Why is the combination of fluconazole and atorvastatin (Lipitor) contraindicated?

From the Guidelines

The combination of fluconazole and atorvastatin is not absolutely contraindicated but requires caution due to a significant drug interaction. When taken together, fluconazole inhibits the CYP3A4 enzyme that metabolizes atorvastatin, potentially causing atorvastatin levels to increase substantially in the bloodstream. This elevation can increase the risk of serious side effects, particularly myopathy and rhabdomyolysis, a severe form of muscle damage that can lead to kidney failure. If both medications are necessary, dose adjustment of atorvastatin is typically recommended, often reducing the statin dose by 50% or more while monitoring for muscle pain, weakness, or tenderness. Laboratory monitoring of creatine kinase levels may be warranted. The interaction occurs because fluconazole is a moderate inhibitor of the cytochrome P450 system, specifically the CYP3A4 isoenzyme responsible for metabolizing many statins including atorvastatin. Alternative antifungal medications or statins with different metabolic pathways might be considered if appropriate for the patient's condition, as suggested by 1. Key considerations include:

• Monitoring for signs of myopathy and rhabdomyolysis
• Adjusting the dose of atorvastatin to minimize risk
• Considering alternative medications when possible
• Being aware of the potential for increased risk of adverse events when combining fluconazole with atorvastatin, as noted in 1 and 1. Given the potential for serious adverse effects, careful management and monitoring are essential when prescribing these medications together, with the goal of minimizing morbidity, mortality, and impact on quality of life.

From the FDA Drug Label

HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin (decreased hepatic metabolism of the statin) If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected. Dose reduction of statins may be needed Refer to the statin-specific prescribing information for details.

The combination of fluconazole and atorvastatin is contraindicated due to the increased risk of myopathy and rhabdomyolysis. This is because fluconazole can decrease the hepatic metabolism of atorvastatin, a HMG-CoA reductase inhibitor metabolized through CYP3A4, leading to increased levels of atorvastatin in the body.

• Key points to consider:
  • Increased risk of myopathy and rhabdomyolysis
  • Need for monitoring of creatinine kinase and observation for symptoms of myopathy and rhabdomyolysis
  • Possible need for dose reduction of atorvastatin
  • Importance of referring to statin-specific prescribing information for details 2

From the Research

Combination of Fluconazole and Atorvastatin

The combination of fluconazole and atorvastatin is contraindicated due to the increased risk of rhabdomyolysis, a severe and potentially life-threatening condition characterized by muscle breakdown and kidney damage.

Mechanism of Interaction

• Fluconazole is a moderate inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme, which is responsible for metabolizing atorvastatin 3, 4.
• When fluconazole is co-administered with atorvastatin, it can increase the plasma concentrations of atorvastatin, leading to an increased risk of myopathy and rhabdomyolysis 5, 6, 4.

Clinical Evidence

• A case report described a 67-year-old man who developed rhabdomyolysis after receiving atorvastatin, amiodarone, and fluconazole, highlighting the potential for drug interactions to cause this condition 5.
• Another case report described a 70-year-old woman who developed rhabdomyolysis after receiving fluconazole while on stable atorvastatin therapy, demonstrating that even moderate CYP3A4 inhibitors like fluconazole can increase the risk of rhabdomyolysis in patients taking statins 4.
• Studies have also shown that co-administration of CYP3A4 inhibitors, including fluconazole, with simvastatin or atorvastatin can increase the risk of myopathy and rhabdomyolysis 3, 6, 7.

Risk Management

• To minimize the risk of rhabdomyolysis, it is recommended to avoid co-administering fluconazole with atorvastatin or other statins that are metabolized by CYP3A4 3, 4.
• If co-administration is necessary, patients should be closely monitored for signs and symptoms of myopathy and rhabdomyolysis, and the dose of atorvastatin should be adjusted accordingly 3, 4.