Do Simvastatin (Zocor) and Norvasc (Amlodipine) interact?

Simvastatin and Norvasc (Amlodipine) Drug Interaction

Yes, simvastatin and Norvasc (amlodipine) have a clinically significant drug interaction. When used together, amlodipine increases simvastatin exposure by 77%, requiring simvastatin dose limitation to 20 mg daily to reduce the risk of myopathy and rhabdomyolysis. 1

Mechanism of Interaction

The interaction occurs through the following mechanisms:

• Amlodipine is a weak inhibitor of CYP3A4 1
• Simvastatin is extensively metabolized by CYP3A4 2
• When co-administered, amlodipine increases simvastatin systemic exposure by 77% compared to simvastatin alone 1

Clinical Significance and Risk

This interaction can lead to:

• Increased risk of muscle-related toxicity, including myopathy and rhabdomyolysis 2
• In the SEARCH trial, patients taking high-dose simvastatin with amiodarone (another CYP3A4 inhibitor) had significantly higher rates of myopathy and rhabdomyolysis compared to those on lower doses 2
• The interaction with simvastatin appears to be mainly driven by CYP3A4 inhibition at the intestinal level 3

FDA Recommendations and Risk Management

The FDA has established specific dosing restrictions:

• Simvastatin dose should be limited to 20 mg daily when co-administered with amlodipine 1
• This limitation was implemented to minimize the risk of myopathy 4

Management Options

1. Dose limitation approach:

   • Limit simvastatin to 20 mg daily if amlodipine must be continued 1
   • Monitor for muscle symptoms (pain, tenderness, weakness)
   • Check creatine kinase (CK) levels if muscle symptoms develop

2. Alternative statin approach:

   • Switch to a statin less dependent on CYP3A4 metabolism:
     • Pravastatin, rosuvastatin, fluvastatin, or pitavastatin do not require dose adjustments when used with amlodipine 2
     • Atorvastatin is also metabolized by CYP3A4 but has a smaller intestinal first-pass effect, making it less susceptible to this interaction than simvastatin 3

3. Non-concurrent dosing approach:

   • If both medications must be continued, separating administration times may reduce interaction
   • Non-concurrent dosing (taking simvastatin and amlodipine at different times) has been shown to reduce simvastatin acid exposure by approximately 34% compared to concurrent dosing 5

Monitoring Recommendations

For patients on combined therapy:

• Monitor for muscle symptoms (pain, weakness, tenderness)
• Consider baseline and periodic CK measurements in high-risk patients
• Be especially vigilant in elderly patients, those with renal impairment, or patients taking multiple medications

Common Pitfalls to Avoid

• Exceeding the 20 mg daily dose limit for simvastatin when used with amlodipine
• Ignoring patient reports of muscle pain or weakness
• Failing to recognize that this interaction may be delayed in onset
• Overlooking the potential for increased risk when additional CYP3A4 inhibitors are added to the regimen (e.g., ciprofloxacin) 6
• Assuming all statins have the same interaction potential with amlodipine

This interaction requires careful clinical management to minimize the risk of adverse effects while maintaining effective treatment of both hypertension and hyperlipidemia.