Simvastatin

• High Cholesterol
• Cardiovascular Disease Prevention
• Familial Hypercholesterolemia
• Coronary Heart Disease

Simvastatin is an HMG-CoA reductase inhibitor (statin) used to treat hyperlipidemia and reduce cardiovascular risk. It was one of the first statins introduced and remains widely used for its proven efficacy in preventing cardiovascular events.

Mechanism of Action

Simvastatin inhibits cholesterol synthesis:

• Prodrug conversion: Lactone form converted to active hydroxy acid form
• HMG-CoA reductase inhibition: Blocks the rate-limiting step in cholesterol biosynthesis
• Upregulates LDL receptors: Compensatory response to reduced hepatic cholesterol increases LDL clearance
• Reduces LDL cholesterol: 27-47% reduction depending on dose
• Pleiotropic effects: Anti-inflammatory, antithrombotic, and endothelial benefits

Available Formulations

Simvastatin is available as tablets:

• 5 mg, 10 mg, 20 mg, 40 mg, 80 mg tablets

Also available in combination with ezetimibe (Vytorin).

Medical Uses

FDA-Approved Indications:

• Hyperlipidemia: Reduces total cholesterol, LDL-C, apoB, and triglycerides; increases HDL-C
• Prevention of cardiovascular events in patients with coronary heart disease or at high cardiovascular risk
• Homozygous familial hypercholesterolemia
• Heterozygous familial hypercholesterolemia in adolescents 10-17 years

Dosing Guidelines

Adults (General Hyperlipidemia):

• Initial: 10-20 mg once daily in the evening
• Range: 5-40 mg daily
• Maximum: 40 mg daily (80 mg restricted to patients who have taken it for ≥12 months without muscle problems)

High Cardiovascular Risk:

• 20-40 mg once daily in the evening

Pediatric (Heterozygous FH, 10-17 years):

• Initial: 10 mg once daily in the evening
• Range: 10-40 mg daily

Timing:

• Take in the evening (cholesterol synthesis peaks at night)

Important Safety Information

80 mg Dose Restriction:

• 80 mg should not be started in new patients
• Only continue 80 mg in patients who have been stable on this dose for ≥12 months without evidence of muscle toxicity

Contraindications:

• Active liver disease or unexplained persistent transaminase elevations
• Pregnancy and breastfeeding
• Concomitant use with strong CYP3A4 inhibitors, gemfibrozil, cyclosporine, danazol

Warnings and Precautions:

• Myopathy/Rhabdomyolysis: Risk dose-related; higher risk at 80 mg
• Hepatotoxicity: Monitor liver enzymes
• Diabetes: May increase HbA1c and fasting glucose

Drug Interactions

Contraindicated Combinations:

• Strong CYP3A4 inhibitors (itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, cobicistat)
• Gemfibrozil, cyclosporine, danazol

Dose Limitations:

• Amiodarone, dronedarone, amlodipine, ranolazine: Max 20 mg simvastatin
• Diltiazem, verapamil: Max 10 mg simvastatin
• Lomitapide: Max 20 mg simvastatin

Other:

• Warfarin: Monitor INR
• Grapefruit juice: Avoid large quantities

Special Populations

• Hepatic Impairment: Contraindicated in active liver disease
• Renal Impairment: Start 5 mg for severe impairment; use caution with doses >10 mg
• Pregnancy: Contraindicated (Category X)
• Lactation: Contraindicated
• Elderly: No specific adjustment; start conservatively
• Chinese descent: Avoid simvastatin 80 mg (increased myopathy risk with niacin)