Safety Evaluation Of Five Triazole Antifungal Drugs Based On FDA Adverse Event Reporting System

Objective: The adverse event data of five triazole antifungal drugs,fluconazole,itraconazole,voriconazole,posaconazole,and esaconazole,were statistically analyzed through the adverse event reporting system(FAERS)of the U.S.Food and Drug Administration(FDA),and the safety of triazole antifungal drugs was re-evaluated by identifying signals of high incidence or serious adverse events.The risk of myopathy caused by the combination of triazole antifungal drugs and statins was also evaluated to provide a reference for the rational use of triazole antifungal drugs in clinical practice.Methods: Data from the FAERS from the first quarter(Q1)of 2004 to the third quarter(Q3)of 2022 were counted to assess patient information for the five triazole antifungals.The high-risk adverse events and significant involvement of systemic organs associated with these five triazole antifungal drugs were also analyzed using the report-to-value ratio method.The risk of myalgia due to the interaction of these five triazole antifungals with statins was further investigated by additive and multiplicative modeling.Results: A total of 28,384 reports related to triazole antifungals were identified,including 84,659 adverse events for triazole antifungals and 4,908 medically important events for triazole antifungals.The median age of the reported patient information was 50-60 years old,the weight range was 55-66 kg,the top three in number were in the United States,Germany,and France,and patients taking such drugs were mainly used for the prevention and treatment of fungal infections,and the most reported serious adverse events were hospitalizations.More adverse events were reported in the following system organ classes(SOC): skin and subcutaneous tissue diseases(3027 cases in total),various types of examinations(2229 cases),and diseases of the hepatobiliary system(2147 cases).The top reported numbers were respiratory failure,skin rash,liver function abnormalities,and hypokalemia.Less common but higher signal value adverse reaction signals included changes in the QT interval,pseudoaldosteronism,and hallucinations.When a class analysis of statins and triazole antifungals was performed,a threshold ROR value was found for the combination of the two classes(ROR 4.99,95% CI 4.09-6.1),and further sensitivity analysis of triazoles in combination with atorvastatin and reserpine showed a correlation with myalgia when atorvastatin was combined with triazole antifungals.When drug-level interactions between triazole antifungals and atorvastatin were analyzed,it was found that atorvastatin drugs with fluconazole,itraconazole,and posaconazole showed a disproportionately elevated signal for myalgia.Conclusion: Adverse events with high incidence in triazole antifungals(e.g.,rash,liver function abnormalities,QT interval changes)were essentially the same as the results in the instructions,as well as adverse events with high signal values such as pseudoaldosteronism and hallucinations were found.However,more pharmacoepidemiological studies are needed to validate the lower incidence but stronger signal adverse reactions.Compared to triazole antifungals alone versus statins alone,the combination of atorvastatin with triazole antifungals produced a disproportionately higher signal for myalgia,especially when combined between atorvastatin and fluconazole,itraconazole,and posaconazole.Therefore,switching to other triazole antifungal agents or other statins should be considered when combining drugs.