Fenofibrate

Usage

• Fenofibrate is prescribed to lower high levels of cholesterol and triglycerides (types of fat) in the blood. Specifically, it reduces elevated LDL-C (“bad” cholesterol), total cholesterol, triglycerides, Apo B, and increases HDL-C (“good” cholesterol). It’s used when dietary changes and lifestyle modifications are insufficient. Fenofibrate is also used to treat severe hypertriglyceridemia. It has shown benefits in reducing the risk of pancreatitis in individuals with very high triglyceride levels.
• Pharmacological classification: Fibrate, Antihyperlipidemic agent.
• Mechanism of Action: Fenofibrate is a peroxisome proliferator-activated receptor alpha (PPARα) agonist. It activates PPARα, which increases the activity of lipoprotein lipase, an enzyme that breaks down triglycerides. This leads to increased clearance of triglyceride-rich particles. Fenofibrate also decreases the liver’s production of VLDL (very-low-density lipoprotein), a precursor to LDL, and increases HDL production. It also promotes fatty acid oxidation.

Alternate Names

• Fenofibric acid (the active form of fenofibrate)
• Brand Names: Antara, Fenoglide, Lipofen, TriCor, Triglide, Trilipix

How It Works

• Pharmacodynamics: Fenofibrate primarily lowers triglyceride and VLDL cholesterol levels. It also moderately reduces LDL cholesterol and may increase HDL cholesterol. These effects are mediated through activation of PPARα.
• Pharmacokinetics:
  • Absorption: Fenofibrate is well-absorbed orally, and absorption is enhanced when taken with food. Micronized formulations have improved bioavailability.
  • Metabolism: Fenofibrate is rapidly hydrolyzed to its active form, fenofibric acid, in the gastrointestinal tract. Fenofibric acid is primarily glucuronidated, though some CYP450 metabolism occurs.
  • Elimination: Primarily eliminated in the urine as fenofibric acid glucuronide, with a small amount eliminated in the feces.
• Mode of Action: Upon binding to PPARα, fenofibrate modulates gene expression of proteins involved in lipid metabolism. It increases the synthesis of lipoprotein lipase and other enzymes involved in triglyceride breakdown, leading to increased clearance of VLDL. It also reduces the production of Apo C-III, which inhibits lipoprotein lipase activity. Finally, it enhances hepatic fatty acid oxidation.
• Receptor binding: PPARα agonist
• Elimination pathways: Primarily renal excretion as glucuronide conjugates; some fecal excretion.

Dosage

Standard Dosage

Adults:

• Primary Hypercholesterolemia or Mixed Dyslipidemia: 145 mg of Tricor or 160 mg of Lofibra, Triglide, or generic fenofibrate once daily. The dose can be adjusted based on the individual’s response and tolerance, with the maximum dose at 145mg (Tricor) or 160mg (Lofibra, Triglide, and generic).
• Severe Hypertriglyceridemia: 48-145 mg of Tricor or 54-160 mg of Lofibra, Triglide, or generic fenofibrate, or 40-120 mg of Fenoglide once daily.
• Administer with food to enhance absorption (except Tricor).

Children: Fenofibrate is not recommended for use in patients under 18 years of age as safety and efficacy have not been established.

Special Cases:

• Elderly Patients: Initiate therapy with a lower dose (e.g., 48 mg/day) and monitor renal function before increasing the dose.
• Patients with Renal Impairment: In patients with mild to moderately impaired renal function (eGFR 30-59 mL/min/1.73 m²), the dose of fenofibrate should not exceed 100 mg (standard) or 67 mg (micronized) once daily. It is contraindicated in severe renal impairment (eGFR <30 mL/min/1.73 m²).
• Patients with Hepatic Dysfunction: Use with caution and monitor liver function tests.
• Patients with Comorbid Conditions: Use with caution in patients with diabetes, hypothyroidism, or preexisting muscle disorders. Monitor closely for myopathy.

Clinical Use Cases

Fenofibrate isn’t typically used in acute clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary use is for long-term management of dyslipidemias.

Dosage Adjustments

Adjustments are based on renal function, liver function, and comorbid conditions. Genetic polymorphisms affecting drug metabolism are not routinely considered.

Side Effects

Common Side Effects

• Headache, back pain, nausea, indigestion, stuffy or runny nose, stomach pain, diarrhea, constipation, joint pain, muscle pain, elevated liver enzymes.

Rare but Serious Side Effects

• Myopathy (muscle pain, weakness, tenderness), rhabdomyolysis (muscle breakdown), pancreatitis, cholelithiasis (gallstones), hepatitis, blood clots, pulmonary embolism, severe allergic reactions.

Long-Term Effects

• Potential for chronic myopathy, liver dysfunction, gallbladder disease.

Adverse Drug Reactions (ADR)

• Rhabdomyolysis, severe allergic reaction, pancreatitis.

Contraindications

• Severe renal impairment (including dialysis patients).
• Active liver disease (including biliary cirrhosis).
• Gallbladder disease.
• Hypersensitivity to fenofibrate.
• Nursing mothers.

Drug Interactions

• Statins: Increased risk of myopathy and rhabdomyolysis.
• Bile Acid Sequestrants: Reduced absorption of fenofibrate; administer at least 1 hour before or 4-6 hours after bile acid sequestrants.
• Warfarin: Enhanced anticoagulant effect; monitor INR closely.
• Cyclosporine: Increased risk of nephrotoxicity; monitor renal function.
• Sulfonylureas: Increased risk of hypoglycemia.
• Colchicine: Increased risk of myopathy.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: C. Limited data available; use only if the potential benefit outweighs the risk. Animal studies have shown adverse effects at high doses.
• Breastfeeding: Contraindicated. It is unknown if fenofibrate is excreted in human milk, but due to the potential for serious adverse reactions in nursing infants and concerns about disrupting infant lipid metabolism, breastfeeding should be avoided.

Drug Profile Summary

• Mechanism of Action: PPARα agonist, increases lipoprotein lipase activity, decreases VLDL production, enhances fatty acid oxidation.
• Side Effects: Common: headache, back pain, GI upset. Serious: rhabdomyolysis, pancreatitis, cholelithiasis.
• Contraindications: Severe renal/liver disease, gallbladder disease, nursing mothers.
• Drug Interactions: Statins, bile acid sequestrants, warfarin, cyclosporine, sulfonylureas.
• Pregnancy & Breastfeeding: Category C; contraindicated in breastfeeding.
• Dosage: Varies by indication and formulation; typically 145-160 mg/day for hypercholesterolemia or mixed dyslipidemia; 48-145 mg/day for hypertriglyceridemia.
• Monitoring Parameters: Lipid panel, liver function tests, renal function (especially in at-risk patients), creatine kinase (if myopathy suspected).

Popular Combinations

• Statins (despite interaction risk, sometimes used in combination for severe dyslipidemia under close monitoring).

Precautions

• Assess renal and liver function before initiating therapy.
• Monitor for signs and symptoms of myopathy, pancreatitis, and cholelithiasis.
• Pregnant Women: Use only if clearly needed and benefits outweigh risks.
• Breastfeeding Mothers: Avoid breastfeeding.
• Children & Elderly: Not recommended for children; adjust dose for elderly based on renal function.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Fenofibrate?

A: For adults with primary hypercholesterolemia or mixed dyslipidemia, the typical dose is 145 mg (Tricor) or 160 mg (Lofibra, Triglide, or generic fenofibrate) once daily. For severe hypertriglyceridemia, the dose ranges from 40-160 mg/day, depending on the formulation.

Q2: What are the most serious side effects of fenofibrate?

A: The most serious side effects include rhabdomyolysis (muscle breakdown), myopathy, pancreatitis, and liver toxicity.

Q3: Can fenofibrate be used during pregnancy?

A: Fenofibrate is a pregnancy category C drug. It should only be used during pregnancy if the potential benefit outweighs the potential risk to the fetus.

Q4: Is it safe to take fenofibrate while breastfeeding?

A: No, fenofibrate is contraindicated during breastfeeding due to potential harm to the infant.

Q5: How does fenofibrate interact with statins?

A: Co-administration with statins increases the risk of myopathy and rhabdomyolysis. Close monitoring is necessary if these drugs are used together.

Q6: What should patients do if they experience muscle pain while taking fenofibrate?

A: Patients should immediately report any muscle pain, tenderness, or weakness to their physician as it could indicate myopathy or rhabdomyolysis.

Q7: Does fenofibrate need to be taken with food?

A: Some formulations of fenofibrate (Antara, Lipofen, Lofibra, Triglide) are better absorbed with food. However, Tricor may be taken without regard to meals. Consult the specific product information.

Q8: How often should liver function tests be monitored in patients taking fenofibrate?

A: Liver function tests should be monitored periodically, particularly at the start of therapy and with any dose adjustments. The exact frequency depends on the patient’s individual risk factors and clinical status.

Q9: What is the mechanism of action of fenofibrate?

A: Fenofibrate is a PPARα agonist that increases lipoprotein lipase activity, leading to increased triglyceride breakdown and clearance. It also decreases VLDL production and enhances fatty acid oxidation.