Usage
Atorvastatin + Ezetimibe is prescribed to reduce elevated levels of total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C). It is specifically indicated for:
- Primary Hyperlipidemia (Heterozygous Familial and Non-familial): In adults and adolescents (10-17 years) as adjunctive therapy to diet.
- Mixed Hyperlipidemia: In adults as adjunctive therapy to diet.
- Homozygous Familial Hypercholesterolemia (HoFH): In adults and adolescents (10-17 years) as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or alone if such treatments are unavailable.
Pharmacological Classification: Lipid-lowering combination therapy (HMG-CoA reductase inhibitor [statin] + cholesterol absorption inhibitor).
Mechanism of Action: Atorvastatin inhibits HMG-CoA reductase, an enzyme crucial for cholesterol synthesis in the liver, thus reducing cholesterol production. Ezetimibe inhibits the intestinal absorption of cholesterol, decreasing the amount of cholesterol entering the bloodstream from the diet. The combination of these mechanisms results in a more significant reduction in LDL-C than either agent alone.
Alternate Names
There is no official international nonproprietary name (INN) for the combination. It is often referred to as ezetimibe/atorvastatin.
Brand Names: Liptruzet, Atozet, Atozetr, and various generic formulations.
How It Works
Pharmacodynamics: Atorvastatin lowers LDL-C, total-C, Apo B, and TG, and increases HDL-C. Ezetimibe lowers LDL-C, total-C, and Apo B. The combination produces additive effects on LDL-C lowering.
Pharmacokinetics:
- Absorption: Both drugs are orally absorbed. Atorvastatin’s absorption is enhanced by food, while ezetimibe’s absorption is not affected.
- Metabolism: Atorvastatin is extensively metabolized by CYP3A4 enzymes in the liver to active metabolites. Ezetimibe undergoes glucuronidation in the intestine and liver to form an active metabolite, ezetimibe-glucuronide.
- Elimination: Atorvastatin and its metabolites are primarily eliminated in the bile, with a small portion excreted in the urine. Ezetimibe and its glucuronide are eliminated primarily in the feces, with a small portion excreted in the urine.
Mode of Action: Atorvastatin competitively inhibits HMG-CoA reductase, blocking the conversion of HMG-CoA to mevalonate, a precursor of cholesterol. Ezetimibe inhibits the Niemann-Pick C1-Like 1 (NPC1L1) protein, a transporter responsible for cholesterol absorption in the small intestine.
Receptor Binding/Enzyme Inhibition: Atorvastatin acts through enzyme inhibition (HMG-CoA reductase). Ezetimibe inhibits the NPC1L1 transporter.
Dosage
Standard Dosage
Adults:
Initial dose: 10/10 mg (ezetimibe/atorvastatin) or 10/20 mg orally once daily.
For patients requiring a greater reduction in LDL-C (>55%): Initial dose of 10/40 mg orally once daily.
Dosage range: 10/10 mg to 10/80 mg once daily.
Titration: Monitor lipid levels 2 or more weeks after initiation or titration and adjust dose accordingly.
Children (10-17 years): Similar dosing to adults for HoFH and primary hyperlipidemia. Not recommended for other types of hyperlipidemia.
Special Cases:
- Elderly Patients: Start with the lowest dose and titrate cautiously.
- Patients with Renal Impairment: No dose adjustment necessary.
- Patients with Hepatic Dysfunction: Contraindicated in moderate to severe hepatic impairment (Child-Pugh B or C). Not recommended in mild hepatic impairment.
- Patients with Comorbid Conditions: Exercise caution with diabetes, hypothyroidism, or recent stroke.
Clinical Use Cases
Atorvastatin + Ezetimibe is not indicated for acute clinical settings such as intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. It’s a long-term treatment for chronic hyperlipidemia.
Dosage Adjustments
Dose adjustments may be necessary based on concomitant medications, especially CYP3A4 inhibitors or inducers.
Side Effects
Common Side Effects:
Myalgia, arthralgia, elevated liver enzymes, headache, nasopharyngitis, diarrhea.
Rare but Serious Side Effects:
Rhabdomyolysis, myopathy, hepatotoxicity, pancreatitis.
Long-Term Effects:
Potential for muscle-related complications with long-term statin use.
Adverse Drug Reactions (ADR):
Angioedema, hypersensitivity reactions.
Contraindications
Active liver disease, unexplained persistent elevations in hepatic transaminases, pregnancy, breastfeeding, hypersensitivity to atorvastatin or ezetimibe.
Drug Interactions
CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, some HIV protease inhibitors) can increase atorvastatin levels.
CYP3A4 inducers (e.g., rifampin) can decrease atorvastatin levels.
Bile acid sequestrants can decrease the absorption of ezetimibe.
Fibrates, cyclosporine, and some antivirals can increase the risk of myopathy.
Pregnancy and Breastfeeding
Contraindicated in pregnancy and breastfeeding due to potential fetal harm.
Drug Profile Summary
- Mechanism of Action: Atorvastatin inhibits HMG-CoA reductase; ezetimibe inhibits cholesterol absorption.
- Side Effects: Myalgia, arthralgia, elevated liver enzymes, rhabdomyolysis (rare).
- Contraindications: Active liver disease, pregnancy, breastfeeding.
- Drug Interactions: CYP3A4 inhibitors/inducers, bile acid sequestrants, fibrates.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: 10/10 mg to 10/80 mg once daily.
- Monitoring Parameters: Lipid profile, liver function tests, creatine kinase (if myopathy suspected).
Popular Combinations
Often used alone or in combination with other lipid-lowering agents if target levels are not achieved.
Precautions
Monitor liver function tests before and periodically during treatment. Assess for muscle symptoms (myalgia, weakness) and creatine kinase if myopathy is suspected. Patients should be advised to report any unexplained muscle pain, tenderness, or weakness, especially if accompanied by malaise or fever. Alcohol should be limited.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Atorvastatin + Ezetimibe?
A: The initial dose is typically 10/10 mg or 10/20 mg once daily. Patients requiring a larger LDL-C reduction may start at 10/40 mg. The maximum dose is 10/80 mg once daily.
Q2: How should Atorvastatin + Ezetimibe be taken?
A: Orally, once daily, with or without food.
Q3: What are the common side effects?
A: Muscle aches, joint pain, elevated liver enzymes, headache, and gastrointestinal upset.
Q4: What are the serious side effects?
A: Rhabdomyolysis (muscle breakdown), liver damage, and pancreatitis.
Q5: Can it be used in pregnancy?
A: No, it’s contraindicated in pregnancy and breastfeeding.
Q6: What if a patient has liver disease?
A: Contraindicated in moderate to severe liver impairment. Use with caution in mild impairment.
Q7: What are the major drug interactions?
A: CYP3A4 inhibitors, CYP3A4 inducers, bile acid sequestrants, and fibrates.
A: Atorvastatin is metabolized by CYP3A4; ezetimibe undergoes glucuronidation.
Q9: What should be monitored during therapy?
A: Lipid panel, liver function tests, and creatine kinase levels if muscle symptoms develop.
