Rosuvastatin-Fluconazole Interaction: Minimal Clinical Concern in Routine Practice
The interaction between rosuvastatin and fluconazole is not clinically significant in routine practice and does not require dose adjustment or avoidance of the combination. 1, 2
Pharmacokinetic Basis for Low Risk
Rosuvastatin has minimal metabolism through the cytochrome P450 system, with only limited participation of CYP2C9 and virtually no participation of CYP3A4. 1, 3 This is fundamentally different from simvastatin, lovastatin, and atorvastatin, which undergo significant CYP3A4 metabolism and are therefore more susceptible to interactions with fluconazole. 1
Key Metabolic Pathways
- Rosuvastatin's elimination depends mainly on OATP1B1/1B3 transporters rather than enzymatic metabolism. 1, 3
- While fluconazole is listed as a CYP2C9 inhibitor, rosuvastatin's minor CYP2C9 metabolism means this pathway is not clinically important for the drug's clearance. 1, 2
- Fluconazole does not inhibit OATP1B1 or OATP1B3 transporters, which are the primary elimination pathways for rosuvastatin. 1
Clinical Evidence
A randomized, double-blind, placebo-controlled crossover trial in 14 healthy volunteers demonstrated that fluconazole 200 mg daily increased rosuvastatin AUC by only 14% and Cmax by only 9%, changes that were not considered clinically relevant. 2 The 90% confidence intervals (0.967-1.341 for AUC and 0.874-1.355 for Cmax) fell within the bioequivalence range, confirming lack of clinical significance. 2
A 2021 systematic review of 70 randomized controlled trials involving 2,355 healthy subjects confirmed that the interaction between rosuvastatin and fluconazole was statistically significant but noted that clinical relevance requires investigation with repeated dosing. 4 However, the small magnitude of the interaction (14% increase in exposure) is well within the normal pharmacokinetic variability of rosuvastatin, which has a coefficient of variation of 48%. 4
Contrast with High-Risk Statin-Fluconazole Combinations
This stands in stark contrast to simvastatin and atorvastatin, which have documented cases of rhabdomyolysis when combined with fluconazole. 5, 6
- An 83-year-old patient developed severe rhabdomyolysis one week after adding fluconazole to simvastatin 40 mg daily. 5
- A 70-year-old woman on stable atorvastatin therapy for 4 years developed rhabdomyolysis 2 weeks after starting intravenous fluconazole. 6
- These cases occurred because simvastatin and atorvastatin undergo significant CYP3A4 metabolism, which fluconazole inhibits. 1, 5, 6
Practical Management Recommendations
No dose adjustment of rosuvastatin is required when initiating fluconazole, and the combination can be used safely. 2, 7 However, standard monitoring practices should continue:
- Monitor for symptoms of myopathy (muscle pain, tenderness, or weakness), especially with fever or general malaise, as recommended for all statin therapy. 3
- Consider periodic liver function tests for patients on rosuvastatin, per standard practice. 3
- Be aware that individual variability exists, with treatment ratios for AUC ranging from 0.59 to 2.23 in the clinical trial, though most patients had minimal changes. 2
Common Pitfall to Avoid
Do not confuse rosuvastatin's safety profile with fluconazole with that of other statins. 1 The American Heart Association guidelines clearly distinguish rosuvastatin's metabolism (primarily OATP-mediated with minor CYP2C9 involvement) from simvastatin and lovastatin (significant CYP3A4 metabolism) and atorvastatin (moderate CYP3A4 metabolism). 1 Fluconazole is listed as both a CYP2C9 and CYP3A4 inhibitor, but the clinical impact depends entirely on which pathway is relevant for the specific statin. 1
A 2010 review confirmed that rosuvastatin combination treatment with antifungal azoles appears to be safe, as there is no evidence to support any clinically significant pharmacokinetic or pharmacodynamic interaction. 7