Ezetimibe with Fenofibrate Interaction Details

Brand Names Associated with Ezetimibe

Brand Names Associated with Fenofibrate

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Feb 28, 2024

Interaction Effect

Increased ezetimibe exposure and an increased risk of cholelithiasis

Interaction Summary

Fibrates may have an additive effect on cholesterol excretion into the bile resulting in an increased risk for cholelithiasis[1]. In a pharmacokinetic study in healthy subjects (n=16), concomitant administration of ezetimibe 10 mg once daily with fenofibrate 145 mg once daily for 10 days significantly increased total ezetimibe and ezetimibe glucuronide (active metabolite) AUC and Cmax by 43.4% and 48.8%, and 32.8% and 33.9%, respectively, compared with ezetimibe 10 mg once daily alone [2]. If ezetimibe and fenofibrate are coadministered, monitor patients for signs and symptoms of cholelithiasis. If cholelithiasis is suspected, initiate gallbladder studies and consider alternative lipid-lowering therapy [1].

Severity

Major

Onset

Delayed

Evidence

Established

How To Manage Interaction

Both ezetimibe and fibric acids may increase the excretion of cholesterol into the bile, potentially leading to cholelithiasis. If ezetimibe and fenofibrate are coadministered, monitor patients for signs and symptoms of cholelithiasis. If cholelithiasis is suspected, initiate gallbladder studies and consider alternative lipid-lowering therapy[3][1].

Mechanism Of Interaction

Additive increase in cholesterol excretion into the bile

Literature Reports

A) In a study of 32 healthy adults with hypercholesterolemia (low-density lipid cholesterol, 130 mg/dL or greater), total ezetimibe Cmax and AUC increased by an approximate mean of 64% and 48%, respectively, following the concomitant administration of ezetimibe 10 mg and fenofibrate 200 mg once daily. The pharmacokinetics of fenofibrate were not significantly altered [1].

B) Concomitant administration of ezetimibe 10 mg daily with fenofibrate 145 mg daily significantly increased total ezetimibe and ezetimibe glucuronide exposure (p less than 0.05) in a phase 1, open-label, 3-regimen, crossover study in healthy subjects (n=16; mean age 43.4 years; range, 27 to 55 years). Subjects were randomized to 1 of 3 regimens: ezetimibe 10 mg, combination ezetimibe 10 mg with fenofibrate 145 mg, or fenofibrate 145 mg, each regimen was administered once daily for 10 days with at least a 14-day washout period before crossover. Following 10 days of concomitant ezetimibe/fenofibrate administration, total ezetimibe AUC and Cmax values were 43.4% (90% confidence interval (CI), 29.3% to 59%) and 32.8% (90% CI, 20.5% to 46.2%) higher, respectively, compared with ezetimibe alone. Total ezetimibe AUC increased from 794.8 +/- 334.8 to 1119.7 +/- 434.8 nanograms (ng) x hour/mL, and Cmax increased from 84.9 +/- 28.6 to 112.5 +/- 32.4 ng/mL. Similarly, on day 10 of ezetimibe/fenofibrate coadministration, ezetimibe glucuronide (active metabolite) AUC and Cmax significantly increased by 48.8% (90% CI, 33.9% to 65.3%) and 33.9% (90% CI, 21.6% to 47.4%), respectively compared with ezetimibe alone. Ezetimibe glucuronide AUC increased from 708.5 +/- 311.6 to 1032.1 +/- 418.9 ng x hour/mL, and Cmax increased from 80.2 +/- 27.1 to 107 +/- 31.1 ng/mL. The Cmin for total ezetimibe and ezetimibe glucuronide also significantly increased with coadministration; however, fenofibrate and free ezetimibe were not significantly affected [2].

References

1 ) Product Information: ZETIA(R) oral tablets, ezetimibe oral tablets. Organon LLC (per FDA), Jersey City, NJ, 2023.

2 ) Gustavson LE, Schweitzer SM, Burt DA, et al: Evaluation of the potential for pharmacokinetic interaction between fenofibrate and ezetimibe: A phase I, open-label, multiple-dose, three-period crossover study in healthy subjects. Clin Ther 2006; 28(3):373-387.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...

3 ) Product Information: TRICOR(R) oral tablets, fenofibrate oral tablets. Abbott Laboratories, North Chicago, IL, 2007.

Ezetimibe Overview

• Ezetimibe is used together with lifestyle changes (diet, weight-loss, exercise) to reduce the amount of cholesterol (a fat-like substance) and other fatty substances in the blood. It may be used alone or in combination with an HMG-CoA reductase inhibitor (statin). Ezetimibe is in a class of medications called cholesterol-lowering medications. It works by preventing the absorption of cholesterol in the intestine.

• Buildup of cholesterol and fats along the walls of the blood vessels (a process known as atherosclerosis) decreases blood flow, which decreases the oxygen supply to the heart, brain, and other parts of the body. Lowering blood levels of cholesterol and fats may help reduce this buildup and may decrease your chances of developing heart conditions such as angina (chest pain), strokes, and heart attacks. Results of a clinical study that compared people who took ezetimibe and simvastatin with people who took simvastatin alone found that although the group of people taking ezetimibe and simvastatin had lower amounts of cholesterol in the blood, there was no difference between the two groups in the amount of cholesterol and fat buildup on the insides of the blood vessels in the neck. It is not currently understood why the additional lowering of cholesterol levels in the blood did not lead to a greater decrease in cholesterol and fat buildup along the walls of the blood vessels in people taking ezetimibe and simvastatin. Further studies are underway to compare treatment with ezetimibe and simvastatin to treatment with simvastatin alone to see if there is a difference in the risk of developing heart disease. Talk to your doctor if you have questions about the risks and benefits of treating increased amounts of cholesterol in your blood with ezetimibe and other medications.

• In addition to taking a cholesterol-lowering medication, making certain changes in your daily habits can also lower your blood cholesterol levels. You should eat a diet that is low in saturated fat and cholesterol (see SPECIAL DIETARY); exercise 30 minutes on most, if not all, days; and lose weight if you are overweight.

Fenofibrate Overview

• Fenofibrate is used with a low-fat diet, exercise, and sometimes with other medications to reduce the amounts of fatty substances such as cholesterol and triglycerides in the blood and to increase the amount of HDL (high-density lipoprotein; a type of fatty substance that decreases the risk of heart disease) in the blood. Build-up of cholesterol and fats along the walls of the arteries (a process known as atherosclerosis) decreases the blood flow and, therefore, the oxygen supply to the heart, brain, and other parts of the body. This increases the risk of heart disease, angina (chest pain), strokes, and heart attacks. Although fenofibrate decreases the levels of fatty substances in the blood, it has not been shown to decrease the risk of heart attacks or strokes. Fenofibrate is in a class of medications called antilipemic agents. It works by speeding the natural processes that remove cholesterol from the body.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.