Atorvastatin + Ezetimibe

Approved Indications:

• Primary Hyperlipidemia (heterozygous familial and non-familial): For patients inadequately controlled with statin monotherapy or requiring additional LDL-C reduction.
• Homozygous Familial Hypercholesterolemia (HoFH): As adjunct to other lipid-lowering therapies (e.g., LDL apheresis) or if such treatments are not available.
• Mixed Dyslipidemia (elevated LDL-C and triglycerides with low HDL-C).
• Sitosterolemia (Phytosterolemia): Ezetimibe component is indicated to reduce elevated sitosterol and campesterol levels.
• Cardiovascular Risk Reduction: For high-risk patients, such as those with coronary heart disease or diabetes, to reduce the risk of myocardial infarction, stroke, and revascularization procedures.

Adults:

• Usual starting dose: Atorvastatin 10 mg + Ezetimibe 10 mg once daily.
• Maximum dose: Atorvastatin 80 mg + Ezetimibe 10 mg once daily.
• Dose titration should be based on LDL-C response, with lipid levels reassessed after 2–4 weeks.

Pediatrics:

• Safety and efficacy not established for combination in patients under 10 years.
• Ezetimibe use in children 10–17 years is only for familial hypercholesterolemia and must be combined with dietary therapy and monitored by a specialist.

Elderly:

• No dose adjustment required; monitor renal and hepatic function.

Renal Impairment:

• No dosage adjustment required; however, caution in severe impairment due to lack of data.

Hepatic Impairment:

• Contraindicated in active liver disease or persistent elevations in transaminases.

Route: Oral; with or without food. Swallow whole with water.

Atorvastatin is a selective HMG-CoA reductase inhibitor that blocks the rate-limiting step in hepatic cholesterol synthesis, leading to upregulation of LDL receptors and enhanced clearance of LDL-C from plasma.
Ezetimibe acts at the brush border of the small intestine by inhibiting the Niemann-Pick C1-Like 1 (NPC1L1) protein, reducing the absorption of dietary and biliary cholesterol.
Together, they provide dual inhibition of cholesterol production and absorption, offering an additive effect in lowering LDL-C and total cholesterol levels.

Atorvastatin:

• Absorption: Rapid; peak plasma levels in 1–2 hours.
• Bioavailability: ~14%; extensive first-pass metabolism.
• Distribution: Highly protein-bound (~98%).
• Metabolism: Hepatic via CYP3A4; active metabolites include ortho- and parahydroxyatorvastatin.
• Elimination: Primarily via bile; <2% in urine; half-life ~14 hours.

Ezetimibe:

• Absorption: Rapid; peak concentration in 1–2 hours.
• Bioavailability: Not determined due to extensive conjugation.
• Distribution: ~90% plasma protein-bound.
• Metabolism: Undergoes glucuronidation in the intestinal wall and liver; active metabolite: ezetimibe-glucuronide.
• Elimination: Feces (~78%) and urine (~11%); half-life ~22 hours.

Pregnancy:

• Atorvastatin: Contraindicated. Category X (FDA classification before removal); lipid-lowering drugs offer no benefit during pregnancy and may cause fetal harm.
• Ezetimibe: Should be avoided due to insufficient human data; animal studies have shown adverse fetal effects.

Lactation:

• Both components are excreted in animal milk. Avoid use in breastfeeding women due to potential for serious adverse reactions in infants, especially due to statin-related risk of muscle toxicity.

• Primary Class: Lipid-lowering agent
• Subclasses:
• Atorvastatin: HMG-CoA Reductase Inhibitor (Statin)
• Ezetimibe: Cholesterol Absorption Inhibitor

• Hypersensitivity to atorvastatin, ezetimibe, or any excipients.
• Active liver disease or unexplained persistent elevations in liver enzymes.
• Pregnancy and breastfeeding.
• Severe hepatic impairment (Child-Pugh C).
• Concurrent use with strong CYP3A4 inhibitors (e.g., clarithromycin) without dose adjustment.

• Hepatotoxicity: Monitor liver enzymes before initiation and periodically thereafter.
• Myopathy/Rhabdomyolysis: Increased risk when combined with fibrates, niacin, or strong CYP3A4 inhibitors. Monitor CK levels if muscle symptoms occur.
• Renal Impairment: Increased risk of statin-associated myopathy.
• New-onset Diabetes Mellitus: Statins may slightly increase risk.
• Cognitive Impairment: Rare reversible memory loss or confusion reported with statins.
• Immunologic/Hematologic Effects: Rare cases of thrombocytopenia and immune-mediated necrotizing myopathy.

Common (≥1%):

• Gastrointestinal: Diarrhea, abdominal pain, flatulence
• Neurologic: Headache, dizziness
• Musculoskeletal: Myalgia, joint pain, muscle cramps
• Hepatic: Transaminase elevation

Less Common/Serious:

• Rhabdomyolysis with acute renal failure
• Hepatitis, jaundice
• Hypersensitivity reactions: Rash, pruritus, angioedema
• Pancreatitis
• Thrombocytopenia

Onset: Generally within the first few weeks to months of therapy; myopathy may be dose-related.

• CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin): Increase atorvastatin levels → myopathy risk.
• Fibrates (especially gemfibrozil): Increase risk of muscle toxicity.
• Cyclosporine: Increases ezetimibe and atorvastatin levels; dose adjustment needed.
• Antacids: May decrease absorption of ezetimibe slightly.
• Grapefruit Juice: Inhibits CYP3A4, increasing atorvastatin levels.
• Warfarin: Ezetimibe may slightly enhance anticoagulant effect.

• ACC/AHA 2018 & 2022 Guidelines: Support addition of ezetimibe to statin therapy when LDL-C goals are not met with statins alone, particularly in secondary prevention or high-risk primary prevention patients.
• FDA Update: Reinforced warnings on statin-associated myopathy and hepatic monitoring recommendations.
• ESC 2019: Includes ezetimibe as second-line agent after statins in high and very high-risk patients.

• Temperature: Store below 25°C.
• Humidity: Store in a dry place; protect from moisture.
• Light Protection: Store in original packaging away from direct light.
• Handling Precautions: Do not crush or chew tablets.
• Refrigeration: Not required.