ezetimibe

Action and Spectrum

Actions and spectrum: 

ezetimibe is a lipid-lowering agent that inhibits the absorption of cholesterol and related phytosterols. It lowers total cholesterol, low-density lipoprotein (LDL) cholesterol, and apolipoprotein B, and increases high-density lipoprotein (HDL) cholesterol.

It has no effect on the absorption of triglycerides or fat-soluble vitamins. ezetimibe works by binding to and inhibiting the Niemann-Pick C1-like 1 (NPC1L1) protein on the brush border of the small intestine, thereby reducing the uptake of cholesterol from the gut. 

Drug Interaction

Adverse Reaction

Frequency defined 

1-10% 

Increased liver transaminases (1%) 

Influenza (2%) 

Fatigue (2%) 

Arthralgia (2-3%) 

Sinusitis (3%) 

Pain in extremity (3%) 

Cough (2-4%) 

Upper respiratory tract symptoms (2-4%) 

Diarrhea (4%)  

Post marketing Reports 

Hypersensitivity reactions 

Elevated creatine phosphokinase 

Thrombocytopenia 

Abdominal pain 

Nausea 

Paresthesia 

Headache 

abnormalities of liver function test 

Erythema multiforme 

Rhabdomyolysis/myopathy 

Back pain 

Pancreatitis 

Dizziness 

Depression 

Cholecystitis and cholelithiasis 

Black Box Warning

Contraindication / Caution

Contraindication/Caution: 

Contraindication: 

ezetimibe is contraindicated in individuals with a known hypersensitivity to ezetimibe or any of its components. It is also contraindicated in patients with moderate to severe hepatic impairment. Additionally, it should not be used during pregnancy and lactation unless the potential benefits outweigh the potential risks.  

Caution: 

• Liver disease: ezetimibe should be used with caution in patients with liver disease or hepatic impairment. 
• Renal impairment: The use of ezetimibe in patients with severe renal impairment is not recommended. 
• Pregnancy and lactation: ezetimibe should only be used in pregnant or nursing women if the benefits outweigh the risks. 
• Geriatric population: Elderly patients may be more sensitive to the effects of ezetimibe. 
• Pediatric use: The safety and effectiveness of ezetimibe in pediatric patients have not been established. 
• Concomitant use with fibrates: Concomitant use of ezetimibe with fibrates may increase the risk of cholelithiasis. 
• Concomitant use with cyclosporine: Concomitant use of ezetimibe with cyclosporine may increase the risk of myopathy and rhabdomyolysis.

Comorbidities: 

There are no specific comorbidities associated with the use of ezetimibe. However, caution should be exercised in patients with a history of liver disease or those taking other medications that can affect liver function.

Additionally, it is recommended to monitor liver function tests in patients taking ezetimibe. Patients with renal impairment should also be closely monitored when taking ezetimibe, as there is limited data available in this patient population. 

Pregnancy / Lactation

Pregnancy consideration: pregnancy category: C 

Lactation: safety and efficacy not established  

Pregnancy category: 

• Category A: Satisfactory and well-controlled studies show no risk to the fetus in the first or later trimester. 
• Category B: There is no evidence of risk to the fetus found in animal reproduction studies and there are not enough studies on pregnant women. 
• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for an effect in humans, care must be taken for potential risks in pregnant women. 
• Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms, but despite potential risks may be used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh risks over benefits These category drugs should be prohibited for pregnant women. 
• Category N: There is no data available for the drug under this category. 

Pharmacology

Pharmacology: 

ezetimibe is a selective cholesterol absorption inhibitor that acts locally in the small intestine to inhibit the absorption of cholesterol, leading to decreased delivery of intestinal cholesterol to the liver. This results in reduced hepatic cholesterol stores, which stimulates the upregulation of hepatic low-density lipoprotein (LDL) receptors.

This ultimately leads to increased clearance of LDL cholesterol from the bloodstream, resulting in lowered levels of total cholesterol, LDL cholesterol, and apolipoprotein B. ezetimibe does not affect the absorption of triglycerides or fat-soluble vitamins.  ezetimibe works in conjunction with a healthy diet and exercise to help reduce LDL cholesterol levels in the blood.  

Pharmacodynamics: 

ezetimibe works by inhibiting the absorption of biliary and dietary cholesterol by the small intestine. It specifically inhibits the Niemann-Pick C1-Like 1 (NPC1L1) protein, which is responsible for the uptake of cholesterol by enterocytes in the small intestine. This results in a decrease in circulating levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and apolipoprotein B (apoB), as well as an increase in high-density lipoprotein (HDL) cholesterol. 

ezetimibe also reduces the absorption of plant sterols, which are structurally similar to cholesterol and compete with it for absorption in the small intestine. This results in a decrease in circulating levels of plant sterols as well. ezetimibe has no effect on the absorption of triglycerides or fat-soluble vitamins. It is usually administered in combination with a statin to achieve further reduction in LDL cholesterol levels.  

Pharmacokinetics: 

Absorption 

ezetimibe is rapidly absorbed following oral administration, with a peak plasma concentration (Cmax) achieved within 4-12 hours after dosing. The absolute bioavailability of ezetimibe is approximately 35%, due to both extensive first-pass metabolism and incomplete absorption. 

Distribution 

ezetimibe has a high degree of binding to human plasma proteins (> 90%), primarily albumin, and it is distributed mainly to the liver and small intestine. It has a low volume of distribution of approximately 0.4 L/kg. 

Metabolism 

ezetimibe undergoes extensive first-pass metabolism in the small intestine and liver, primarily by glucuronide conjugation to form the active metabolite, ezetimibe glucuronide. ezetimibe is metabolized via the hepatic and intestinal cytochrome P450 enzymes (CYP3A4 and CYP2C8) and eliminated through the feces and urine as metabolites. The half-life of ezetimibe is about 22 hours for the parent compound and 19 hours for the active metabolite. 

Elimination and excretion 

ezetimibe undergoes extensive first-pass metabolism in the small intestine and liver, primarily by glucuronide conjugation to form the active metabolite, ezetimibe glucuronide. ezetimibe is metabolized via the hepatic and intestinal cytochrome P450 enzymes (CYP3A4 and CYP2C8) and eliminated through the feces and urine as metabolites. The half-life of ezetimibe is about 22 hours for the parent compound and 19 hours for the active metabolite. 

Adminstartion

Administration: 

ezetimibe is available in tablet form for oral administration. It is taken with or without food. The usual recommended dose for ezetimibe is 10 mg once daily. It may be taken alone or in combination with a statin medication.

It is important to take the missed dosage as soon as possible. But if it’s almost time for the next dosage, you should skip the missed dose and go back to the usual dosing schedule. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: ezetimibe 

Pronounced: (ez-ET-i-mibe)  

Why do we use ezetimibe? 

ezetimibe is primarily used for the treatment of hypercholesterolemia, particularly in patients with primary hypercholesterolemia (heterozygous familial and non-familial) and mixed hyperlipidemia.

It is used in combination with other lipid-lowering agents, such as statins, to further lower cholesterol levels. ezetimibe may also be used off-label for the treatment of other conditions, such as sitosterolemia, a rare genetic disorder that causes elevated levels of plant sterols in the blood.