Ezetimibe

• Approved Indications:
• Primary hypercholesterolemia (heterozygous familial and non-familial) to reduce elevated total cholesterol, LDL cholesterol, apolipoprotein B, and triglycerides.
• Homozygous familial hypercholesterolemia, as adjunct therapy with other lipid-lowering treatments.
• Sitosterolemia (phytosterolemia), to reduce elevated sitosterol and campesterol levels.
• Adjunct to diet and exercise for treatment of mixed hyperlipidemia (elevated cholesterol and triglycerides).
• Used in combination with statins for additional LDL cholesterol reduction in patients inadequately controlled on statins alone.
• Off-label / Clinically Accepted Uses:
• As monotherapy in patients intolerant to statins.
• Prevention of cardiovascular events in certain high-risk patients, as part of lipid management strategies.

• Route: Oral.
• Adults:
• Typical dose: 10 mg once daily.
• Can be given as monotherapy or combined with statins.
• Pediatrics (≥10 years):
• Dose: 10 mg once daily, usually in combination with statins for familial hypercholesterolemia.
• Elderly: No dosage adjustment necessary.
• Renal impairment: No dosage adjustment required; use with caution in severe impairment.
• Hepatic impairment: Not recommended in moderate to severe hepatic impairment or active liver disease.
• Administration:
• May be taken with or without food.
• Tablets should be swallowed whole with water.
• Missed Dose: Take as soon as remembered unless near the next scheduled dose; do not double dose.

Ezetimibe selectively inhibits the Niemann-Pick C1-Like 1 (NPC1L1) transporter in the small intestine’s brush border membrane, blocking the absorption of cholesterol and related phytosterols from the intestinal lumen. This inhibition decreases the delivery of intestinal cholesterol to the liver, leading to increased clearance of cholesterol from the blood via upregulation of hepatic LDL receptors, thereby reducing plasma LDL cholesterol levels. It does not affect the absorption of fat-soluble vitamins or triglycerides significantly.

• Absorption: Rapidly absorbed with peak plasma concentrations reached within 4 to 12 hours.
• Bioavailability: Approximately 35-65%; food does not significantly affect absorption.
• Distribution: Highly protein bound (~90%) mainly to plasma proteins.
• Metabolism: Extensively metabolized via glucuronidation in the intestinal wall and liver to an active metabolite, ezetimibe-glucuronide.
• Half-life: Terminal half-life is approximately 22 hours (combined for parent drug and active metabolite).
• Elimination: Mainly excreted via feces (~78%) and urine (~11%), primarily as metabolites.

• Pregnancy: FDA Category C. Use only if potential benefits justify potential risks to the fetus; animal studies showed adverse effects.
• Lactation: Unknown if excreted in human milk; caution is advised. Breastfeeding is generally not recommended during treatment.

• Primary Class: Lipid-lowering agent.
• Subclass: Cholesterol absorption inhibitor.

• Known hypersensitivity to ezetimibe or any component of the formulation.
• Active liver disease or unexplained persistent elevations of serum transaminases, especially when used with statins.
• Pregnancy and breastfeeding (use only if clearly needed and benefits outweigh risks).

• Monitor liver function tests before and periodically during treatment, especially when used with statins.
• Use caution in patients with moderate or severe hepatic impairment.
• Rare cases of myopathy and rhabdomyolysis reported, especially with concurrent statin use; monitor for muscle pain or weakness.
• May cause hypersensitivity reactions including angioedema.
• Caution in patients with biliary obstruction as drug undergoes enterohepatic circulation.
• Safety and efficacy in children under 10 years not established.

• Common:
• Upper respiratory tract infections
• Diarrhea
• Arthralgia (joint pain)
• Fatigue
• Less Common/Serious:
• Elevated liver enzymes
• Myopathy or rhabdomyolysis (especially with statins)
• Hypersensitivity reactions (rash, urticaria, angioedema)
• Side effects are generally mild and transient.

• Statins: Increased risk of liver enzyme abnormalities and myopathy; monitor closely.
• Bile acid sequestrants (e.g., cholestyramine): May reduce ezetimibe absorption; administer ezetimibe at least 2 hours before or 4 hours after bile acid sequestrants.
• Cyclosporine: Increases ezetimibe plasma concentrations; dose adjustment or monitoring advised.
• Warfarin: Monitor INR closely as ezetimibe may increase anticoagulant effects.
• No significant interaction with food or alcohol.

• Recent guidelines emphasize ezetimibe as a recommended add-on therapy to statins for patients not achieving LDL-C goals or who are statin-intolerant.
• ESC/EAS and ACC/AHA recommend ezetimibe in combination with statins for secondary prevention in high-risk cardiovascular patients.
• No recent major changes in dosing or safety warnings.
• Ongoing studies assess cardiovascular outcome benefits beyond LDL lowering.

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light.
• Keep tablets in the original container until use.
• Keep out of reach of children.
• Do not freeze.