Introduction
Zetia (ezetimibe) is a selective cholesterol absorption inhibitor used in the management of hyperlipidemia. It represents a unique class of lipid-lowering agents that work through a mechanism distinct from statins, fibrates, or bile acid sequestrants. Approved by the FDA in 2002, Zetia is commonly used as monotherapy or in combination with other lipid-lowering agents to reduce elevated LDL cholesterol levels.
Mechanism of Action
Zetia works by selectively inhibiting the absorption of cholesterol and related phytosterols at the brush border of the small intestine. It targets the Niemann-Pick C1-Like 1 (NPC1L1) protein, which is responsible for cholesterol uptake into enterocytes. By blocking this transporter, Zetia reduces the delivery of intestinal cholesterol to the liver, leading to decreased 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) as an adjunct to diet
- Homozygous familial hypercholesterolemia: In combination with atorvastatin or simvastatin
- Homozygous sitosterolemia: To reduce elevated sitosterol and campesterol levels
- Mixed hyperlipidemia: In combination with fenofibrate
Dosage and Administration
Standard dosing: 10 mg orally once daily, with or without food Special populations:- Renal impairment: No dosage adjustment necessary
- Hepatic impairment: Contraindicated in moderate to severe hepatic impairment
- Geriatric patients: No dosage adjustment necessary
- Pediatric patients: Safety and effectiveness established for children ≥10 years old
Pharmacokinetics
Absorption: Rapidly absorbed with time to peak plasma concentration of 4-12 hours. Oral bioavailability not significantly affected by food. Distribution: Highly protein-bound (>90%) to human plasma proteins. Volume of distribution not determined in humans. Metabolism: Primarily metabolized in the small intestine and liver via glucuronide conjugation (phase II metabolism). Minimal cytochrome P450-mediated metabolism. Elimination: Half-life approximately 22 hours. Primarily excreted in feces (78%) with minimal renal excretion (11%). Not removed by hemodialysis.Contraindications
- Hypersensitivity to ezetimibe or any component of the formulation
- Moderate to severe hepatic impairment (Child-Pugh B or C)
- Concomitant use with statins in patients with active liver disease or unexplained persistent elevations in serum transaminases
- Pregnancy and breastfeeding (when used in combination with statins)
Warnings and Precautions
- Hepatic effects: Monitor liver enzymes before initiation and during therapy. Discontinue if ALT or AST >3× ULN persist
- Myopathy/rhabdomyolysis: Risk increased when used with statins. Monitor for muscle pain, tenderness, or weakness
- Cholelithiasis: May increase risk of gallbladder disease due to increased cholesterol excretion in bile
- Fenofibrate combination: Increased risk of cholelithiasis and elevated transaminases
- Cyclosporine combination: Significantly increases ezetimibe levels - avoid concomitant use
Drug Interactions
- Statins: Additive lipid-lowering effects; monitor for increased risk of myopathy
- Fibrates: May increase risk of cholesterol gallstones and transaminase elevations
- Cyclosporine: Increases ezetimibe concentrations approximately 15-fold - contraindicated
- Cholestyramine: Reduces ezetimibe absorption by approximately 55% - administer at least 2 hours apart
- Warfarin: Possible potentiation of anticoagulant effect - monitor INR closely
Adverse Effects
Common (≥2%):- Upper respiratory tract infection
- Diarrhea
- Arthralgia
- Sinusitis
- Pain in extremity
- Fatigue
- Rhabdomyolysis
- Hepatitis
- Pancreatitis
- Myopathy
- Hypersensitivity reactions (including angioedema)
- Thrombocytopenia
Monitoring Parameters
- Baseline: Lipid profile, LFTs, CPK
- During therapy:
- Lipid panel at 2-4 weeks and periodically thereafter - LFTs at initiation and periodically (especially with combination therapy) - CPK in patients with muscle symptoms - Symptoms of gallstone formation (right upper quadrant pain, nausea)
- Long-term: Annual lipid profile and liver function monitoring
Patient Education
- Take medication exactly as prescribed, typically once daily
- Continue adherence to cholesterol-lowering diet and exercise regimen
- Report any unexplained muscle pain, tenderness, or weakness immediately
- Report signs of liver problems (unusual fatigue, loss of appetite, abdominal pain, dark urine, jaundice)
- Inform all healthcare providers about all medications being taken
- Do not stop taking without consulting healthcare provider
- Women of childbearing potential should use effective contraception when taking with statins
References
1. FDA Prescribing Information: Zetia (ezetimibe) tablets. Revised 2021. 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. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J. 2003;24(8):729-741. 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. 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):1092-1097. 6. Bays HE, et al. Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies. Clin Ther. 2001;23(8):1209-1230.