuing fenofibrate 1

Bile Acid Resins

• Bile acid sequestrants (cholestyramine, colestipol, colesevelam) can decrease fenofibrate absorption 6
• Administer fenofibrate ≥2 hours before or ≥4 hours after bile acid resins 5
• These agents also decrease mycophenolate mofetate (MMF) levels by 35% and can reduce calcineurin inhibitor absorption 6

Immunosuppressants

• Use caution when combining fenofibrate with immunosuppressive agents in transplant recipients 1
• Monitor for increased myopathy risk, particularly in patients on cyclosporine 6

Special Populations

Chronic Kidney Disease

• Fenofibrate is not recommended for reducing cardiovascular mortality in CKD patients due to uncertain net clinical benefit 2
• Dose reduction to 54 mg daily is mandatory for eGFR 30–59 mL/min/1.73 m² 2, 3
• Avoid entirely if eGFR <30 mL/min/1.73 m² 2, 3

Nephrotic Syndrome

• Before starting fenofibrate, investigate causes of secondary hyperlipidemia, especially nephrotic syndrome 4
• In the presence of chronic renal failure and hypoalbuminemia, fenofibrate dose must be adjusted downward 4
• Case reports document rhabdomyolysis with fenofibrate monotherapy in nephrotic syndrome patients with chronic renal failure 4

Diabetes Mellitus

• Patients with diabetes combined with chronic renal failure require extra vigilance when using fenofibrate-statin combinations 5
• The ACCORD trial showed no significant reduction in fatal cardiovascular events, non-fatal MI, or non-fatal stroke when fenofibrate was added to simvastatin in type 2 diabetes 5
• Post-hoc analysis suggested possible benefit in patients with triglycerides ≥204 mg/dL and HDL-C ≤34 mg/dL 5

Liver Transplant Recipients

• Fenofibrate can cause biliary sludge, dyspepsia, or myopathy in transplant patients 6
• The combination of fenofibrate with a lipophilic statin significantly increases myotoxicity risk in this population 6
• Close patient follow-up is required to observe for medication side effects 6

HIV-Infected Patients on Antiretroviral Therapy

• Micronized fenofibrate 54–160 mg daily is appropriate for triglycerides >500 mg/dL 2

Pregnancy and Lactation

• Fenofibrate is contraindicated in nursing mothers 1
• Use in pregnancy only if potential benefit justifies potential risk to fetus (FDA labeling does not specify pregnancy category in current format) 1

High-Risk Scenarios Requiring Extra Caution

Advanced age (>65 years), small body frame, frailty, multisystem disease, multiple medications, and diabetes combined with chronic renal failure all increase myopathy risk. 5

• Older, thin, or frail women face particularly high risk when fenofibrate is combined with statins 5
• Perioperative periods require heightened vigilance; consider withholding therapy during major surgery 5
• Patients with hypothyroidism have increased myopathy risk 1

Adverse Effects and Safety Signals

Common Adverse Reactions (>2% and ≥1% greater than placebo)

• Abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis 1

Serious Adverse Effects

• Hepatotoxicity: Serious drug-induced liver injury, including cases requiring liver transplantation and death, has been reported 1
• Myopathy and rhabdomyolysis: Risk increases during co-administration with statins, particularly in elderly patients and those with diabetes, renal failure, or hypothyroidism 1
• Serum creatinine elevation: Fenofibrate can reversibly increase serum creatinine levels 1
• Cholelithiasis: Fenofibrate increases cholesterol excretion into bile, raising gallstone risk 1

Hypersensitivity Reactions

• Acute hypersensitivity reactions, including anaphylaxis and angioedema, have been reported postmarketing 1
• Delayed hypersensitivity reactions, including severe cutaneous adverse drug reactions, have occurred 1
• Some cases were life-threatening and required emergency treatment 1
• Discontinue fenofibrate immediately and treat appropriately if reactions occur 1

Other Adverse Effects

• Gastrointestinal disturbances, headache, and muscle cramps are common 7
• Transient elevations in transaminase and creatine phosphokinase levels commonly occur 7
• Fenofibrate has uricosuric properties that may lower uric acid levels 8

Clinical Indications and Treatment Algorithms

Primary Hypercholesterolemia or Mixed Dyslipidemia

• Fenofibrate is indicated as adjunct to diet to reduce elevated LDL-C, total cholesterol, triglycerides, and apolipoprotein B, and to increase HDL-C 1
• Initial dose: 160 mg once daily with meals (if eGFR ≥60 mL/min/1.73 m²) 1

Severe Hypertriglyceridemia

• Fenofibrate is first-line pharmacologic therapy for triglycerides ≥500 mg/dL to reduce pancreatitis risk 2
• Initial dose: 54–160 mg once daily with meals, individualized based on triglyceride levels and renal function 2

Moderate Hypertriglyceridemia (200–499 mg/dL)

• Optimize statin therapy and lifestyle modifications for 3 months before adding fenofibrate 5
• Add fenofibrate when LDL-C remains above goal despite statin therapy AND triglycerides remain elevated (>150 mg/dL) 5
• Add fenofibrate when HDL-C remains low (<40 mg/dL in men, <50 mg/dL in women) despite statin therapy 5

Combination Therapy Algorithm

1. Start with high-dose statin monotherapy plus optimized glycemic control (in diabetic patients) to address elevated LDL-C and moderately elevated triglycerides 5
2. Add fenofibrate if LDL-C remains above goal AND triglycerides >150 mg/dL after 3 months 5
3. Use only low- or moderate-intensity statins when combining with fenofibrate 5, 2
4. Monitor closely for muscle symptoms and renal function 5, 2

Lipid Targets

• LDL-C: <100 mg/dL for high-risk patients; <70 mg/dL for very-high-risk patients 5
• Non-HDL-C: <130 mg/dL when triglycerides are elevated 5
• HDL-C: >50 mg/dL is optimal for women; >40 mg/dL for men 5
• Triglycerides: <150 mg/dL is desirable; <500 mg/dL to reduce pancreatitis risk 5

Limitations of Use

Fenofibrate was not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus. 1

• The ACCORD trial demonstrated no significant reduction in fatal cardiovascular events, non-fatal MI, or non-fatal stroke with fenofibrate-simvastatin versus simvastatin alone in type 2 diabetes 5
• Combination therapy has not been shown to improve cardiovascular outcomes compared to statin monotherapy in large trials 5
• Fenofibrate should not be used as first-line LDL-C lowering; statins are superior with proven cardiovascular outcomes benefit 2

Administration

• Always administer fenofibrate with meals to optimize absorption 1
• Fenofibrate is well absorbed after oral administration, with peak plasma levels at 6–8 hours 8
• Protein binding is approximately 99% 8
• Half-life of fenofibric acid is 20 hours 8

Common Pitfalls to Avoid

• Never prescribe 160 mg to patients with eGFR 30–59 mL/min/1.73 m²—this is the most frequent error 2
• Never combine gemfibrozil with any statin—use fenofibrate instead 5, 2
• Do not delay combination therapy in severe hypertriglyceridemia (≥500 mg/dL)—initiate promptly to prevent pancreatitis 5
• Do not overlook renal function—combination therapy risk increases significantly in renal disease 5
• Do not assume all fibrates are equivalent—fenofibrate has a fundamentally different drug interaction profile than gemfibrozil 5
• Do not forget to space fenofibrate from bile acid resins—give fenofibrate ≥2 hours before or ≥4 hours after 5