Fenofibrate - Drug Monograph

Of course. Here is a comprehensive, evidence-based drug monograph for Fenofibrate, formatted as a complete blog post.

Introduction

Fenofibrate is a widely prescribed lipid-modifying agent belonging to the fibrate class of drugs. It is primarily used as an adjunct to diet and lifestyle modifications to manage dyslipidemias, particularly those characterized by elevated triglycerides and low levels of high-density lipoprotein cholesterol (HDL-C). While effective, its use requires careful patient selection and monitoring due to its effects on kidney and liver function and its potential to increase serum creatinine.

Mechanism of Action

Fenofibrate is a prodrug that, upon ingestion, is hydrolyzed to its active metabolite, fenofibric acid. Fenofibric acid acts as an agonist for the peroxisome proliferator-activated receptor-alpha (PPAR-α). Activation of PPAR-α alters the transcription of genes involved in lipid metabolism, leading to: * Increased Lipolysis: Enhanced lipoprotein lipase activity, accelerating the catabolism of triglyceride-rich very-low-density lipoproteins (VLDL) and chylomicrons. * Reduced Synthesis: Decreased production of apolipoprotein C-III (an inhibitor of lipoprotein lipase), further promoting VLDL clearance. * Increased HDL Production: Stimulation of the synthesis of apolipoproteins A-I and A-II, leading to increased production and circulation of High-Density Lipoprotein (HDL) cholesterol.

The net effect is a significant reduction in serum triglycerides (TG), a moderate reduction in Low-Density Lipoprotein Cholesterol (LDL-C), and an increase in HDL-C.

Indications

Fenofibrate is FDA-approved for the following indications: * Primary Hypercholesterolemia or Mixed Dyslipidemia: As an adjunct to diet to reduce elevated LDL-C, total cholesterol, triglycerides, and apo B, and to increase HDL-C in adult patients. * Severe Hypertriglyceridemia: As an adjunct to diet for the treatment of adult patients with very high (≥500 mg/dL) triglyceride levels. The goal is to reduce the risk of pancreatitis. * Important Note: Fenofibrate has not been shown to reduce all-cause mortality or coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus.

Dosage and Administration

* Available Formulations: Tablets (e.g., 48 mg, 145 mg), capsules (e.g., 67 mg, 134 mg, 200 mg), and micronized formulations. Dosing is not equivalent between all formulations; prescribers must specify the brand or type. * Standard Adult Dose: The dose must be individualized based on patient factors and the specific product used. A common dose for many formulations is 145 mg once daily. * Administration: Should be taken with food to enhance bioavailability. * Special Populations: * Renal Impairment: Dose reduction is required. Contraindicated in patients with severe renal impairment (eGFR <30 mL/min). For mild to moderate impairment (eGFR 30-59 mL/min), the initial dose should not exceed 48 mg/day (or its equivalent for other products). * Hepatic Impairment: Contraindicated in patients with active liver disease, including primary biliary cholangitis and unexplained persistent liver enzyme elevations. * Geriatric Patients: Select dose carefully due to the higher likelihood of hepatic, renal, or cardiac impairment. * Pediatric Patients: Safety and effectiveness have not been established.

Pharmacokinetics

* Absorption: Well absorbed but bioavailability is increased approximately 35% when taken with food. Peak plasma concentrations of fenofibric acid occur within 4 to 5 hours. * Distribution: Highly bound to plasma albumin (>99%). * Metabolism: Fenofibrate is rapidly hydrolyzed by esterases to fenofibric acid, which is the active circulating species. It is primarily metabolized in the liver via glucuronidation and CYP450-mediated oxidation (minor pathway). * Elimination: Primarily excreted in the urine (approximately 60%) as fenofibric acid and its glucuronide conjugate, and in the feces. The elimination half-life of fenofibric acid is approximately 20 hours, allowing for once-daily dosing.

Contraindications

* Hypersensitivity to fenofibrate, fenofibric acid, or any component of the formulation. * Active liver disease, including primary biliary cholangitis and unexplained persistent liver function abnormalities. * Severe renal impairment (eGFR <30 mL/min). * Gallbladder disease. * Nursing mothers.

Warnings and Precautions

* Hepatotoxicity: Serum transaminases (ALT, AST) can increase. Regular monitoring is required. Discontinue if levels persist >3 times the upper limit of normal (ULN). * Myotoxicity: Can cause myopathy, rhabdomyolysis, and elevated creatine kinase (CK). Risk is increased with renal impairment, advanced age, and concomitant use with statins. Monitor for muscle pain, tenderness, or weakness. * Renal Effects: Increases serum creatinine and can cause acute kidney injury, particularly in patients with pre-existing renal disease. Monitor renal function periodically. * Cholelithiasis: Fibrates increase cholesterol secretion into bile, leading to an increased risk of gallstones. * Pancreatitis: Can occur in patients with significant triglyceride reduction; however, this is rare and must be distinguished from pancreatitis due to severe hypertriglyceridemia itself. * Venous Thromboembolism: Some fibrate trials have shown an increased risk of deep vein thrombosis and pulmonary embolism.

Drug Interactions

| Interacting Drug Class/Agent | Effect & Clinical Management | | :--- | :--- | | HMG-CoA Reductase Inhibitors (Statins) | Increased risk of myopathy and rhabdomyolysis. Use the lowest effective dose of both agents and monitor CK levels and for muscle symptoms. | | Bile Acid Sequestrants (e.g., Cholestyramine) | May bind to fenofibrate and reduce its absorption. Administer fenofibrate at least 1 hour before or 4-6 hours after the resin. | | Warfarin | Fenofibrate may potentiate anticoagulant effect, increasing INR and risk of bleeding. Monitor INR closely upon initiation, dosage change, or discontinuation of fenofibrate. Warfarin dose adjustment is often necessary. | | Cyclosporine | May increase the risk of renal toxicity. Avoid concomitant use. | | Other Highly Protein-Bound Drugs | Fenofibrate is highly protein-bound and may compete for binding sites, potentially increasing the free fraction of either drug (e.g., oral hypoglycemics, other anticoagulants). Monitor for efficacy/toxicity. |

Adverse Effects

* Common (>5%): Abnormal liver function tests, increased creatinine, respiratory disorders, abdominal pain, back pain, headache, nausea. * Less Common but Serious: * Myopathy/Rhabdomyolysis * Pancreatitis * Hepatitis, cirrhosis * Renal failure, increased creatinine * Venous thromboembolism * Severe cutaneous reactions (e.g., Stevens-Johnson Syndrome)

Monitoring Parameters

* Baseline: Lipid panel (TG, LDL-C, HDL-C), LFTs (ALT, AST), renal function (serum creatinine, eGFR), CK (if symptomatic or on concomitant statin). * Ongoing: * Lipid Panel: Check within 4-8 weeks after initiation or dose change to assess efficacy. * LFTs: Monitor periodically (e.g., every 3-6 months for the first 12 months). * Renal Function: Monitor serum creatinine within 3 months of initiation and periodically thereafter. * CK: As clinically indicated, especially if patient reports muscle pain or weakness. * INR: If on concomitant warfarin, monitor frequently after any change in fenofibrate therapy.

Patient Education

* This medication is an adjunct to, not a replacement for, a heart-healthy diet and regular exercise. * Take with food to improve absorption. * Report any unexplained muscle pain, tenderness, or weakness (especially with fever or malaise) to your doctor immediately. * Report any symptoms of liver problems (e.g., nausea, vomiting, abdominal pain, fatigue, dark urine, jaundice) or pancreatitis (severe abdominal pain that may radiate to the back, with or without vomiting). * Inform all your healthcare providers that you are taking fenofibrate, especially before starting any new medication, including over-the-counter drugs and supplements. * Attend all scheduled blood tests to monitor the drug's effect and your safety.

References

1. FDA Prescribing Information for Fenofibrate (TriCor®). Revised [Please consult latest label]. 2. Grundy, S. M., et al. (2018). "2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines." Journal of the American College of Cardiology, 73(24), e285-e350. 3. Davidson, M. H., et al. (2007). "Efficacy and safety of fenofibrate in patients with type 2 diabetes mellitus: a systematic review and meta-analysis." The American Journal of Cardiology, 99(12A), 91S-101S. 4. Keech, A., et al. (2005). "Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial." The Lancet, 366(9500), 1849-1861. 5. Lexicomp Online®, Hudson, Ohio: Lexi-Comp, Inc.; 2023; [May 27, 2023]. 6. Micromedex® Solutions, Truven Health Analytics, Inc. Ann Arbor, MI; [May 27, 2023].