Can we prescribe diltiazem and simvastatin together?

Diltiazem and Simvastatin Co-prescription: Safety Considerations

Diltiazem and simvastatin should not be prescribed together at doses of simvastatin >10 mg daily due to significant drug interaction risks that can lead to rhabdomyolysis and hepatitis. 1

Mechanism of Interaction

Diltiazem is a moderate inhibitor of CYP3A4, the enzyme responsible for metabolizing simvastatin. This interaction has significant clinical implications:

• Diltiazem increases simvastatin exposure by approximately 5-fold 1, 2
• Increases simvastatin peak concentration by 3.6-fold 2
• Increases elimination half-life by 2.3-fold 2

Recommendations for Management

Preferred Approach

1. Use a non-CYP3A4-metabolized statin instead of simvastatin when diltiazem is required 1, 3
   • Rosuvastatin, pravastatin, pitavastatin, or fluvastatin are preferred alternatives
   • These statins have different metabolic pathways and are less likely to interact with diltiazem

Alternative Approach (if simvastatin must be used)

1. Limit simvastatin to ≤10 mg daily when co-administered with diltiazem 1, 3
2. Limit diltiazem to ≤240 mg daily when co-administered with simvastatin 3
3. Monitor closely for signs of myopathy and hepatotoxicity 3, 4
   • Muscle pain, tenderness, or weakness
   • Elevated creatine kinase (CK)
   • Elevated liver enzymes

Clinical Evidence of Harm

Several case reports document serious adverse events with this combination:

• Rhabdomyolysis and hepatitis have been reported when diltiazem was added to stable simvastatin therapy 5, 6
• Similar interactions have been reported with atorvastatin and diltiazem 7
• Risk appears higher with:
  • Higher statin doses (≥40 mg daily) 4
  • New initiation of either medication 4

Practical Algorithm for Management

1. For patients already on diltiazem who need statin therapy:

   • Choose rosuvastatin, pravastatin, pitavastatin, or fluvastatin
   • If simvastatin is necessary, limit dose to ≤10 mg daily

2. For patients already on simvastatin who need calcium channel blocker therapy:

   • Consider amlodipine instead of diltiazem (less interaction potential)
   • If diltiazem is necessary:
     • Reduce simvastatin to ≤10 mg daily
     • Consider switching to a non-CYP3A4-metabolized statin

3. For all patients on this combination:

   • Educate about symptoms of myopathy (muscle pain, weakness)
   • Monitor CK and liver enzymes at baseline and periodically
   • Discontinue simvastatin immediately if myopathy symptoms develop

Conclusion

The combination of diltiazem and simvastatin poses significant risks due to pharmacokinetic interactions. When possible, use a non-CYP3A4-metabolized statin with diltiazem. If the combination cannot be avoided, limit simvastatin to ≤10 mg daily and monitor closely for adverse effects.