What are the drug interactions of simvastatin?

Simvastatin Drug Interactions: Clinical Management Guidelines

Simvastatin has numerous clinically significant drug interactions that require dose limitations or contraindications to prevent serious adverse effects, particularly rhabdomyolysis. 1 These interactions must be carefully managed to ensure patient safety while maintaining effective lipid-lowering therapy.

Key Drug Interaction Categories

Strong CYP3A4 Inhibitors (CONTRAINDICATED)

• Complete contraindication with:
  • Select azole antifungals (itraconazole, ketoconazole, posaconazole, voriconazole)
  • Select macrolide antibiotics (erythromycin, clarithromycin)
  • HIV protease inhibitors (nelfinavir, ritonavir, darunavir/ritonavir)
  • HCV protease inhibitors (boceprevir, telaprevir)
  • Cobicistat-containing products
  • Nefazodone 2

Other Contraindicated Medications

• Cyclosporine
• Danazol
• Gemfibrozil 2

Dose-Limited Interactions (Require Simvastatin Dose Adjustment)

1. Limit simvastatin to 10 mg daily with:

   • Verapamil
   • Diltiazem
   • Dronedarone 1, 2

2. Limit simvastatin to 20 mg daily with:

   • Amiodarone
   • Amlodipine
   • Ranolazine 1, 2

3. Lomitapide interactions:

   • Reduce simvastatin dose by 50% when initiating lomitapide
   • Maximum 20 mg daily (or 40 mg if previously on 80 mg chronically) 2

Other Notable Interactions

• Warfarin: Monitor INR more closely after initiating simvastatin or changing dose 1
• Daptomycin: Consider temporarily suspending simvastatin during daptomycin treatment 2
• Niacin (≥1g/day): Increased risk of myopathy, particularly in Chinese patients 2
• Ticagrelor: Potential for increased simvastatin levels 1

Mechanism of Interactions

Most clinically significant interactions with simvastatin occur through:

1. CYP3A4 inhibition: Simvastatin is extensively metabolized by CYP3A4. Inhibitors of this enzyme increase simvastatin exposure, raising the risk of myopathy and rhabdomyolysis 2

2. Transport protein inhibition: Simvastatin is a substrate of OATP1B1. Inhibitors of this transporter can increase simvastatin exposure 2

Clinical Monitoring Recommendations

• Baseline assessment: Check liver enzymes before starting combination therapy 3
• Follow-up monitoring:
  • Monitor liver enzymes at 12 weeks and then annually 3
  • Measure creatine kinase (CK) if muscle symptoms develop 3
  • Monitor for muscle symptoms (pain, tenderness, weakness) at 6-12 weeks and each follow-up visit 3

Alternative Statin Recommendations

When simvastatin interactions cannot be avoided, consider switching to:

• Pravastatin: Not significantly metabolized by CYP3A4, safer with amiodarone 1
• Rosuvastatin: Alternative with amiodarone, ranolazine 1
• Pitavastatin: Alternative with amiodarone, ranolazine 1
• Fluvastatin: Alternative with amiodarone, ranolazine 1

Special Considerations

• Elderly patients: Higher risk due to polypharmacy and altered pharmacokinetics 3
• Asian patients: Higher risk of myopathy with certain combinations, particularly niacin 2
• Medication reconciliation: Review all medications at each clinical encounter to identify potential interactions 1

Common Pitfalls to Avoid

1. Failure to recognize "hidden" CYP3A4 inhibitors in patient medication lists
2. Not adjusting simvastatin dose when adding interacting medications
3. Overlooking OTC medications and supplements that may interact with simvastatin
4. Assuming all statins have the same interaction profile (they don't - pravastatin, rosuvastatin, and pitavastatin have fewer interactions)
5. Not monitoring patients after adding potentially interacting medications

By carefully managing these interactions and following appropriate dose limitations, the risk of serious adverse effects from simvastatin can be minimized while maintaining effective lipid management.