Usage
- Ezetimibe + Simvastatin is prescribed to lower high cholesterol levels, specifically low-density lipoprotein cholesterol (LDL-C), in adults and children 10 years and older. It is used as an adjunct to diet and other LDL-C lowering therapies in patients with primary hyperlipidemia, heterozygous familial hypercholesterolemia (HeFH), and homozygous familial hypercholesterolemia (HoFH). Simvastatin, a component of this combination, also reduces the risk of cardiovascular events (coronary heart disease death, non-fatal myocardial infarction, stroke) and the need for revascularization procedures in adults with established coronary heart disease, cerebrovascular disease, peripheral artery disease, and/or diabetes at high risk of coronary events.
- Pharmacological Classification: Antihyperlipidemic, HMG-CoA reductase inhibitor (statin), dietary cholesterol absorption inhibitor.
- Mechanism of Action: Ezetimibe inhibits the intestinal absorption of cholesterol. Simvastatin inhibits HMG-CoA reductase, an enzyme crucial for cholesterol synthesis in the liver. The combination has a synergistic effect, leading to greater LDL-C reduction than either drug alone.
Alternate Names
- International/Regional Variations: The generic name Ezetimibe + Simvastatin remains consistent internationally.
- Brand Name(s): Vytorin
How It Works
- Pharmacodynamics: Ezetimibe acts on the brush border of the small intestine to inhibit cholesterol absorption. Simvastatin inhibits HMG-CoA reductase, leading to decreased hepatic cholesterol synthesis and increased LDL receptor expression, enhancing LDL clearance from the bloodstream.
- Pharmacokinetics: Both drugs are orally absorbed. Ezetimibe undergoes glucuronidation in the intestine and liver. Simvastatin is extensively metabolized by the liver, primarily via CYP3A4. Both drugs and their metabolites are eliminated in the feces and urine.
- Mode of Action: Ezetimibe blocks the Niemann-Pick C1-Like 1 (NPC1L1) protein, which is responsible for cholesterol absorption. Simvastatin competitively inhibits HMG-CoA reductase, reducing mevalonate production, a precursor to cholesterol.
- Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Ezetimibe specifically targets NPC1L1. Simvastatin inhibits HMG-CoA reductase.
- Elimination Pathways: Ezetimibe is primarily excreted in feces (via biliary excretion); a small amount is renally excreted. Simvastatin and its metabolites are predominantly eliminated in bile and feces, with a smaller fraction renally excreted.
Dosage
Standard Dosage
Adults:
- Initial dose: One Ezetimibe 10 mg/Simvastatin 10 mg tablet orally once daily, in the evening.
- The maximum recommended dose is Ezetimibe 10 mg/Simvastatin 40 mg once daily.
- The Ezetimibe 10 mg/Simvastatin 80 mg dose is reserved for patients at high cardiovascular risk who have tolerated lower doses for at least 12 months without muscle toxicity and haven’t achieved their LDL-C goals.
Children:
- Children 10-17 years old with HeFH: Initial dose: One Ezetimibe 10 mg/Simvastatin 10 mg tablet orally once daily, in the evening.
- Maximum dose for children is Ezetimibe 10 mg/Simvastatin 40 mg once daily.
- Not recommended for children under 10 years of age.
Special Cases:
- Elderly Patients: Administer with caution due to increased risk of myopathy; no dose adjustment is generally required unless renal impairment is present.
- Patients with Renal Impairment: For GFR <60 mL/min/1.73 m², the maximum dose is Ezetimibe 10 mg/Simvastatin 20 mg daily; higher doses may be used with caution and close monitoring.
- Patients with Hepatic Dysfunction: Contraindicated in patients with active liver disease or unexplained persistent transaminase elevations. Use with caution in patients with a history of liver disease.
- Patients with Comorbid Conditions: Dose adjustment may be necessary based on concomitant medications and coexisting medical conditions.
Clinical Use Cases
Ezetimibe + Simvastatin is not indicated for acute conditions requiring intubation, surgical procedures, mechanical ventilation, intensive care, or emergency situations. Its use is focused on chronic cholesterol management.
Dosage Adjustments
Dosage modifications are necessary for renal impairment and drug interactions (see Drug Interactions section).
Side Effects
Common Side Effects
- Headache
- Muscle pain (myalgia)
- Upper respiratory tract infection
- Diarrhea
- Abdominal pain
Rare but Serious Side Effects
- Myopathy/rhabdomyolysis (muscle breakdown)
- Hepatotoxicity
- Immune-mediated necrotizing myopathy
Long-Term Effects
- Increased risk of diabetes
- Cognitive impairment
Adverse Drug Reactions (ADR)
- Angioedema
- Hypersensitivity reactions
Contraindications
- Hypersensitivity to ezetimibe or simvastatin
- Active liver disease or unexplained persistent transaminase elevation
- Pregnancy and breastfeeding
- Concomitant use of strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, ketoconazole), cyclosporine, danazol, gemfibrozil
Drug Interactions
-
CYP3A4 Inhibitors: Increase simvastatin levels, elevating myopathy risk. Avoid concomitant use of strong CYP3A4 inhibitors. Dose adjustments needed for moderate CYP3A4 inhibitors.
-
CYP3A4 Inducers: Decrease simvastatin levels, reducing efficacy.
-
Other Interactions:
- Bile acid sequestrants: Decrease ezetimibe absorption; administer Ezetimibe + Simvastatin at least 2 hours before or 4 hours after bile acid sequestrants.
- Coumarin anticoagulants: Monitor INR closely.
- Digoxin: Monitor digoxin levels.
- Fenofibrates: Increase ezetimibe exposure.
- Niacin: Increased myopathy risk; limit Simvastatin dose to 20 mg when used with niacin.
-
Food and Lifestyle Factors: Grapefruit juice inhibits CYP3A4, increasing simvastatin levels. Alcohol can increase triglyceride levels and liver damage risk.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: X. Contraindicated in pregnancy due to potential fetal harm.
- Breastfeeding: Not recommended due to potential for infant exposure and disruption of lipid metabolism.
Drug Profile Summary
- Mechanism of Action: Inhibits intestinal cholesterol absorption (ezetimibe) and hepatic cholesterol synthesis (simvastatin).
- Side Effects: Headache, myalgia, upper respiratory tract infection, diarrhea, abdominal pain; rarely, myopathy/rhabdomyolysis, hepatotoxicity.
- Contraindications: Hypersensitivity, active liver disease, pregnancy, breastfeeding, concomitant use of strong CYP3A4 inhibitors.
- Drug Interactions: CYP3A4 inhibitors, CYP3A4 inducers, bile acid sequestrants, coumarin anticoagulants, digoxin, fenofibrates, niacin.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy; breastfeeding not recommended.
- Dosage: Adults: 10/10 mg to 10/40 mg daily; Children (10-17 years): 10/10 to 10/40 mg daily.
- Monitoring Parameters: Lipid panel (LDL-C, HDL-C, triglycerides), liver function tests (ALT, AST), creatine kinase (CK) to monitor for myopathy.
Popular Combinations
Ezetimibe + Simvastatin is often combined with other lipid-lowering agents (e.g., PCSK9 inhibitors) in patients with severe hypercholesterolemia who do not achieve target LDL-C levels with Ezetimibe + Simvastatin alone.
Precautions
- Assess liver function before and during treatment.
- Monitor for signs and symptoms of myopathy.
- Counsel patients on lifestyle modifications (diet, exercise).
- Advise patients to avoid grapefruit products and excessive alcohol consumption.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Ezetimibe + Simvastatin?
A: Adults: 10/10 to 10/40 mg daily. Children (10-17 years): 10/10 to 10/40 mg daily.
Q2: What are the serious side effects of Ezetimibe + Simvastatin?
A: Myopathy/rhabdomyolysis, hepatotoxicity, and immune-mediated necrotizing myopathy are rare but serious side effects.
Q3: Can Ezetimibe + Simvastatin be used during pregnancy?
A: No, it is contraindicated in pregnancy due to the risk of fetal harm.
Q4: What are the main drug interactions with Ezetimibe + Simvastatin?
A: Strong CYP3A4 inhibitors (e.g., some antifungals and antibiotics), cyclosporine, gemfibrozil, and danazol should be avoided.
Q5: How does Ezetimibe + Simvastatin work to lower cholesterol?
A: Ezetimibe reduces cholesterol absorption in the intestine, while simvastatin reduces cholesterol synthesis in the liver.
Q6: What should patients avoid while taking Ezetimibe + Simvastatin?
A: Grapefruit products and excessive alcohol consumption.
Q7: Who should not take Ezetimibe + Simvastatin?
A: Patients with active liver disease, pregnant or breastfeeding women, and those with hypersensitivity to the components.
Q8: What are the signs of myopathy, a serious side effect of Ezetimibe + Simvastatin?
A: Unexplained muscle pain, tenderness, or weakness, especially if accompanied by fever or dark urine.
Q9: How should Ezetimibe + Simvastatin be taken?
A: Orally, once daily in the evening, with or without food.
