What contraindications, precautions, and monitoring are required when initiating ezetimibe in a patient who needs additional cholesterol lowering beyond diet, lifestyle changes, or statin therapy?

What to Watch Out for When Giving Ezetimibe

Ezetimibe is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B or C) and requires baseline liver function testing with ongoing monitoring for transaminase elevations, particularly when combined with statins. 1, 2

Absolute Contraindications

• Hypersensitivity to ezetimibe or any excipient 2
• Moderate to severe hepatic impairment (Child-Pugh B or C) due to unknown effects of increased drug exposure 1, 2
• When combined with a statin, fenofibrate, or other LDL-C lowering therapy, ezetimibe is contraindicated in patients for whom those agents are contraindicated (refer to the specific drug's prescribing information) 2

Hepatic Monitoring Requirements

Obtain baseline hepatic transaminases before initiating ezetimibe in all patients. 1, 2

• Monitor liver function tests as clinically indicated, especially when coadministered with statins 1, 2
• Discontinue ezetimibe if persistent ALT or AST elevations ≥3 times the upper limit of normal occur 1, 2
• Persistent transaminase elevations occur more commonly when ezetimibe is combined with statins 1

Skeletal Muscle Effects

Ezetimibe may cause myopathy and rhabdomyolysis, particularly when combined with statins or fibrates. 2

• Most post-marketing reports of rhabdomyolysis occurred in patients taking a statin or other agents known to increase rhabdomyolysis risk, such as fibrates 2
• If myopathy is suspected, discontinue ezetimibe and other concomitant medications as appropriate 2
• Monitor for unexplained muscle pain, tenderness, or weakness 2

Drug Interactions Requiring Attention

Cyclosporine: Combination increases exposure of both ezetimibe and cyclosporine. Monitor cyclosporine concentrations closely in patients taking ezetimibe concomitantly. 2, 3

Bile Acid Sequestrants (e.g., cholestyramine): Significantly decrease ezetimibe bioavailability. Administer ezetimibe either ≥2 hours before or ≥4 hours after bile acid sequestrant administration. 2, 3

Fibrates other than fenofibrate: Coadministration is not recommended until use is adequately studied 2

Fenofibrate: When combined with ezetimibe, if cholelithiasis is suspected, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered 2

Clinical Monitoring Algorithm

1. Before initiating ezetimibe:

   • Assess for moderate to severe hepatic impairment (contraindication) 1, 2
   • Obtain baseline hepatic transaminases 1, 2
   • Review concomitant medications for interactions (cyclosporine, bile acid sequestrants, fibrates) 2, 3

2. During treatment:

   • Monitor hepatic transaminases as clinically indicated, particularly with statin combination 1, 2
   • Assess for muscle symptoms (pain, tenderness, weakness) 2
   • Assess LDL-C response as early as 4 weeks after initiating therapy 2
   • Monitor adherence to medications and lifestyle modifications 4

3. If adverse effects occur:

   • Discontinue if ALT/AST ≥3× ULN persists 1, 2
   • Discontinue if myopathy is suspected 2

Common Pitfalls to Avoid

• Do not use ezetimibe in patients with moderate to severe liver disease without recognizing the contraindication 1, 2
• Do not administer ezetimibe simultaneously with bile acid sequestrants—this significantly reduces ezetimibe absorption 2, 3
• Do not ignore muscle symptoms in patients on statin-ezetimibe combination—rhabdomyolysis risk is increased 2
• Do not forget to monitor cyclosporine levels when coadministering with ezetimibe 2, 3

Special Populations

No dosage adjustment is necessary in patients with mild hepatic impairment or mild-to-severe renal insufficiency 3

Pediatric use: Approved for patients ≥10 years of age with heterozygous familial hypercholesterolemia (in combination with statins) and ≥9 years for homozygous familial sitosterolemia 2