Ezetimibe + Fenofibrate

Usage

Ezetimibe + Fenofibrate is a combination medication prescribed to lower cholesterol levels in individuals with primary hypercholesterolemia or mixed hyperlipidemia. It belongs to the pharmacological class of lipid-lowering agents. The combination works through distinct mechanisms to reduce cholesterol absorption and synthesis.

Alternate Names

While “Ezetimibe + Fenofibrate” is the generic name, this combination is frequently encountered under various brand names. Some examples include Lipofen EZ.

How It Works

Pharmacodynamics: Ezetimibe inhibits the absorption of cholesterol at the brush border of the small intestine, reducing dietary and biliary cholesterol entering the bloodstream. Fenofibrate, a fibrate, activates peroxisome proliferator-activated receptor alpha (PPARα), increasing lipoprotein lipase activity, leading to enhanced triglyceride breakdown and reduction of VLDL production. This ultimately reduces LDL cholesterol and increases HDL cholesterol.

Pharmacokinetics: Ezetimibe is well-absorbed orally and undergoes glucuronide conjugation in the intestine and liver. It is primarily excreted in feces (via bile) and to a lesser extent in urine. Fenofibrate is also well-absorbed orally and is hydrolyzed to fenofibric acid, its active metabolite. Fenofibric acid is highly protein-bound and is primarily excreted in urine.

Mode of Action: Ezetimibe specifically targets Niemann-Pick C1-Like 1 (NPC1L1) protein, a key transporter responsible for intestinal cholesterol absorption. By inhibiting NPC1L1, ezetimibe effectively blocks cholesterol uptake. Fenofibrate, as a PPARα agonist, affects gene expression related to lipid metabolism, promoting triglyceride clearance and HDL synthesis.

Dosage

Standard Dosage

Adults: The standard dosage is 10 mg ezetimibe combined with a fenofibrate product. The dose of the fenofibrate product may depend on the exact medicine used as there are various fenofibrate products with different dosages. Administration is typically once daily, with or without food, preferably at the same time each day.

Children: Ezetimibe is approved for children aged 10 years and older with familial hypercholesterolemia. Safety and efficacy in children below 10 years have not been established. Fenofibrate products have various recommendations for children.

Special Cases:

• Elderly Patients: No specific dosage adjustments are typically required for elderly patients. However, renal function should be assessed.

• Patients with Renal Impairment: For mild to moderate renal impairment, fenofibrate dosage may need to be reduced. Ezetimibe dosage adjustment is usually not required. For severe renal impairment, the combination should be used with caution.

• Patients with Hepatic Dysfunction: Ezetimibe is not recommended in patients with moderate or severe hepatic impairment. Fenofibrate should be used cautiously in patients with hepatic impairment.

• Patients with Comorbid Conditions: Care should be taken in patients with pre-existing gallbladder disease, as the combination may increase the risk of cholelithiasis. Patients with diabetes should be monitored for changes in blood glucose.

Clinical Use Cases

This combination is not typically used in acute settings such as intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary role is in long-term management of chronic hyperlipidemia.

Dosage Adjustments

Dosage adjustments may be required based on individual patient response, renal/hepatic function, and other factors. Monitoring liver function tests and lipid profiles is essential, especially during initial therapy.

Side Effects

Common Side Effects:

• Headache
• Upper respiratory tract infection
• Myalgia
• Back pain
• Abdominal pain

Rare but Serious Side Effects:

• Myopathy/Rhabdomyolysis
• Cholelithiasis/Cholecystitis
• Hepatitis
• Pancreatitis

Long-Term Effects: Long-term effects include potential for muscle and liver-related issues if not monitored closely. Gallbladder complications are a concern.

Adverse Drug Reactions (ADR): Myopathy, rhabdomyolysis, and hepatotoxicity are serious ADRs requiring immediate intervention. Allergic reactions can also occur.

Contraindications

• Hypersensitivity to ezetimibe or fenofibrate
• Active liver disease
• Severe renal impairment
• Pre-existing gallbladder disease
• Pregnancy and breastfeeding (when used with a statin)

Drug Interactions

• Bile Acid Sequestrants: Ezetimibe should be administered at least 2 hours before or 4 hours after a bile acid sequestrant.
• Fibrates (other than fenofibrate): Co-administration is not recommended.
• Cyclosporine: Monitor cyclosporine levels when used with ezetimibe.
• Statins: No significant pharmacokinetic interactions, but combined use increases the risk of myopathy.
• Anticoagulants: Monitor INR when initiating or changing ezetimibe therapy in patients on warfarin.

Pregnancy and Breastfeeding

Ezetimibe’s safety during pregnancy is uncertain. Concomitant use with statins is contraindicated. Fenofibrate is also contraindicated. The combination should be avoided during breastfeeding.

Drug Profile Summary

• Mechanism of Action: Ezetimibe inhibits cholesterol absorption; fenofibrate enhances triglyceride breakdown and raises HDL.
• Side Effects: Myalgia, back pain, abdominal pain, elevated liver enzymes, cholelithiasis, rarely myopathy/rhabdomyolysis.
• Contraindications: Active liver/gallbladder disease, severe renal impairment, hypersensitivity.
• Drug Interactions: Bile acid sequestrants, fibrates, cyclosporine, statins, warfarin.
• Pregnancy & Breastfeeding: Generally avoided.
• Dosage: Ezetimibe 10 mg once daily plus fenofibrate (dose depending on product) once daily.
• Monitoring Parameters: Liver function tests, lipid panel, creatinine kinase (if myopathy suspected), gallbladder studies (if indicated).

Popular Combinations

Ezetimibe is sometimes combined with statins or fenofibrate for synergistic effects in lowering LDL cholesterol and other lipids.

Precautions

• Assess liver and renal function before and during therapy.
• Monitor for muscle symptoms (myalgia, weakness).
• Evaluate gallbladder function if symptoms arise.
• Caution in patients with diabetes.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Ezetimibe + Fenofibrate?

A: Ezetimibe 10 mg once daily plus fenofibrate (dose depending on product) once daily.

Q2: How does this combination differ from statin therapy?

A: Ezetimibe + Fenofibrate works through different mechanisms than statins. This combination may be used in patients who cannot tolerate statins or for whom statins are not sufficiently effective.

Q3: What are the main concerns with using this combination in patients with diabetes?

A: Fenofibrate may affect blood glucose levels. Careful monitoring of blood glucose is warranted.

Q4: How should I manage a patient who develops muscle pain while on this medication?

A: Evaluate for myopathy/rhabdomyolysis by checking creatinine kinase levels. Discontinue the medication if myopathy/rhabdomyolysis is suspected.

Q5: Can this combination be used in patients with liver disease?

A: Ezetimibe is not recommended in moderate to severe liver disease, and fenofibrate should be used with caution in patients with any degree of hepatic dysfunction.

Q6: Are there any dietary recommendations for patients on Ezetimibe + Fenofibrate?

A: Patients should follow a cholesterol-lowering diet.

Q7: How soon can I expect to see a lipid response to this therapy?

A: Lipid levels should be assessed after 4 weeks of treatment.

Q8: What are the signs and symptoms of cholelithiasis to be aware of?

A: Watch for severe right upper quadrant abdominal pain, nausea, vomiting, fever, and jaundice. Gallbladder studies may be indicated.

Q9: Can I use other fibrates besides fenofibrate with ezetimibe?

A: Co-administration of Ezetimibe with fibrates other than fenofibrate is not recommended.