Ezetimibe

Ezetimibe is an oral cholesterol absorption inhibitor that lowers LDL cholesterol by about 18% alone and by a further 15% to 25% when added to a statin. It is used when the target is not reached on the maximum tolerated statin, when statins are not tolerated, and in sitosterolaemia. It lowered cardiovascular events when added to simvastatin after acute coronary syndrome. It is cheap and has few side effects, but it is not always available in East Africa.

Classification. Cholesterol absorption inhibitor.

Mechanism. Blocks the NPC1L1 sterol transporter at the small intestine brush border, cutting absorption of dietary and bile cholesterol; the liver then takes more LDL from the blood.

Pharmacodynamics. LDL cholesterol falls within 2 weeks. Effect is additive to statins because both act on different sources of cholesterol.

Pharmacokinetics. Absorbed and glucuronidated to an active metabolite that is recycled through bile. Half life about 22 hours. Bioavailability is variable. Excreted mostly in faeces (about 78%) and 11% in urine. Protein binding over 90%.

Primary hypercholesterolaemia, adult. 10 mg once daily, alone or with a statin.

Added to a statin when the target is not reached, adult. 10 mg once daily with the maximum tolerated statin.

Homozygous familial hypercholesterolaemia, adult. 10 mg once daily with a statin (specialist).

Sitosterolaemia, adult. 10 mg once daily.

Children aged 6 years and over (specialist). 10 mg once daily for heterozygous familial hypercholesterolaemia (with a statin from age 10 years) and for homozygous familial hypercholesterolaemia.

Kidney impairment. No adjustment.

Liver impairment. Mild: no adjustment; moderate to severe: not advised.

Contraindications. Active liver disease or unexplained persistent rise in transaminases when combined with a statin; pregnancy and breastfeeding when combined with a statin; hypersensitivity.

Warnings. Raised liver enzymes (mostly with a statin); myopathy and rhabdomyolysis (rare); gallstones when combined with fenofibrate; hypersensitivity reactions including angioedema and rash.

Adverse effects. Diarrhoea, abdominal pain, fatigue, muscle aches, headache, raised liver enzymes, rash.

Interactions. Colestyramine: give ezetimibe 2 hours before or 4 hours after. Ciclosporin: raised levels of both drugs, so monitor ciclosporin and the INR where used. Fibrates (fenofibrate, gemfibrozil): raised ezetimibe levels and gallstone risk; avoid gemfibrozil. Warfarin: check the INR when starting.

Special groups.

• Pregnancy: alone, avoid unless essential; with a statin, contraindicated.

• Breastfeeding: avoid.

• Patients of African ancestry: no dose change.

• Older adults: no dose change.

• Kidney impairment: no adjustment.

• Liver impairment: avoid in moderate to severe disease.

Formulations. Tablets 10 mg; fixed combinations with statins in some markets.

Administration. Oral once daily at any time of day, with or without food.

Baseline. Lipid profile, alanine aminotransferase if combined with a statin, pregnancy status, a full list of other medicines.

Monitoring. Lipid profile 4 to 12 weeks after starting, then every 6 to 12 months. Alanine aminotransferase as the statin requires. Muscle symptoms.

Stopping. Stop for a persistent transaminase rise above 3 times the upper limit of normal, severe muscle symptoms, or pregnancy when combined with a statin.

Common prescribing errors. Giving it at the same time as colestyramine; adding it without trying to optimise the statin dose; combining with gemfibrozil; continuing during pregnancy with a statin.