Ezetimibe - Drug Monograph

Introduction

Ezetimibe is a selective cholesterol absorption inhibitor that represents a unique class of lipid-lowering agents. Approved by the FDA in 2002, it works through a mechanism distinct from statins and other lipid-modifying drugs. Ezetimibe is commonly used as monotherapy or in combination with statins for the management of hypercholesterolemia.

Mechanism of Action

Ezetimibe selectively inhibits the Niemann-Pick C1-Like 1 (NPC1L1) protein located in the brush border of the small intestine. This protein is responsible for the absorption of dietary and biliary cholesterol. By blocking this transporter, ezetimibe reduces the intestinal absorption of cholesterol by approximately 54%, leading to decreased delivery of intestinal cholesterol to the liver. This results in reduced hepatic cholesterol stores and increased clearance of cholesterol from the blood.

Indications

• Primary hyperlipidemia: As monotherapy or in combination with HMG-CoA reductase inhibitors (statins) to reduce elevated total cholesterol, LDL-C, and Apo B
• Homozygous familial hypercholesterolemia: In combination with atorvastatin or simvastatin
• Homozygous sitosterolemia: To reduce elevated sitosterol and campesterol levels
• Cardiovascular risk reduction: In combination with statin therapy for patients with clinical atherosclerotic cardiovascular disease

Dosage and Administration

• Renal impairment: No dosage adjustment necessary
• Hepatic impairment: Contraindicated in moderate to severe hepatic impairment
• Geriatric patients: No dosage adjustment necessary
• Pediatric patients (10-17 years): 10 mg orally once daily

Pharmacokinetics

Contraindications

• Hypersensitivity to any component of the formulation
• Moderate to severe hepatic impairment (Child-Pugh B or C)
• Use with statins in patients with active liver disease or unexplained persistent elevations in serum transaminases
• Pregnancy and breastfeeding (category C)
• Concomitant use with fibrates (except fenofibrate)

Warnings and Precautions

• Hepatic effects: Monitor liver enzymes before initiation and during therapy. Discontinue if persistent elevations occur
• Rhabdomyolysis: Rare reports, especially when combined with statins. Monitor for muscle pain, tenderness, or weakness
• Gallbladder effects: May increase the risk of cholelithiasis
• Pregnancy considerations: Cholesterol is essential for fetal development. Use only if potential benefit justifies potential risk
• Pediatric use: Safety and effectiveness established in children 10 years and older

Drug Interactions

• Bile acid sequestrants: Decreased ezetimibe absorption (administer at least 2 hours before or 4 hours after)
• Cyclosporine: Significantly increases ezetimibe levels (monitor closely)
• Fibrates: Increased risk of cholelithiasis (avoid combination except with fenofibrate)
• Warfarin: Possible potentiation of anticoagulant effect (monitor INR closely)
• Statins: Additive lipid-lowering effects with potential increased risk of adverse effects

Adverse Effects

• Headache (4.8%)
• Diarrhea (4.1%)
• Arthralgia (3.8%)
• Upper respiratory tract infection (3.7%)
• Sinusitis (3.5%)

• Rhabdomyolysis (<0.1%)
• Hepatitis (<0.1%)
• Pancreatitis (<0.1%)
• Allergic reactions including angioedema (<0.1%)
• Myopathy (0.1-0.2%)

Monitoring Parameters

• Lipid panel: Baseline, 2-4 weeks after initiation, and periodically thereafter
• Liver function tests: Baseline and as clinically indicated
• CPK levels: If muscle symptoms occur
• Signs and symptoms of gallstone formation
• Pregnancy testing in women of childbearing potential
• INR monitoring if co-administered with warfarin

Patient Education

• Take medication as prescribed, typically once daily with or without food
• Continue adherence to dietary and lifestyle modifications
• Report any unexplained muscle pain, tenderness, or weakness immediately
• Inform healthcare providers of all medications being taken
• Notify physician if pregnant, planning pregnancy, or breastfeeding
• Be aware that ezetimibe may take 2 weeks to achieve full therapeutic effect
• Understand that this medication is used as part of a comprehensive cardiovascular risk reduction program

References

1. FDA Prescribing Information: Zetia (ezetimibe) tablets 2. Cannon CP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372(25):2387-2397 3. Knopp RH, et al. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol. 2002;90(10):1084-1091 4. Grundy SM, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation. 2019;139(25):e1082-e1143 5. Gagne C, et al. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol. 2002;90(10):1092-1097 6. Dujovne CA, et al. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol. 2002;90(10):1098-1101