Fenofibrate

Approved Indications:

• Primary Hypercholesterolemia (Type IIa): As an adjunct to diet for reducing elevated total cholesterol (Total-C), LDL-C, Apo B, and triglycerides (TG), and to increase HDL-C in adults.
• Mixed Dyslipidemia (Type IIb): To treat adults with combined elevation in LDL-C and TG.
• Severe Hypertriglyceridemia (Type IV and V): For reducing triglyceride levels in adults at risk of pancreatitis and those with very high triglycerides.
• Hyperlipidemia associated with Type 2 Diabetes Mellitus: Especially in patients not adequately managed by statins alone.
• Homozygous Familial Dysbetalipoproteinemia (Type III): In patients unresponsive to dietary changes and other lipid-lowering treatments.

Clinically Accepted Off-label Uses:

• Non-alcoholic Fatty Liver Disease (NAFLD)/Non-alcoholic Steatohepatitis (NASH): Used experimentally to improve lipid profiles and liver enzymes.
• Prevention of Cardiovascular Events: In statin-intolerant patients or those with persistently high triglycerides despite statin use.

Adults:

• Usual Oral Dose (Tablet or Capsule):
• 145 mg once daily (standard micronized tablet or capsule formulations).
• Administer with food to enhance absorption.

Dose Adjustments:

• Renal Impairment:
• Mild to Moderate (eGFR 30–59 mL/min/1.73 m²): Start at 54 mg once daily; monitor renal function regularly.
• Severe Renal Impairment (eGFR <30 mL/min/1.73 m²): Contraindicated.
• Hepatic Impairment: Avoid use due to lack of safety data.

Geriatric Use:

• No specific dose adjustment required, but renal function should be considered.

Pediatric Use:

• Not recommended under 18 years of age due to insufficient safety and efficacy data.

Administration Route:

• Oral only; swallow whole with water.
• Take with meals to improve bioavailability.

Treatment Duration:

• Long-term use may be necessary; lipid levels should be monitored periodically to adjust therapy.

Fenofibrate is a prodrug that is hydrolyzed to fenofibric acid, its active metabolite. It activates peroxisome proliferator-activated receptor-alpha (PPAR-α), which regulates gene expression involved in lipid metabolism. This results in:

• Enhanced lipolysis and clearance of triglyceride-rich lipoproteins.
• Increased expression of lipoprotein lipase (LPL).
• Reduced production of apoprotein C-III (an inhibitor of LPL).
• Increased HDL-C through upregulation of apolipoproteins A-I and A-II.
  These actions cumulatively lower triglycerides, total cholesterol, and LDL-C, while increasing HDL-C.

• Absorption: Improved with food; bioavailability ~60%.
• Onset of Action: Within several days; peak lipid-lowering effect in 4–8 weeks.
• Peak Plasma Time: 4–6 hours after dosing.
• Distribution: Highly protein-bound (>99% to albumin).
• Metabolism: Rapidly hydrolyzed to fenofibric acid (active form); no significant CYP450 metabolism.
• Elimination:
• Half-life: ~20 hours (fenofibric acid).
• Excretion: Primarily via urine (~60%) as fenofibric acid and its conjugates; minor fecal elimination.

• Pregnancy:
• FDA Pregnancy Category C: Animal studies have shown adverse fetal effects, but there are no adequate human studies. Should be used during pregnancy only if clearly needed.
• Contraindicated during pregnancy unless benefits outweigh risks.
• Lactation:
• Unknown if fenofibrate is excreted in human milk.
• Potential for serious adverse effects in nursing infants; breastfeeding is not recommended during use.

• Primary Class: Lipid-lowering agent
• Subclass: Fibric acid derivative (Fibrate)

• Known hypersensitivity to fenofibrate or its components
• Active liver disease, including primary biliary cirrhosis
• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• Pre-existing gallbladder disease
• Nursing mothers
• History of pancreatitis, except due to severe hypertriglyceridemia

• Hepatotoxicity: Monitor liver enzymes; discontinue if persistent elevations.
• Myopathy/Rhabdomyolysis: Risk increases with statin co-administration; monitor for muscle pain, especially in elderly or renal impairment.
• Renal Function Monitoring: Check serum creatinine and eGFR periodically.
• Cholelithiasis Risk: May increase biliary cholesterol excretion; monitor for gallstone symptoms.
• Pancreatitis: Has been reported; discontinue if suspected.
• Hypoalbuminemia or Nephrotic Syndrome: Use caution as protein binding may be affected.

Common Side Effects:

• Gastrointestinal: Nausea, abdominal pain, dyspepsia, diarrhea
• Musculoskeletal: Myalgia, back pain
• Hepatic: Elevated liver enzymes (ALT/AST)
• General: Headache, fatigue

Serious or Rare Side Effects:

• Rhabdomyolysis, especially when combined with statins
• Cholestatic hepatitis
• Gallstones
• Pancreatitis
• Anemia or leukopenia (rare)

Timing & Severity:

• Most mild side effects occur early and may resolve.
• Severe effects like muscle toxicity can occur weeks to months after initiation.

Major Drug-Drug Interactions:

• Statins (e.g., Simvastatin): Increased risk of myopathy and rhabdomyolysis.
• Anticoagulants (e.g., Warfarin): Potentiates anticoagulant effects; requires INR monitoring.
• Bile Acid Sequestrants: May impair fenofibrate absorption; administer fenofibrate 1 hour before or 4–6 hours after.
• Cyclosporine: May cause nephrotoxicity; monitor renal function closely.

CYP450 Involvement:

• Not significantly metabolized by CYP enzymes; low risk for CYP-mediated interactions.

Drug-Food/Alcohol Interactions:

• Food enhances absorption — always take with meals.
• Avoid excessive alcohol due to increased risk of liver and muscle toxicity.

• No recent changes in FDA or EMA-approved indications as of 2025.
• NICE (UK) and AHA/ACC lipid guidelines continue to recommend fenofibrate as add-on therapy for patients with elevated triglycerides despite statin therapy.
• Ongoing interest in fenofibrate’s role in managing metabolic syndrome and NAFLD, but not yet approved for these uses.

• Storage Temperature: Store below 30°C (room temperature).
• Humidity: Store in a dry place; avoid excess moisture.
• Light Protection: Keep in original packaging to protect from light.
• Handling: No reconstitution required. Do not crush or chew tablets or capsules.