What is the interaction between amlodipine and simvastatin?

Amlodipine and Simvastatin Interaction

When amlodipine is co-administered with simvastatin, the simvastatin dose should be limited to 20 mg daily due to increased risk of myopathy and rhabdomyolysis from elevated simvastatin exposure. 1, 2

Mechanism of Interaction

The interaction between amlodipine and simvastatin occurs primarily through:

• Amlodipine is a weak inhibitor of CYP3A4, the primary enzyme responsible for simvastatin metabolism 1
• Co-administration of multiple doses of 10 mg amlodipine with simvastatin results in a 77% increase in exposure to simvastatin compared to simvastatin alone 1
• This increased exposure raises the risk of concentration-dependent adverse effects of simvastatin, particularly myopathy and rhabdomyolysis 2

Clinical Significance and Recommendations

Dosing Limitations

• The FDA drug label explicitly states that simvastatin dosage should be limited to 20 mg daily when co-administered with amlodipine 1, 2
• The American Heart Association guidelines similarly recommend limiting simvastatin to 20 mg daily when used with amlodipine 3

Risk Factors for Adverse Events

Patients at higher risk for myopathy with this combination include:

• Age ≥65 years 2
• Chinese ethnicity 2
• Renal impairment 2
• Uncontrolled hypothyroidism 2
• Addition of other medications that affect CYP3A4 metabolism 4

Alternative Approaches

If higher statin doses are required:

1. Switch to a non-CYP3A4 metabolized statin such as pravastatin, rosuvastatin, or pitavastatin 3
2. Consider non-concurrent dosing (separating administration times by several hours) which has been shown to reduce the interaction 5
3. For patients already on simvastatin 80 mg (not recommended for new patients), switch to an alternative statin if amlodipine is added 2

Monitoring Recommendations

For patients on combined therapy:

• Monitor for symptoms of myopathy (muscle pain, tenderness, or weakness)
• Consider baseline and follow-up CK measurements in high-risk patients
• Discontinue simvastatin if markedly elevated CK levels occur or if myopathy is diagnosed or suspected 2

Evidence Quality Assessment

The recommendation to limit simvastatin to 20 mg daily when co-administered with amlodipine is based on:

• FDA drug labeling requirements 1, 2
• American Heart Association scientific statement 3
• Pharmacokinetic studies showing increased simvastatin exposure 1, 6

While some European sources suggest higher doses may be tolerable 7, the FDA guidance and American Heart Association recommendations prioritize patient safety by limiting the simvastatin dose to reduce the risk of serious adverse events.