Fenofibrate

Mechanism of Action

Fibrates such as fenofibrate activate peroxisome proliferator-activated receptors alpha (PPAR-alpha), which upregulate lipoprotein lipase, induce high-density lipoprotein (HDL) synthesis, and decrease liver production of apolipoprotein C. Fibrates ultimately enhance the clearance of triglyceride-rich particles and plasma catabolism. Fibrates also enhance fatty acid oxidation via acyl CoA synthetase and other enzymes, further reducing triglycerides' synthesis. The end result is an overall reduction of plasma triglyceride and very-low-density lipoprotein (VLDL) levels. The decrease in VLDL can cause plasma triglyceride levels to decrease by 30% to 60%. In addition, fenofibrate may facilitate an increase in uric acid excretion and reduction of fibrinogen, which may help patients with gout and thrombosis.[3]

Pharmacokinetics

Fenofibrate is well-absorbed (approximately 60%) after oral administration with a time of peak plasma concentration reaching 4 to 8 hours. It is a highly protein-bound drug (99%), and its steady-state concentration is reached within five days of administration. It is hydrolyzed into a primary metabolite, fenofibric acid, which is further conjugated with glucuronic acid. Fenofibrate has a terminal half-life of 20 to 23 hours. About 60% of the dose is excreted in the urine, and about 25% is excreted in the feces.[4]

Administration

Fenofibrate capsules and tablets are administered orally once daily with or without food. The capsules should be swallowed whole and should not be crushed, dissolved, or chewed. Fenofibrate therapy may be considered an option for individuals taking moderate-intensity statin therapy if the benefits (i.e., decreasing cardiovascular disease risk) outweigh the potential risks of adverse effects. Dose adjustments are made at 4 to 8-week intervals based on the individual patient response.[3]

It is available in the following oral dosage formulations, and formulation change should be done carefully as formulations are not bio-equivalent:

Capsule of fenofibrate: 30 mg, 43 mg, 50 mg, 67 mg, 90 mg, 130 mg, 134 mg, 150 mg, and 200 mg

Delayed-Release capsule of choline fenofibrate: 45 mg and 135 mg

Tablet of feno-fibric acid: 35 mg and 105 mg

Tablet of fenofibrate: 40 mg, 48 mg, 54 mg, 120 mg, 145 mg, and 160 mg

Adult Dosing  (dose of tablets of fenofibrate)

• Hypertriglyceridemia (type IV or V)
  • 54 to 160 mg daily 
• Primary Hypercholesterolemia
  • 160 mg daily 
• Mixed dyslipidemia
  • 160 mg daily 

 Specific Patient Population 

• Patient with Hepatic Impairment: There is no dose adjustment guidance in the manufacturer label for patients with hepatic impairment. However, the drug should be used with caution in these patients. Liver function monitoring is recommended.[4]

• Patient with Renal Impairment:  No dose adjustment is necessary for patients with renal impairment if creatinine clearance is above 80 mL/min. For moderate impairment, start the patient at 40 to 54 mg daily. Fenofibrate is contraindicated if creatinine clearance is under 30 mL/min or if the patient has severe renal dysfunction. 

• Pregnancy Implications: It is considered as pregnancy category C medicine. However, due to limited data on fenofibrate use in pregnant women, it is not sufficient to determine the risk of major congenital disabilities, adverse maternal or fetal outcomes, or miscarriage-related risk associated with this drug.

• Breastfeeding Implications: There is no information available on the presence of this drug in human milk. The effects of the drug on milk production or the breastfed infant are also unknown.[5]

• Pediatric Patients: The safety and efficacy are not established in pediatric patients. 

• Geriatric Patients: Based on the safety and efficacy studies in elderly volunteers 77 – 87 years of age, the oral clearance of the drug in geriatric patients is similar to that of adults, so there is no dose adjustment or specific dosage regimen needed for geriatric patients. It is recommended to start the dose based on renal function and product-specific labeling.[3]

Adverse Effects

Some of the most common adverse effects of fibrates include headaches, dizziness, back pain, joint pain, asthenia, diarrhea, nausea, constipation, dyspepsia, cough, wheezing, nasopharyngitis, and flu-like symptoms. Some potentially serious adverse effects that may require dose adjustment or discontinuation may include elevated liver enzymes, elevated creatine phosphokinase (CPK), cholelithiasis development, arrhythmia exacerbation, pulmonary embolism, pancreatitis, agranulocytosis, and myocardial infarction.[6]

Drug Interactions

Bile acid sequestrants: It is recommended to modify therapy when bile acid sequestrants are coadministered with fenofibrate as they may decrease the overall absorption of the fibric acid. If coadministration of these drugs is necessary, it is recommended to administer the fenofibrate one hour prior or four to six hours after a bile acid sequestrant. 

Ciprofibrate: As both ciprofibrate and fenofibrate are fabric acid derivatives, the coadministration of these medicines may enhance the adverse toxic effect associated with fibric acid derivatives. It is highly recommended to avoid this combination.

Systemic cyclosporine: It is recommended to modify therapy when fenofibrate is coadministered with systemic cyclosporine. This combination may lead to the increased nephrotoxic effect of fibric acid. Therefore, it is recommended to either modify therapy or monitor renal function closely if these drugs are coadministered.[7]

Warfarin or vitamin K antagonists: It is recommended to modify therapy when fenofibrate is coadministered with warfarin or vitamin K antagonists as fenofibrate may enhance the anticoagulant effect of warfarin or vitamin K antagonists.[8]

Contraindications

Fenofibrate is contraindicated for patients with a history of hypersensitivity to fenofibrate, liver disease, severe renal dysfunction, preexisting gallbladder disease, or breastfeeding. Fenofibrate may also interact with other drugs and may require a change in dose, frequency, or switching to a new therapy. When prescribing fenofibrate in conjunction with statins (HMG-CoA reductase inhibitors) or colchicine, rhabdomyolysis and myopathy may occur. There is also an increased incidence of myopathy related to fenofibrate therapy in patients diagnosed with diabetes mellitus, thyroid disorder, or a renal disorder.[3]

Fibrates, especially gemfibrozil, are associated with an increased risk of cholecystitis and cholelithiasis due to their ability to increase the cholesterol saturation in bile. Patients with severe renal dysfunction, including those on dialysis, should avoid fenofibrate due to reduced drug clearance and increased risk of myositis. Caution is necessary if patients are on anticoagulation therapy as fenofibrate may potentiate the effects of coumarin-type medications.[9]

Monitoring

Patients on fenofibrate should undergo monitoring for the effectiveness of treating a medical condition and any adverse effects pertaining to the medication. A complete list of patient medications should be reviewed before initiating drug therapy. The clinician should discontinue treatment if an inadequate response is not seen within two to three months of beginning the fenofibrate therapy. Kidney function labs such as uric acid (UA), blood urea nitrogen (BUN), and creatine clearance (CrCl) should have regular monitoring in individuals with renal impairment, and dosing should be adjusted as needed. The hepatic function is crucial to monitor to avoid administering the medication to individuals with an active hepatic disorder or persistently elevated serum transaminases.[10] Regular monitoring of creatine phosphokinase (CPK) levels is required to check for any signs and symptoms of myopathy or rhabdomyolysis. Blood counts should also be periodically monitored to reduce risks of thrombocytopenia and agranulocytosis. A periodic lipid panel, including total cholesterol, HDL, LDL, and triglyceride levels, should be conducted to assess drug safety and efficacy. Fenofibrate should be stored in a cool place away from light and moisture.[11]

Toxicity

The most common toxicity associated with fenofibrate is myopathy when given with statin medicines concurrently. If rhabdomyolysis is excluded and other muscle-related diseases are suspected, the statin-associated muscle symptoms clinical index (SAMS-CI) should be evaluated to determine if muscle symptoms are due to statin therapy. Discontinuing fenofibrate, administering vitamin D replacement (for low vitamin D levels), and switching the medication are all possible options depending on the cause of myopathy.[12]

There is no specific treatment available for the overdose of fenofibrate. General supportive care is recommended for the patient. The vital signs and clinical status should be monitored if an overdose occurs. If needed, the elimination of unabsorbed drugs should be attained by emesis or gastric lavage. Monitoring of clear airway is also recommended. As fenofibric acid has high plasma proteins binding, hemodialysis for eliminating drugs should not be considered.

Enhancing Healthcare Team Outcomes

An interprofessional healthcare team including clinicians, mid-level practitioners (NPs and PAs), nurses, and pharmacists is optimal for managing treatment with fenofibrate. Medical professionals should be aware of the signs and symptoms accompanying fenofibrate toxicity. The involvement of other specialized professionals, including a nephrologist or toxicologist, should be considered to ensure an optimal patient result. Clinicians must counsel patients regarding any symptoms associated with liver damage (weakness, weight change, abdominal pain, jaundice). Interprofessional care coordination with open communication among team members will result in the best possible outcomes with the fewest adverse events. [Level 5]

Pharmacists should actively monitor drug interactions before dispensing medication and notify the prescriber or nurse of potential issues. In addition, the medical care provider should advise the patient on the importance of reading labels pertaining to the medication to avoid drug misuse or overdose. An interactive team dynamic for fenofibrate therapy is essential in managing any adverse effects and providing successful patient care for an optimal therapeutic outcome.