How long should simvastatin be held while on Diflucan (fluconazole)?

Simvastatin and Fluconazole Interaction: Recommendations for Holding Therapy

Simvastatin should be held for the entire duration of fluconazole therapy and for at least 3-5 days after discontinuing fluconazole due to the high risk of rhabdomyolysis from this drug interaction.

Mechanism of Interaction

• Fluconazole is a potent inhibitor of CYP3A4, the major enzyme responsible for simvastatin metabolism, which can lead to increased simvastatin levels and risk of myopathy and rhabdomyolysis 1, 2
• This interaction is similar to other documented statin-azole antifungal interactions that have resulted in severe rhabdomyolysis 3

Evidence Supporting Recommendation

• Case reports document rhabdomyolysis occurring when fluconazole is added to ongoing simvastatin therapy, with symptoms developing within one week of starting the antifungal 1, 2
• The American Heart Association guidelines specifically address statin-drug interactions and recommend limiting simvastatin dosing with certain medications due to increased risk of myopathy 4
• Similar interactions have been documented between statins and other CYP3A4 inhibitors such as macrolide antibiotics and other azole antifungals 3, 5

Risk Factors That Increase Concern

• Higher doses of simvastatin (>20mg) significantly increase the risk of this interaction 4
• Pre-existing renal insufficiency further increases the risk of rhabdomyolysis 5
• Advanced age is an additional risk factor for statin-induced myopathy when combined with interacting medications 1, 2

Management Algorithm

1. Immediately discontinue simvastatin when fluconazole therapy is initiated 1, 2
2. Hold simvastatin for the entire duration of fluconazole therapy 1, 2
3. Wait 3-5 days after completing fluconazole therapy before restarting simvastatin to allow for clearance of fluconazole and normalization of CYP3A4 activity 1
4. Monitor for symptoms of myopathy during and shortly after concurrent therapy, including muscle pain, tenderness, or weakness 1, 2
5. Consider laboratory monitoring (CK, renal function) if symptoms develop 1, 6

Alternative Approaches

• If statin therapy cannot be interrupted, consider switching to a statin with less dependency on CYP3A4 metabolism, such as rosuvastatin, atorvastatin, pitavastatin, fluvastatin, or pravastatin 4
• For patients requiring both medications, pravastatin may be the safest statin option as it undergoes minimal CYP450 metabolism 4

Common Pitfalls to Avoid

• Failure to recognize the interaction: Many clinicians may not be aware of this specific interaction between simvastatin and fluconazole 1, 2
• Inadequate monitoring: Patients may develop symptoms of myopathy days after starting the combination therapy 1
• Incomplete holding period: Resuming simvastatin too soon after stopping fluconazole may still result in interaction due to the elimination half-life of fluconazole 2
• Ignoring patient symptoms: Muscle pain or weakness in patients on this combination should prompt immediate discontinuation of both medications and laboratory evaluation 1, 2