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\begin{document}

\title{Hepatic dysfunction events associated with voriconazole: a real-world
study from FDA adverse event reporting system (FAERS) database}



\author[1]{Juping Yun}%
\author[1]{Liping Fan}%
\author[1]{Jingna Chai}%
\author[1]{Xuewei Liu}%
\author[1]{Wei Liu}%
\affil[1]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Aims: Although voriconazole-induced hepatotoxicity has been reported
previously, the direct cause-effect relationship in the real world
remains to be established. The aim of this study was to investigate the
association between voriconazole and hepatic dysfunction based on the
FAERS database. Methods: Data from January 2004 to March 2022 in FAERS
were retrieved. We estimate the association between the hepatic
dysfunction and voriconazole using reporting odds ratios (RORs) for
mining the adverse event report signals and compare voriconazole with
the full database and other antifungal drugs. Results: 646 reports of
hepatic dysfunction related to voriconazole as the primary suspect drug
were collected totally. The median time to event of the hepatic
dysfunction events was 8 (interquartile range {[}IQR{]} 2-28) days.
62.20\% hepatic-related adverse events appeared within the first 15 days
since the initiation of voriconazole administration. The overall ROR
(95\% CI) for hepatic-related adverse events was 6.82 (95\% CI
6.26-7.42). Comparing to other antifungal drugs, the RORs for
hepatic-related adverse events of fluconazole, isavuconazole and
amphotericin B were 2.19 (95\% CI 1.94-2.47), 2.31 (95\% CI 1.66-3.33)
and 1.26 (95\% CI 1.08-1.48), respectively. Conclusions: We observed
strong signals of higher frequency of reporting hepatic dysfunction
events associated with voriconazole in the events of hepatic
dysfunction. Since the risk of developing liver injury and possible
hepatic dysfunction by voriconazole depends on several factors including
underlying hepatic disease, close clinical and laboratory monitoring,
including therapeutic drug monitoring (TDM), are essential to prevent or
promptly recognize further deterioration of the hepatic function.%
\end{abstract}%



\sloppy


\textbf{Hepatic dysfunction events associated with voriconazole: a
real-world study from FDA adverse event reporting system (FAERS)
database}

Juping Yun\textsuperscript{1}, Liping Fan\textsuperscript{2}, Jingna
Chai\textsuperscript{3}, Xuewei Liu\textsuperscript{4}, Wei
Liu\textsuperscript{1}

1 Beijing You'an Hospital, Capital Medical University, Beijing, China

2 Tianjin AiForward Science and Technology Co., Ltd., Tianjin, China

3 Hebei Province Shunping County Hospital, Hebei, China

4 Beijing Chao'yang Hospital, Capital Medical University, Beijing, China

\textbf{Abstract}

\textbf{Aims} : Although voriconazole-induced hepatotoxicity has been
reported previously, the direct cause-effect relationship in the real
world remains to be established. The aim of this study was to
investigate the association between voriconazole and hepatic dysfunction
based on the FAERS database.

\textbf{Methods} : Data from January 2004 to March 2022 in FAERS were
retrieved. We estimate the association between

the hepatic dysfunction and voriconazole using reporting odds ratios
(RORs) for mining the adverse event report signals and compare
voriconazole with the full database and other antifungal drugs.

\textbf{Results} : 646 reports of hepatic dysfunction related to
voriconazole as the primary suspect drug were collected totally. The
median time to event of the hepatic dysfunction events was 8
(interquartile range {[}IQR{]} 2-28) days. 62.20\% hepatic-related
adverse events appeared within the first 15 days since the initiation of
voriconazole administration. The overall ROR (95\% CI) for
hepatic-related adverse events was 6.82 (95\% CI 6.26-7.42). Comparing
to other antifungal drugs, the RORs for hepatic-related adverse events
of fluconazole, isavuconazole and amphotericin B were 2.19 (95\% CI
1.94-2.47), 2.31 (95\% CI 1.66-3.33) and 1.26 (95\% CI 1.08-1.48),
respectively.

\textbf{Conclusions} : We observed strong signals of higher frequency of
reporting hepatic dysfunction events associated with voriconazole in the
events of hepatic dysfunction. Since the risk of developing liver injury
and possible hepatic dysfunction by voriconazole depends on several
factors including underlying hepatic disease, close clinical and
laboratory monitoring, including therapeutic drug monitoring (TDM), are
essential to prevent or promptly recognize further deterioration of the
hepatic function.

\textbf{Keywords} : voriconazole, hepatic dysfunction, invasive
aspergillosis, real-world study, FAERS

\textbf{INTRODUCTION}

Invasive aspergillosis is a life-threatening infection among individuals
with long-lasting or severe impairment of the immune system {[}1{]}.
Compared with other triazole antifungals, voriconazole has enhanced
activity against the Aspergillus species, and as an alternative therapy
for candidemia, in individuals who do not have neutropenia {[}2, 3{]},
so it remains the standard of care and is recommended by international
guidelines for the primary treatment of invasive aspergillosis {[}4,
5{]}. Although voriconazole-induced hepatotoxicity has been reported
previously, the direct cause-effect relationship remains to be
established systematically based on the real world data.

The FAERS includes several million spontaneous reports of
drug-associated adverse events and is used to evaluate drug safety
profiles. The database includes all adverse drug events (ADEs)
information and medication error information collected by the FDA. It is
one of the primary tools used for post-marketing surveillance and
pharmacovigilance {[}6{]}. We conducted this study to examine the
association between voriconazole and hepatic dysfunction, and compared
RORs of hepatic dysfunction caused by voriconazole and other antifungal
drugs. All data analysis is based on FAERS database.

\textbf{2. METHODS}

In this study, we followed the method of Mingxing Guo et al. and the
methods description partly reproduced their wording {[}7{]}.

\textbf{2.1 Data Source}

This study was designed as a retrospective study, the interventions of
interest was voriconazole. All records in the FAERS database from
January 2004 to March 2022 were included in this study {[}8{]}. We used
both generic names and brand names to identify voriconazole and control
drugs (see details in \textbf{Supplementary Materials Table S1} ).

A deduplication procedure was performed according to the FDA's
recommendations to select the latest FDA\_DT with the same CASEID and
select the higher PRIMARYID when CASEID and FDA\_DT are both the same
adverse events (AE) were included when they were considered the
``Primary Suspect (PS) drug (drugs which directly suspected of causing
the adverse events)''.

\textbf{2.2 Definition of hepatic dysfunction Events}

We identified hepatic dysfunction events which were in preferred terms
(PTs) using Medical Dictionary for Regulatory Activities terms (V23.0).
Different PTs were identified with the Standardized MedDRA Query (SMQ)
for ``livery injury'', ``liver related'', ``hepatic failure'' and
``acute hepatic failure'' and the System Organ Class (SOC) for
hepatobiliary disorder, and only reports that met both criteria were
extracted. One case could be reported more than one PTs of the same SMQ,
duplicate records was removed, the number of selected PTs was 48 (see
details in \textbf{Supplementary Materials Table S2} ).

\textbf{2.3 Analysis}

We performed disproportionality analysis using the reporting odds ratio
(ROR) with relevant Confidential Interval (CI) to indicate the presence
of signals of potential increased risk of drug-related AE {[}9{]}. The
ROR was calculated by dividing the odds of hepatic dysfunction events
reporting for voriconazole by the odds of hepatic dysfunction events
reporting for the comparison drug. A signal of increased hepatic
dysfunction risk was defined as the lower limit of 95\% CI exceed one
with the number of cases [?]3 {[}10{]}.

To validate the robustness of the findings, we conducted five specific
comparisons: (1) compared voriconazole with the full database; (2)
compared voriconazole with the other triazole antifungal drugs:
fluconazole, itraconazole, posaconazole and isavuconazole; (3) compared
voriconazole with the echinocandins antifungal drugs: caspofungin,
micafungin and anidulafungin; (4) compared voriconazole with the polyene
antifungal drug amphotericin B; (5) compared voriconazole with the
5-fluorocytosine.

The primary outcomes were overall hepatic-related adverse events
compared with the full database and the other antifungal drugs (see
details in \textbf{Supplementary Materials Table S3} ). The secondary
outcomes were the high frequency reporting of hepatic dysfunction events
(see details in \textbf{Supplementary Materials Table S4/S5} ): hepatic
function abnormal, cholestasis, alanine aminotransferase increased,
blood alkaline phosphatase increased, aspartate aminotransferase
increased, liver function test abnormal, gamma-glutamyl transferase
increased, liver disorder, hepatocellular injury, blood bilirubin
increased.

All the data extraction were performed by Microsoft Access 2010, and the
statistical analyses were performed using SPSS 26.0.

\textbf{3. RESULTS}

\textbf{3.1 Descriptive analysis}

After data cleaning, 17,710,899 reports in the FAERS database were of
use. Overall, from January 2004 to March 2022, there were 3694 reports
listing voriconazole were identified as PS, the number of hepatic
dysfunction events was 646 (17.48\%). The clinical characteristics of
patients with voriconazole induced hepatic dysfunction were described
in\textbf{Table 1} . The hepatic disorders associated with voriconazole
were slightly higher in male than in female (56.50\% vs. 33.90\%,
P<0.05), and 27.40\% of them are elderly patients ([?]65 years old). The
fatality rate of the reported hepatic disorders was 9.75\%, which is
lower than non-hepatic disorders.

The median time to event of the hepatic dysfunction events was 8 (IQR
2-28) days, and 62.20\% of patients developed hepatic dysfunction in 15
days of voriconazole use (\textbf{Fig. 1} ).

\textbf{Table 1 The clinical characteristics of patients}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& & Hepatic disorder events (\%) & Non-hepatic disorders events
(\%)\tabularnewline
\midrule
\endhead
Gender & Gender & Gender & Gender\tabularnewline
& F & 219(33.90) & 1304(35.30)\tabularnewline
& M & 365(56.50) & 2273(61.53)\tabularnewline
& Miss/Unknown & 62(9.60) & 117(3.17)\tabularnewline
Age & Age & Age & Age\tabularnewline
& [?]65y & 177(27.40) & 1059(28.67)\tabularnewline
& <65y & 396(61.30) & 2390(64.70)\tabularnewline
& Miss/Unknown & 73(11.30) & 245(6.63)\tabularnewline
Outcome* & Outcome* & Outcome* & Outcome*\tabularnewline
& DE & 63(9.75) & 931(25.20)\tabularnewline
& DS & 8(1.24) & 49(1.33)\tabularnewline
& HO & 146(22.60) & 762(20.63)\tabularnewline
& LT & 20(3.10) & 102(2.76)\tabularnewline
& OT & 370(57.28) & 1691(45.78)\tabularnewline
& RI & 3(0.46) & 5(0.14)\tabularnewline
& MISS & 36(5.57) & 154(4.17)\tabularnewline
OCCP\textsuperscript{\#} & OCCP\textsuperscript{\#} &
OCCP\textsuperscript{\#} & OCCP\textsuperscript{\#}\tabularnewline
& Health care workers & 607(93.96) & 3411(92.34)\tabularnewline
& Non-health care workers & 27(4.18) & 195(5.28)\tabularnewline
& MISS & 12(1.86) & 88(2.38)\tabularnewline
\bottomrule
\end{longtable}

*DE: death; DS: disability; HO: require hospitalization or prolongation
of existing hospitalization; LT: life-threating; RI: required
intervention to prevent permanent impairment/damage; OT: other serious
medical events. \#OCCP:reporter's type of occupation\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Fig.1 Cumulative event time (\%) of hepatic events since the
initiation of voriconazole and the control drugs}

\textbf{3.2 Signal values associated with hepatic dysfunction at SOC
level}

For the specific comparisons, there was a strong signal for increased
hepatic dysfunction risk, when comparing voriconazole with the full
database (\textbf{Fig.2)} , the ROR was 6.82 (95\% CI 6.26-7.42).
Comparing to the other antifungal drugs, voriconazole significantly
increased the risk of hepatic dysfunction compared with fluconazole,
isavuconazole and amphotericin B, with the RORs 2.19 (95\% CI
1.94-2.47), 2.31 (95\% CI 1.66-3.33) and 1.26 (95\% CI 1.08-1.48),
respectively. Analysis showed that voriconazole was not associated with
a higher risk of hepatic dysfunction compared with itraconazole,
posaconazole, caspofungin, micafungin, anidulafungin and
5-fluorocytosine (RORs 1.06 (95\% CI 0.88-1.28), 1.08 (95\% CI
0.89-1.30), 0.81 (95\% CI 0.68-0.96), 0.75 (95\% CI 0.62-0.90), 1.50
(95\% CI 0.94-2.39), 1.00 (95\% CI 0.44-2.27), respectively).

\textbf{3.3 Signal values associated with hepatic dysfunction at PT
level}

In the secondary outcomes for the high frequency reporting of hepatic
dysfunction events associated with voriconazole, the RORs (95\% CI) for
hepatic function abnormal, cholestasis, alanine aminotransferase
increased, blood alkaline phosphatase increased, aspartate
aminotransferase increased, liver function test abnormal, gamma-glutamyl
transferase increased, liver disorder, hepatocellular injury, blood
bilirubin increased were 19.17 ( 95\% CI 15.54-23.63), 37.03 ( 95\% CI
29.95-45.78 ), 8.59 ( 95\% CI 6.71-11.00 ), 21.96 ( 95\% CI 17.14-28.13
), 10.17 ( 95\% CI 7.91-13.08 ), 17.10 ( 95\% CI 13.27-22.04 ), 20.89 (
95\% CI 16.11-27.09 ), 9.23 (95\% CI 7.02-12.14 ), 18.81 (95\%CI
14.26-24.81 ), 13.32 (95\% CI 9.92-17.88 ), respectively (\textbf{Fig.3}
).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Fig.2 Overall hepatic dysfunction signals and RORs comparing
voriconazole with the full database and other antifungal drugs}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

ROR [?] 5 2 [?] ROR \textbf{\textless{}} 5 ROR \textbf{\textless{}} 2

\textbf{Fig.3 Subgroup analysis of different hepatic dysfunction events
in voriconazole and other antifungal drugs}

\textbf{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
\textgreater{} 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 {[}\emph{p} \textless{}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\textless{}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.

\textbf{5. CONCLUSION}

In our article, we observed strong signals of higher frequency of
reporting hepatic dysfunction events associated with voriconazole in the
events of hepatic function abnormal. The median time to event of the
hepatic dysfunction events were 8 days. Most hepatic related adverse
events appeared within the first 15 days since the initiation of
voriconazole administration. Moreover, an increased hepatic dysfunction
event reporting was found in voriconazole when compared with
fluconazole, isavuconazole and amphotericin B. Whereas, in our study, we
observed that echinocandins exhibited a higher hepatotoxicity, which is
inconsistent with the results of previous clinical studies and need
further studies. In any case, since the risk of developing liver injury
and possible hepatic dysfunction by an antifungal agent depends on
several factors including underlying hepatic disease, close clinical and
laboratory monitoring, including TDM for specific antifungal drugs, is
essential in the majority of these patients in order to prevent or
promptly recognize further deterioration of the hepatic function, thus
avoiding unfavorable outcomes.

\textbf{Data Availability Statement}

The FDA adverse events data used to analysis in this study was
downloaded from FDA adverse events reporting system database, which was
open accessed from the
https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html. Those
downloaded data used to support the findings of this study were also
included within the \textbf{Supplementary Material} file.

\textbf{Conflicts of interest}

The authors declare that they are no conflicts of interest.

\textbf{Author Contribution}

JY contributed to the data analysis and writing original draft. LF
contributed to the data processing. JC and XL contributed to the
management of AEs. WL contributed to the supervision, writing reviewing,
and editing of this paper. All authors contributed to the article
approved the submitted version.

\textbf{Supplementary Material}

The Supplementary Material for this article can be found online. Table
S1: Generic and brand names of antifungal agents, Table S2: Preferred
Terms included in this study, Table S3: The RORs of voriconazole
compared with the full database and the other antifungal drugs, Table
S4: The adverse event signals of voriconazole and the RORs compared with
Full database, Table S5: The top ten frequency PTs and RORs of
voriconazole compared with the other antifungal drugs.

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