Fenofibrate
1. Drug Name
Generic Name: Fenofibrate
Brand Names: Tricor, Lipofen, Antara, Fenoglide, and others.
2. Drug Classification
Class: Fibrates
Subclass: Antilipemic agent
3. Mechanism of Action
Peroxisome Proliferator-Activated Receptor Alpha (PPAR-α) Agonist: Fenofibrate primarily works by activating PPAR-α, a nuclear receptor that regulates the expression of genes involved in lipid metabolism. Upon activation, PPAR-α increases the transcription of enzymes involved in fatty acid oxidation, leading to:
Increased breakdown of triglycerides (TG) in the liver and muscle tissue.
Enhanced lipoprotein lipase activity, which leads to the clearance of triglycerides from plasma.
Decreased production of very low-density lipoprotein (VLDL), which is a precursor of low-density lipoprotein (LDL) cholesterol.
Lipid Effects: Fenofibrate lowers plasma triglycerides, reduces total cholesterol, and increases high-density lipoprotein (HDL) cholesterol levels, thereby improving the overall lipid profile.
Additional Effects: Fenofibrate may also have anti-inflammatory and antioxidant effects, and it can improve endothelial function, further contributing to its cardiovascular benefits.
4. Pharmacokinetics
Absorption:
Fenofibrate is well absorbed from the gastrointestinal tract, with peak plasma concentrations typically achieved 4-5 hours after oral administration.
Bioavailability is approximately 60%, but the extent of absorption can be increased if taken with food.
Distribution:
Fenofibrate is extensively protein-bound (about 99%) to plasma proteins, particularly albumin.
It has a moderate volume of distribution (Vd) and is widely distributed in tissues.
Metabolism:
Fenofibrate is extensively metabolized in the liver via hydrolysis to its active metabolite, fenofibric acid, which is responsible for its lipid-lowering effects.
Fenofibric acid is further conjugated with glucuronic acid and excreted in the urine.
Excretion:
Half-life (t½): The half-life of fenofibric acid (the active metabolite) is about 20 hours, allowing for once-daily dosing.
Excretion: Fenofibrate and its metabolites are primarily excreted in the urine, with a small fraction in the feces.
Special Considerations:
Renal Impairment: Fenofibrate is contraindicated in severe renal impairment (e.g., creatinine clearance <30 mL/min). Dose adjustment is necessary in patients with mild to moderate renal impairment.
Hepatic Impairment: Fenofibrate should be used with caution in patients with hepatic impairment, and its use is contraindicated in active liver disease.
5. Indications
Primary Indications:
Hypertriglyceridemia: Fenofibrate is used to reduce elevated triglyceride levels (typically ≥500 mg/dL) and to prevent pancreatitis associated with hypertriglyceridemia.
Dyslipidemia: It is used to manage mixed dyslipidemia (elevated cholesterol and triglycerides), where it lowers triglycerides, LDL cholesterol, and increases HDL cholesterol.
Hypercholesterolemia: Fenofibrate may be used as adjunctive therapy in patients with elevated LDL cholesterol who are not controlled with statins alone.
Off-label Uses:
Cardiovascular Risk Reduction: Fenofibrate may be used to reduce the risk of cardiovascular events in patients with mixed dyslipidemia or a high cardiovascular risk, although evidence for this use is mixed.
Renal Disease: Fenofibrate may be used to reduce proteinuria in patients with chronic kidney disease (off-label).
6. Dosage and Administration
Adult Dosing:
Hypertriglyceridemia: The typical starting dose is 48-145 mg once daily, depending on the formulation (e.g., Tricor or Fenoglide).
Hypercholesterolemia: The dose may range from 48-145 mg once daily, depending on the severity of lipid abnormalities.
Pediatric Dosing:
Fenofibrate is generally not recommended for children, but in certain cases, pediatric dosing may be adjusted under the supervision of a healthcare provider.
Renal Adjustments:
In patients with mild to moderate renal impairment (creatinine clearance 30-80 mL/min), a dose reduction may be necessary.
Contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min).
Hepatic Adjustments:
Contraindicated in patients with active liver disease or unexplained persistent elevations in liver enzymes.
7. Contraindications
Absolute Contraindications:
Severe Renal Impairment: Fenofibrate should not be used in patients with severe renal dysfunction (creatinine clearance <30 mL/min).
Active Liver Disease: Fenofibrate is contraindicated in patients with active liver disease, including cirrhosis or severe hepatic dysfunction.
Gallbladder Disease: Contraindicated in patients with a history of gallstones or gallbladder disease due to the risk of gallbladder-related complications.
Relative Contraindications:
Pregnancy: Fenofibrate is classified as Category C in pregnancy. It should only be used during pregnancy if the benefits outweigh the risks.
Breastfeeding: It is not recommended during breastfeeding, as fenofibrate is excreted in breast milk.
Hypersensitivity: Patients with known hypersensitivity to fenofibrate or other fibrates should avoid its use.
8. Warnings and Precautions
Rhabdomyolysis: Like other fibrates, fenofibrate is associated with an increased risk of muscle damage (myopathy) and rhabdomyolysis, especially when used in combination with statins. Patients should be monitored for unexplained muscle pain or weakness.
Liver Function Monitoring: Liver function tests should be performed before initiation of therapy and periodically thereafter, as fenofibrate can cause liver enzyme elevations.
Gallstones: Fenofibrate can increase the risk of gallstones; patients with a history of gallbladder disease should be monitored.
Renal Impairment: Fenofibrate should be used cautiously in patients with pre-existing renal impairment, and dose adjustments may be necessary.
9. Adverse Effects
Common Adverse Effects:
Gastrointestinal Symptoms: Nausea, abdominal pain, diarrhea, and flatulence.
Rash: A mild, transient rash is common in some patients.
Less Common but Clinically Significant:
Liver Enzyme Elevations: Increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) may occur, and liver function tests should be monitored.
Myopathy and Rhabdomyolysis: Rare but serious, particularly in patients with renal impairment or when used in combination with statins.
Rare/Serious Adverse Effects:
Gallstones: Fenofibrate can increase the risk of gallstone formation, particularly in patients with predisposing factors.
Pancreatitis: Though rare, fenofibrate can cause pancreatitis in some patients.
10. Drug Interactions
Statins: Combining fenofibrate with statins increases the risk of myopathy and rhabdomyolysis. Use caution and monitor for muscle-related symptoms.
Warfarin: Fenofibrate can enhance the anticoagulant effect of warfarin, increasing the risk of bleeding. Close monitoring of the INR is necessary.
Cyclosporine: Fenofibrate may increase cyclosporine levels, requiring dose adjustments.
Oral Contraceptives: Fenofibrate may reduce the effectiveness of oral contraceptives in some patients.
11. Clinical Pharmacology
Pharmacodynamics: Fenofibrate significantly reduces triglycerides, total cholesterol, and LDL cholesterol levels, while it modestly increases HDL cholesterol. Its effects are primarily due to enhanced fatty acid oxidation and increased lipoprotein lipase activity.
Pleiotropic Effects: Fenofibrate also has anti-inflammatory and antioxidant effects, which may further improve endothelial function and reduce the risk of atherosclerosis.
12. Special Populations
Pregnancy: Fenofibrate should be used with caution in pregnancy and only if the potential benefit justifies the potential risk to the fetus.
Lactation: It is contraindicated during breastfeeding.
Pediatrics: Safety and efficacy in children have not been well studied, so fenofibrate is generally not recommended for pediatric use.
Geriatrics: Older adults may be at higher risk for side effects, especially myopathy, and should be monitored closely.
Renal Impairment: Dose adjustments are required in mild to moderate renal impairment, and the drug is contraindicated in severe renal impairment.
13. Therapeutic Uses
Primary Hypertriglyceridemia: Fenofibrate is effective for treating elevated triglycerides and reducing the risk of pancreatitis.
Mixed Dyslipidemia: It is also useful in patients with mixed dyslipidemia (high triglycerides and low HDL).
Cardiovascular Risk Reduction: Fenofibrate may be used to reduce the risk of heart disease in patients with lipid abnormalities.
14. Monitoring and Follow-Up
Liver Function Tests: Periodically monitor liver enzymes for any signs of hepatic dysfunction.
Renal Function Tests: Regularly monitor renal function, especially in patients with existing renal impairment.
Muscle Symptoms: Monitor for any signs of muscle weakness or pain, particularly when used with statins.
15. Overdose Management
Symptoms of Overdose: Overdose may result in severe muscle pain, weakness, liver toxicity, and gastrointestinal distress.
Management: There is no specific antidote for fenofibrate overdose. Treatment is symptomatic and supportive, with particular attention to kidney and liver function.
16. Patient Counseling Information
Administration: Take fenofibrate once daily with food to increase absorption.
Side Effects: Report any unexplained muscle pain, weakness, or tenderness to a healthcare provider, as this may indicate muscle toxicity.
Liver Problems: Notify a healthcare provider if you develop signs of liver dysfunction, such as yellowing of the skin or eyes, dark urine, or persistent abdominal pain.
Gallstones: Fenofibrate may increase the risk of gallstones, and patients should be advised to report any new abdominal symptoms.