Fluconazole Once Weekly with Simvastatin: Safety Assessment
The combination of fluconazole and simvastatin carries significant risk for myopathy and rhabdomyolysis and should be avoided or used with extreme caution, even with once-weekly fluconazole dosing. 1
Drug Interaction Mechanism and Risk
Fluconazole is a potent inhibitor of CYP3A4, the primary enzyme responsible for simvastatin metabolism, leading to dramatically elevated statin levels and increased risk of muscle toxicity 1
The FDA drug label explicitly warns that "the risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized through CYP3A4, such as atorvastatin and simvastatin" 1
This interaction occurs regardless of fluconazole dosing frequency—once weekly dosing does not eliminate the risk, as fluconazole has a long half-life (approximately 30 hours) and maintains therapeutic levels between doses 1
Clinical Evidence of Harm
Case reports document severe rhabdomyolysis requiring hospitalization when simvastatin is combined with azole antifungals, with patients developing marked creatine kinase elevation, muscle weakness, and myoglobinuria 2
One reported case involved an 83-year-old patient who developed severe rhabdomyolysis just one week after adding fluconazole to simvastatin 40 mg daily, with symptoms resolving only after discontinuation of both agents 2
Similar severe reactions have been documented with other azole antifungals (itraconazole, ketoconazole) combined with simvastatin, reinforcing the class effect of CYP3A4 inhibition 3, 4
Risk Management Recommendations
If antifungal therapy is required in a patient taking simvastatin, the following hierarchy should be followed:
First choice: Temporarily discontinue simvastatin during fluconazole therapy (even once-weekly dosing), as this eliminates the interaction risk entirely 1, 3
Second choice: Switch to a non-CYP3A4-metabolized statin such as pravastatin or rosuvastatin, which do not interact significantly with fluconazole 1, 3
Third choice: If continuation is absolutely necessary, reduce simvastatin dose substantially and monitor creatine kinase levels closely, though the FDA label recommends discontinuation of statins if marked CK elevation occurs 1
Monitoring Requirements If Combination Cannot Be Avoided
Patients must be explicitly counseled to report muscle pain, weakness, or dark urine immediately, as these are warning signs of rhabdomyolysis 1, 2
Baseline and serial creatine kinase monitoring is essential, with immediate statin discontinuation if levels rise significantly or if clinical myopathy symptoms develop 1
Renal function should be monitored, as rhabdomyolysis can precipitate acute kidney injury, particularly in elderly patients or those with pre-existing renal impairment 5
Special Populations at Higher Risk
Elderly patients are at substantially increased risk for statin-induced rhabdomyolysis, as demonstrated in the reported case of an 83-year-old who developed severe toxicity 2
Patients with chronic kidney disease have heightened vulnerability, with documented cases of rhabdomyolysis occurring within 48 hours of simvastatin initiation in renal impairment 5
Patients on multiple CYP3A4 inhibitors face compounded risk and should have statins discontinued during fluconazole therapy 1
Clinical Context for Once-Weekly Fluconazole
While once-weekly fluconazole (typically 150 mg) is commonly used for recurrent vulvovaginal candidiasis maintenance therapy 6, this does not mitigate the drug interaction risk with simvastatin. The long half-life of fluconazole means therapeutic (and inhibitory) concentrations persist throughout the week, maintaining CYP3A4 inhibition continuously 1.