4. DISCUSSION
The main objective of this retrospective pharmacovigilance study is to
investigate the hepatic dysfunction events of voriconazole, based on the
real-world data records involved 73 quarters of the FAERS. Among our
study we found that all the top ten frequency ADEs are strong
correlation signal when compared with the full database.
In our study, 62.20% of patients developed hepatic dysfunction in 15
days of voriconazole use. The median time to event of the hepatic
dysfunction events was 8 (IQR 2-28) days. We suggest health
professionals be aware of the potentially risk of voriconazole and
monitor hepatic function during the first 15 days of voriconazole use.
Voriconazole remains the drug of choice for primary therapy of IA, with
liposomal amphotericin B and the newly licensed agent isavuconazole
considered alternatives [1]. Combination therapy with mold-active
triazoles and echinocandins has been used with the hope of improving
outcomes over monotherapy, especially in the setting of refractory
disease [11]. Therefore, our study also did a comparison of
voriconazole with the other antifungal drugs. In analyses stratified on
the triazole antifungal drugs, an increased hepatic dysfunction event
reporting was found in voriconazole when compared with fluconazole and
isavuconazole, with the RORs (the lower limit of ROR 95% CI
> 1) 2.19 (95% CI 1.94-2.47), 2.31 (95% CI 1.66-3.33),
respectively. A randomized, non-inferiority trial found that compared to
voriconazole, isavuconazole was associated with a lower hepatotoxicity
[12]. When comparing voriconazole with amphotericin B, there was a
signal of high frequency of reporting hepatic dysfunction event with ROR
(95% CI) 1.26 (1.08, 1.48). An observational study found that compared
to amphotericin B, voriconazole was significantly associated with
hepatotoxicity [p <0.0002; Odds Ratio=22.2 for
voriconazole (95% CI, 4.3-116)] [13].
In analyses stratified on comparing to echinocandins, no signal of
increased hepatic dysfunction event reporting was found
(ROR<1). In previous studies, the echinocandins were
considered to have a lower hepatotoxicity when compared with triazoles
[14]. A network meta-analysis and systematic review on adverse
reactions of antifungal drugs also showed that caspofungin was more
significantly associated with a lower incidence of hepatobiliary
disorders [15]. Whereas in the real word study, the results showed
that echinocandins exhibited a higher hepatotoxicity which are
consistent with our findings [16,17]. The risk of developing liver
injury and possible hepatic dysfunction by an antifungal agent depends
on several factors including underlying hepatic disease, echinocandins
were considered as second-line or salvage therapy or antifungal combined
therapy when monotherapy is not effective [18,19]. Since
echinocandins can be used in patients with liver damage themselves,
their related liver damage will be higher than the actual liver damage
caused by voriconazole, which is also a shortcoming of this study.
In our hospital, the patient population is mainly liver transplantation
and HIV infection, which are the main risk factors of invasive fungal
infection. Therefore, precise treatment of invasive fungal infections is
crucial in reducing mortality. Since voriconazole is the primary therapy
for invasive aspergillosis, especially in immunocompromised patients,
some clinical trials showed that supratherapeutic concentrations are
correlated with an increased risk of hepatic toxicity [20,21]. Thus,
voriconazole TDM is of paramount importance in patients with
pre-existing liver disease, since the drug is extensively metabolized by
the liver and this population is more difficult to tolerate a
deterioration of hepatic function due to voriconazole-induced liver
injury [22,23]. In our real word study based on the FAERS, we can’t
get the concentration of voriconazole, which is another limitation of
this study.
There are inherent limitations with disproportionality analysis methods
based on FAERS data. Firstly, the inherent nature of the FAERS which
does not allow causality assessment between drug and AE. Secondly,
concomitant drugs have not been considered, we will perform relevant
drug interaction research in the future. Lastly, due to lack of the
patient’s underlying disease status, we did not consider the effect of
disease factor which could be an important factor in hepatic abnormal
events. Despite these drawbacks, the sample size of is enormous, the
prevalence and risk of hepatic dysfunction and other AEs caused by
voriconazole need to be further explored in prospective RCT studies.