Ezetimibe

Generic Name

Ezetimibe

Brand Names

Ezetrol

Zetia

Ezedoc

Ezemib

Lipex

Combination formulations include:

– Ezetimibe + simvastatin (Inegy, Vytorin)

– Ezetimibe + atorvastatin (Liptruzet)

– Ezetimibe + rosuvastatin (Rosuzet)

Drug Class

Cholesterol absorption inhibitor

Lipid-lowering agent (non-statin)

Acts at the level of the small intestine

Mechanism of Action

Ezetimibe selectively inhibits the Niemann-Pick C1-Like 1 (NPC1L1) protein on the brush border of small intestinal enterocytes

This protein is responsible for the uptake of dietary and biliary cholesterol into the intestinal lumen

By blocking NPC1L1, ezetimibe reduces the delivery of intestinal cholesterol to the liver

This reduction leads to a compensatory upregulation of hepatic LDL receptors, which enhances clearance of circulating LDL cholesterol

Unlike statins, it does not inhibit cholesterol synthesis in the liver

It acts locally in the small intestine with minimal systemic exposure

Indications

Monotherapy

Primary hypercholesterolemia (heterozygous familial or non-familial)

When statins are contraindicated or not tolerated

Combination Therapy

With statins to enhance LDL-C lowering when monotherapy is inadequate

With fenofibrate in mixed dyslipidemia (especially when triglycerides are also elevated)

Homozygous familial hypercholesterolemia (HoFH) with statin

Homozygous sitosterolemia (phytosterolemia) as monotherapy or adjunct

Cardiovascular Risk Reduction

Ezetimibe in combination with simvastatin reduces the risk of major cardiovascular events in patients with chronic coronary syndromes as shown in IMPROVE-IT trial

Dosage and Administration

Standard adult dose: 10 mg once daily with or without food

No dose adjustment required for mild to moderate renal impairment

Can be taken at any time of day

If used with bile acid sequestrants (e.g., cholestyramine), ezetimibe should be taken at least 2 hours before or 4 hours after to prevent absorption interference

For children aged ≥10 years (familial hypercholesterolemia): 10 mg daily

Pharmacokinetics

Rapidly absorbed in the intestine

Extensively converted to active glucuronide conjugate (ezetimibe-glucuronide) in the intestinal wall and liver

Peak plasma levels in 1–2 hours (parent), 4–6 hours (conjugate)

High enterohepatic recycling prolongs half-life to about 22 hours

Excretion: 78% in feces, 11% in urine

90% protein bound

Minimal systemic exposure in the brain or peripheral tissues

Contraindications

Hypersensitivity to ezetimibe or any component

Active liver disease or unexplained persistent elevations in hepatic transaminases (when used with statins)

Pregnancy and breastfeeding if used with a statin

Moderate-to-severe hepatic impairment (Child-Pugh B or C)

Warnings and Precautions

Use with statins may increase liver enzyme elevations—monitor ALT/AST at baseline and periodically

Should not be used in pediatric patients under 10 years old

In patients with acute coronary syndrome, combining ezetimibe with statins improves outcomes

Not evaluated in severe renal impairment alone

Should not replace lifestyle interventions—used as adjunct only

Discontinue immediately if unexplained muscle pain, tenderness, or weakness is observed especially when used with statins

May modestly increase risk of gallstones when used with fenofibrate

Adverse Effects

Monotherapy

Well tolerated generally

Headache

Diarrhea

Myalgia

Sinusitis

Upper respiratory tract infections

Abdominal pain

Fatigue

Combination with Statins

Elevated liver enzymes (AST, ALT)

Muscle-related symptoms including myopathy, rhabdomyolysis (rare)

Increased creatine kinase (CK)

Back pain

Arthralgia

Influenza-like symptoms

Combination with Fibrates

Risk of cholelithiasis

Gallbladder-related disorders

GI discomfort

Pregnancy and Lactation

Pregnancy Category C

Monotherapy is not expected to harm fetus but insufficient data

Use with statins is contraindicated in pregnancy and breastfeeding

Ezetimibe appears in animal milk—avoid in lactating women unless necessary

Drug Interactions

Statins

Additive LDL-lowering effect

Risk of hepatic enzyme elevation and myopathy

Close monitoring required

Fibrates

Increased risk of gallstones

Fenofibrate is acceptable if necessary

Avoid combination with gemfibrozil

Bile Acid Sequestrants

Cholestyramine reduces ezetimibe levels

Separate administration: give ezetimibe 2 hours before or 4 hours after

Cyclosporine

Increased plasma concentrations of both ezetimibe and cyclosporine

Monitor cyclosporine levels

Warfarin and other anticoagulants

No significant interaction seen but monitor INR during initiation or discontinuation of ezetimibe

Antacids

Minimal interaction but may delay peak concentration

Monitoring Parameters

Lipid profile (LDL-C, HDL-C, total cholesterol, triglycerides) at baseline and periodically

Liver function tests (ALT, AST) if used with statins

Creatine kinase if muscle symptoms occur

Signs of gallbladder disease when used with fibrates

Adherence to diet and exercise regimen

Counseling Points

Take once daily, with or without meals

Continue dietary cholesterol restrictions

Report muscle pain, weakness, or dark urine immediately

If taking with bile acid sequestrants, time dose appropriately

Do not use during pregnancy if on combination therapy

Avoid alcohol to reduce liver stress when using with statins

Do not discontinue abruptly without consulting physician

Ezetimibe does not affect fat-soluble vitamin absorption

Comparative Notes

Ezetimibe vs Statins

Statins inhibit hepatic cholesterol synthesis

Ezetimibe inhibits intestinal cholesterol absorption

Ezetimibe less effective as monotherapy (15–20% LDL reduction) compared to statins (30–60%)

Synergistic effect when combined—up to 65% LDL reduction with statin + ezetimibe

Ezetimibe vs PCSK9 Inhibitors

PCSK9 inhibitors more potent in LDL-C reduction (>50%)

Ezetimibe is oral, cheaper, and suitable for moderate-risk patients

Used before escalating to injectables

Ezetimibe vs Fibrates

Ezetimibe lowers LDL, fibrates lower triglycerides

Fibrates have greater HDL-raising effect

Combination possible in mixed dyslipidemia but monitor for gallstones

Ezetimibe in Cardiovascular Outcomes

IMPROVE-IT trial showed adding ezetimibe to simvastatin reduced non-fatal MI, stroke, and revascularization events in post-ACS patients

Not associated with increased adverse events vs statin alone

Legal and Regulatory Status

Prescription-only

Available worldwide

Listed on WHO Model List of Essential Medicines

Approved in the US (FDA), UK (MHRA), EU (EMA), and other regulatory bodies