When to withhold statin (HMG-CoA reductase inhibitor) therapy in patients taking fluconazole (Diflucan)?

From the Guidelines

It is recommended to temporarily discontinue statin therapy when starting fluconazole treatment, especially for higher doses of fluconazole (200mg daily or more) or when treatment will last longer than a few days, to minimize the risk of myopathy or rhabdomyolysis, as suggested by the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol 1. When considering the concomitant use of statins and fluconazole, it is essential to weigh the benefits of continued statin therapy against the potential risks of increased statin blood levels due to CYP3A4 inhibition by fluconazole.

• The risk of myopathy or rhabdomyolysis is higher with certain statins, such as simvastatin, lovastatin, and to a lesser extent atorvastatin, which are metabolized by the CYP3A4 enzyme system 1.
• For short courses of fluconazole, such as a single 150mg dose for vaginal candidiasis, statin interruption may not be necessary.
• When longer fluconazole treatment is required, consider holding the statin for the duration of antifungal therapy plus 1-2 days after completion.
• Alternatively, switching to a statin less dependent on CYP3A4 metabolism, such as pravastatin, rosuvastatin, or fluvastatin, may be an option if continued lipid management is essential during antifungal treatment, as recommended by the 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults 1.
• Always monitor for muscle pain, weakness, or dark urine during concomitant therapy, as these may indicate statin toxicity requiring immediate medical attention, and follow the guidelines for monitoring and managing statin-associated side effects, including new-onset diabetes mellitus and statin-associated muscle symptoms (SAMS) 1.

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.

Hold off on statin while on fluconazole if there is a marked increase in creatinine kinase or if myopathy/rhabdomyolysis is diagnosed or suspected.

• Key considerations:
  • Monitor creatinine kinase
  • Observe for symptoms of myopathy and rhabdomyolysis
  • Dose reduction of statins may be needed
  • Refer to the statin-specific prescribing information for details 2

From the Research

Statin Interaction with Fluconazole

• Fluconazole is an inhibitor of the cytochrome P450 (CYP) 3A enzyme, which is involved in the metabolism of certain statins 3.
• Strong inhibitors of CYP3A, such as itraconazole, can greatly increase plasma concentrations of simvastatin, lovastatin, and their active acid forms, thus enhancing the risk of myotoxicity 3.
• Although fluconazole is not explicitly mentioned in the study, its inhibitory effect on CYP3A may lead to increased plasma concentrations of statins that are metabolized by this enzyme.
• It is recommended to exercise caution when concomitantly using fluconazole with statins that are metabolized by CYP3A, such as simvastatin and lovastatin.

Clinical Considerations

• The decision to hold off on statin therapy while on fluconazole should be based on the individual patient's risk factors and the specific statin being used 4.
• Patients with a high risk of myotoxicity, such as those with renal impairment or those taking other medications that increase the risk of myotoxicity, may require closer monitoring or alternative statin therapy 3.
• The benefits of statin therapy in reducing cardiovascular risk should be weighed against the potential risks of interaction with fluconazole 5.

Statin Selection

• Fluvastatin and pravastatin may be better choices than simvastatin or lovastatin for patients who require concomitant use of fluconazole, due to their different pharmacokinetic profiles 3.
• The selection of a statin should be individualized based on the patient's specific clinical situation and the potential for drug interactions 4.