Can ezetimibe be used safely in patients with hepatic impairment, and what dose adjustments or liver‑function monitoring are required, especially in severe (Child‑Pugh class C) disease?

Ezetimibe Use in Hepatic Impairment

Ezetimibe is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh B or C) due to significantly increased drug exposure, while no dose adjustment is needed for mild hepatic impairment (Child-Pugh A) or any degree of renal impairment. 1

Dosing Recommendations by Hepatic Function

Mild Hepatic Impairment (Child-Pugh A)

• No dose adjustment is required for patients with mild hepatic impairment, as the mean AUC for total ezetimibe increases only approximately 1.7-fold compared to healthy subjects 1
• Standard dosing of 10 mg once daily can be safely continued 1

Moderate to Severe Hepatic Impairment (Child-Pugh B or C)

• Ezetimibe is not recommended in patients with moderate (Child-Pugh score 7-9) or severe (Child-Pugh score 10-15) hepatic impairment 1
• In moderate hepatic impairment, mean AUC values for total ezetimibe and parent ezetimibe increase approximately 3- to 4-fold and 5- to 6-fold, respectively 1
• In severe hepatic impairment, these increases are similarly elevated (approximately 4-fold in a 14-day multiple-dose trial) 1
• The clinical effects of this substantially increased exposure are unknown, making use inadvisable 1

Liver Function Monitoring

• No routine liver function monitoring is specifically required for ezetimibe monotherapy, as the drug has minimal hepatotoxicity in most patients 2
• However, rare cases of severe hepatotoxicity have been reported, including cholestatic hepatitis and acute autoimmune hepatitis 3
• When ezetimibe is combined with statins, follow the liver monitoring protocols recommended for the specific statin being used 1

Pharmacokinetic Rationale

• Ezetimibe undergoes extensive glucuronidation in both the small intestine and liver to form the active metabolite ezetimibe-glucuronide 2
• The drug exhibits enterohepatic recycling with a terminal half-life of approximately 22 hours for both parent drug and glucuronide metabolite 1
• In hepatic impairment, the reduced metabolic capacity leads to accumulation of both ezetimibe and its active metabolite, creating unpredictable pharmacologic effects 1
• Approximately 78% of the dose is excreted in feces (predominantly as ezetimibe) and 11% in urine (mainly as ezetimibe-glucuronide), making hepatic function critical for drug clearance 1

Renal Impairment Considerations

• No dosage adjustment is necessary for any degree of renal impairment, including severe renal disease (CrCl ≤30 mL/min/1.73 m²) 1
• In severe renal disease, mean AUC values for total ezetimibe increase only approximately 1.5-fold, which is not clinically significant 1

Critical Clinical Pitfalls

• Do not assume that ezetimibe's favorable safety profile in normal hepatic function extends to patients with cirrhosis—the 3- to 6-fold increase in drug exposure creates substantial risk 1
• Avoid initiating ezetimibe in patients whose hepatic function is deteriorating or uncertain; confirm current Child-Pugh classification before prescribing 1
• Be aware that ezetimibe can cause rare but severe hepatotoxicity even in patients with normal baseline liver function, including cholestatic hepatitis and autoimmune hepatitis 3
• When combining ezetimibe with cyclosporine (common in transplant patients), exercise extreme caution as ezetimibe exposure increases 240% and cyclosporine levels increase 15% 1