What is the indication for Zetia (ezetimibe) 10mg?

Indications for Zetia (Ezetimibe) 10mg

Zetia 10mg is FDA-approved as an adjunct to diet for reducing elevated LDL cholesterol in multiple clinical scenarios, either as monotherapy when statins cannot be used or in combination with statins, fenofibrate, or other LDL-lowering therapies. 1

FDA-Approved Indications

Primary Hyperlipidemia

• Combination with a statin or as monotherapy (when additional LDL-lowering therapy is not possible) to reduce total cholesterol, LDL-C, apolipoprotein B, and non-HDL-C in adults with primary hyperlipidemia 2, 1
• Approved for pediatric patients 10 years and older with heterozygous familial hypercholesterolemia (HeFH) when combined with a statin 1

Familial Hypercholesterolemia

• Heterozygous FH (HeFH): In combination with a statin for adults and pediatric patients ≥10 years old 2, 1
• Homozygous FH (HoFH): In combination with atorvastatin or simvastatin (and other LDL-lowering therapies) for adults and pediatric patients ≥10 years old 2, 1

Mixed Hyperlipidemia

• In combination with fenofibrate to reduce total cholesterol, LDL-C, apolipoprotein B, and non-HDL-C in adults 2, 1

Homozygous Familial Sitosterolemia

• As monotherapy for reduction of elevated sitosterol and campesterol levels in adults and pediatric patients ≥9 years old 1

Clinical Use Algorithm Based on Guidelines

For Patients with Clinical ASCVD

The 2022 ACC Expert Consensus provides a structured approach: 2

Step 1: Initiate maximally tolerated statin therapy

• Target: ≥50% LDL-C reduction from baseline AND LDL-C <70 mg/dL (or non-HDL-C <100 mg/dL) 2

Step 2: If targets not achieved on maximally tolerated statin:

• Add ezetimibe 10mg daily as the initial nonstatin agent when: 2
  • Additional LDL-C lowering <25% is needed
  • Cost considerations favor generic ezetimibe
  • Patient prefers oral therapy with low pill burden
  • Note: Some patients experience >25% LDL-C reduction with ezetimibe despite average 18% reduction as monotherapy 2

Step 3: Consider PCSK9 inhibitor instead if:

• 25% additional LDL-C lowering required 2

• Very high-risk features present (recent ACS, recurrent events, polyvascular disease) 2

For Patients with Baseline LDL-C ≥190 mg/dL

• Ezetimibe 10mg may be added to maximally tolerated statin therapy when additional LDL-C lowering is desired, despite lack of RCT evidence specifically in this population 2
• All such patients should be considered for referral to a lipid specialist 2

Mechanism and Efficacy

How Ezetimibe Works

• Inhibits Niemann-Pick C1-Like 1 (NPC1L1) protein at the intestinal brush border 2, 3
• Reduces cholesterol absorption in the small intestine by approximately 54% 3
• Does not affect absorption of fat-soluble vitamins, triglycerides, or bile acids 2, 3

Expected LDL-C Reduction

• Monotherapy: 18% average reduction 2
• Combination with statin: Additional 25% incremental reduction 2
• The combination of ezetimibe with rosuvastatin achieves >50% LDL-C reduction across all dose combinations 4

Cardiovascular Outcomes Evidence

IMPROVE-IT Trial

• Adding ezetimibe to moderate-intensity statin in patients with recent acute coronary syndrome reduced the composite endpoint of CV death, nonfatal MI, unstable angina requiring rehospitalization, coronary revascularization (≥30 days post-randomization), or nonfatal stroke over median 6-year follow-up 2
• Greatest benefit observed in high-risk patients and those with diabetes 4

SHARP Trial

• Simvastatin plus ezetimibe reduced major ASCVD events (nonfatal MI or CHD death, non-hemorrhagic stroke, or arterial revascularization) compared to placebo in patients with chronic kidney disease over median 4.9-year follow-up 2

Dosing and Administration

• Standard dose: 10mg orally once daily, with or without food 2, 1
• With bile acid sequestrants: Administer ezetimibe either ≥2 hours before or ≥4 hours after the bile acid sequestrant 2, 1
• LDL-C assessment: Check as early as 4 weeks after initiation 1

Safety Profile and Contraindications

Contraindications

• Hypersensitivity to ezetimibe or any excipient 1
• When used with a statin, fenofibrate, or other LDL-lowering therapy, ezetimibe is contraindicated if those agents are contraindicated 1

Key Safety Considerations

• Hepatic monitoring: Not recommended in moderate/severe hepatic impairment; monitor transaminases when combined with statins 2, 1
• Myopathy risk: Cases of myopathy and rhabdomyolysis reported, particularly when combined with statins or fibrates 2, 1
• Pregnancy/lactation: Avoid use due to lack of human safety data 2

Common Adverse Effects

• Monotherapy: Upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremities 2, 1
• With statin: Nasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, diarrhea 2, 1
• Overall tolerability comparable to placebo as monotherapy and similar to statin alone when combined 2

Important Drug Interactions

• Cyclosporine: Increases exposure of both ezetimibe and cyclosporine; monitor cyclosporine concentrations 2, 1
• Fibrates: Coadministration with fibrates other than fenofibrate not recommended until adequately studied 1
• Fenofibrate: If cholelithiasis suspected, perform gallbladder studies and consider alternative therapy 1
• Bile acid sequestrants: Cholestyramine decreases ezetimibe exposure; separate administration as noted above 2, 1

Clinical Pitfalls to Avoid

• Do not use ezetimibe monotherapy when combination with a statin is possible, as combination provides superior LDL-C reduction and proven cardiovascular benefit 4
• Avoid uptitrating statin doses when ezetimibe can be added; rosuvastatin 10mg/ezetimibe 10mg produces greater LDL-C lowering than doubling rosuvastatin dose with fewer adverse events 4
• Do not delay adding ezetimibe in very high-risk patients not at goal on maximally tolerated statin therapy 2
• Remember that ezetimibe has minimal CYP450 interactions, reducing drug-drug interaction concerns compared to other lipid agents 2, 3