Simvastatin

Generic Name: Simvastatin
Brand Names: Zocor, FloLipid (oral suspension)
Drug Class: HMG-CoA reductase inhibitors (statins)
Formulations: Oral tablets (5 mg, 10 mg, 20 mg, 40 mg, 80 mg), Oral suspension (20 mg/5 mL, 40 mg/5 mL)
Route of Administration: Oral

Indications
Simvastatin is primarily used to manage cholesterol levels and reduce cardiovascular risk. Its approved and off-label indications include:

1. Hypercholesterolemia (primary) – reduces elevated total cholesterol, LDL-C, and apo-B.

2. Mixed dyslipidemia – lowers LDL-C and triglycerides while raising HDL-C.

3. Homozygous familial hypercholesterolemia (HoFH) – adjunct to diet and other lipid-lowering therapies.

4. Heterozygous familial hypercholesterolemia (HeFH) in adolescents aged 10–17 years.

5. Primary and secondary prevention of cardiovascular events – including myocardial infarction, stroke, and need for revascularization in high-risk patients with or without established coronary heart disease.

6. Post-myocardial infarction therapy – for secondary prevention of atherosclerotic events.

Mechanism of Action
Simvastatin is a prodrug that is hydrolyzed to its active beta-hydroxyacid form. It competitively inhibits HMG-CoA reductase, the rate-limiting enzyme in hepatic cholesterol biosynthesis.
This leads to:

• Decreased intrahepatic cholesterol synthesis

• Upregulation of LDL receptors

• Increased clearance of LDL from the bloodstream

• Reduction in VLDL and triglyceride levels

• Mild increase in HDL levels

Dosage and Administration

• Initial Dose: 10–20 mg once daily in the evening.

• Moderate risk patients: 40 mg/day may be used.

• Severe hypercholesterolemia: up to 80 mg/day may be used cautiously only in patients who have been taking 80 mg chronically without evidence of muscle toxicity.

• Renal impairment (CrCl <30 mL/min): initial dose should not exceed 5–10 mg/day.

• Pediatric use (HeFH): 10 mg once daily initially, maximum 40 mg/day.

• Administration: Should be taken in the evening for maximal effect on cholesterol synthesis.

Pharmacokinetics

• Absorption: ~85%, but first-pass metabolism reduces systemic availability (~5%).

• Protein Binding: ~95%.

• Metabolism: Hepatic via CYP3A4 to active metabolites.

• Elimination Half-Life: ~2 hours (active metabolites persist longer).

• Excretion: Feces (~60%), urine (~13%).

Contraindications

• Active liver disease or unexplained persistent elevations in hepatic transaminases

• Pregnancy and breastfeeding

• Concomitant use with potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, clarithromycin, HIV protease inhibitors, nefazodone)

• Concomitant use with gemfibrozil, cyclosporine, or danazol (due to high risk of myopathy/rhabdomyolysis)

Warnings and Precautions

• Hepatotoxicity: Monitor liver enzymes before and during treatment.

• Myopathy and rhabdomyolysis: Risk increases with higher doses and drug interactions; monitor CK levels in symptomatic patients.

• Diabetes Mellitus: May increase HbA1c and fasting glucose; benefits outweigh risks.

• Cognitive impairment: Rare reversible cognitive symptoms reported.

• Ophthalmologic effects: Cataract risk is not established, but periodic monitoring is suggested in long-term therapy.

Adverse Effects
Common (≥2%):

• Headache

• Abdominal pain

• Nausea

• Constipation

• Muscle cramps

• Elevated liver enzymes

Serious:

• Myopathy

• Rhabdomyolysis (especially at 80 mg dose or with interacting drugs)

• Hepatic dysfunction

• Hypersensitivity reactions (e.g., rash, pruritus, eosinophilia)

Monitoring Parameters

• Baseline: Lipid panel, liver enzymes (ALT/AST), creatine kinase (if high risk for myopathy)

• Ongoing: Lipid profile at 4–12 weeks after initiation or dose change, then every 3–12 months

• CK levels: If muscle pain or weakness develops

• HbA1c and glucose: Monitor in diabetic and prediabetic patients

Drug Interactions
Simvastatin is extensively metabolized by CYP3A4. Interacting substances can raise plasma concentrations and increase risk of adverse effects.
Major Interactions:

1. CYP3A4 inhibitors (contraindicated or dose-limited):

   • Contraindicated: Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone

   • Dose-limited: Verapamil and diltiazem (maximum simvastatin dose 10 mg/day); amiodarone, amlodipine, ranolazine (max 20 mg/day)

2. Fibrates: Especially gemfibrozil – contraindicated due to high risk of myopathy. Fenofibrate should be used with caution.

3. Niacin (>1 g/day): Increases risk of muscle damage – caution needed

4. Cyclosporine and danazol: Contraindicated due to increased statin exposure

5. Warfarin: May increase INR – monitor closely

6. Grapefruit juice: Avoid due to CYP3A4 inhibition and increased simvastatin levels

7. Colchicine: Concurrent use increases myopathy risk – monitor closely

8. Rifampin: Induces CYP3A4 – may reduce efficacy

Use in Special Populations

• Pregnancy: Contraindicated. Statins are Category X due to interference with cholesterol synthesis, essential for fetal development.

• Breastfeeding: Contraindicated. Drug may be excreted in breast milk.

• Elderly: Higher risk of myopathy; use with caution

• Hepatic impairment: Avoid use in active liver disease

• Renal impairment: Lower starting dose recommended if CrCl <30 mL/min

Use in Combination Therapy

• May be combined with ezetimibe for additional LDL-C reduction

• Combination with bile acid sequestrants may further improve lipid profile

• Use with PCSK9 inhibitors may be considered in very high-risk patients

• Combination with fenofibrate is possible but requires close monitoring for muscle toxicity

Comparative Considerations

• Potency: Simvastatin is considered a moderate-intensity statin.

• Compared to Atorvastatin or Rosuvastatin: Simvastatin has shorter half-life and lower LDL-lowering efficacy at comparable doses.

• Cost: Generally lower than newer statins due to generic availability

• Preferred in: Patients requiring moderate LDL-C reduction and not taking interacting drugs

• Not preferred in: High-risk patients needing intensive LDL-C lowering (atorvastatin or rosuvastatin preferred)

Discontinuation Considerations
Abrupt discontinuation may lead to rebound increases in LDL-C and cardiovascular risk. If needed, tapering is not necessary pharmacologically, but appropriate replacement therapy or risk reassessment should be considered.

Brand Information

• Zocor: Original brand name by Merck

• FloLipid: Oral suspension approved for patients who have difficulty swallowing tablets

• Multiple generics available globally in all standard doses

Recent Safety Updates

• FDA 2011 safety communication: Restricted 80 mg dose due to increased risk of muscle injury

• MHRA UK guidance: Recommends avoiding high-dose simvastatin with CYP3A4 inhibitors; reinforced labeling and patient warnings

Storage

• Store tablets at 20°C to 25°C (68°F to 77°F); protect from moisture and light

• FloLipid suspension should be refrigerated and shaken well before use

Key Counseling Points

• Take in the evening for best effect

• Report unexplained muscle pain, tenderness, or weakness

• Avoid grapefruit or grapefruit juice

• Avoid pregnancy and use effective contraception during treatment

• Adhere strictly to diet and lifestyle changes alongside medication

• Avoid alcohol or limit consumption due to liver effects

• Inform all healthcare providers of statin use before starting any new medication

Alternative Agents

• Atorvastatin, Rosuvastatin: more potent and longer-acting

• Pravastatin: preferred in those with higher interaction risk due to non-CYP metabolism

• Ezetimibe, PCSK9 inhibitors: non-statin alternatives or adjuncts

Regulatory Classification

• Prescription-only medication

• Included in WHO Model List of Essential Medicines