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Adverse Effects of Voriconazole: Analysis of the French Pharmacovigilance

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Article  in  Annals of Pharmacotherapy · May 2007

DOI: 10.1345/aph.1H671 · Source: PubMed

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Adverse Drug Reactions

Adverse Effects of Voriconazole: Analysis of the French

Pharmacovigilance Database

Céline Eiden, Hélène Peyrière, Marylène Cociglio, Samira Djezzar, Sylvie Hansel, Jean-Pierre Blayac, and

Dominique Hillaire-Buys, for the Network of the French Pharmacovigilance Centers

atients with burns, neutropenia, or

P HIV infection or those treated with
immunosuppressive drugs are predisposed
to invasive fungal infection. The risk of
morbidity and mortality is increased in this
population due to a higher incidence of
fungal infections and to rare isolates (eg,
Fusarium, Scedosporium, Pseudallesche-
ria).1 Voriconazole, a triazole agent struc-
turally related to itraconazole and flucona-
zole, was approved in May 2002 by the
Food and Drug Administration for the
treatment of invasive aspergillosis and
serious fungal infections caused by Sce-
dosporium and Fusarium species refrac-
tory to other therapy.2
Voriconazole is characterized by
nonlinear adult pharmacokinetics and is
extensively metabolized by CYP2C19,
CYP2C9, and to a lesser degree, by
CYP3A4.3-5 Furthermore, the activity of
CYP2C19 is highly dependent on genet-
ic polymorphisms, and higher voricona-
zole concentrations may be achieved by
lower than the usual doses in poor me-
tabolizers. 5
BACKGROUND: The most common adverse effects of voriconazole reported
during clinical trials were disturbances of vision (30% of pts.), skin rashes
(17.3%), and elevations in hepatic enzymes level (~10% of pts.; varying with
enzymes). However, postmarketing data concerning safety of voriconazole are
limited.
OBJECTIVE: To describe voriconazole adverse drug effects (ADEs) after 4 years
of the drug’s availability in France and determine their occurrence.
METHODS: All cases of ADEs including voriconazole reported to the French
Pharmacovigilance Database between 2002 and 2005 were analyzed. For each
case, the following data were recorded: age, sex, indication, concomitant disease,
concomitant medications, and ADE description. Causality link between vori-
conazole and ADEs was performed using the Naranjo probability scale.
RESULTS: A total of 227 ADE cases were reported in 178 adults and 9 children
(<12 y), with 66% occurring in males. The patients’ median age was 49.6 (2–80)
years. ADEs included liver function test abnormalities (23%), visual disturbances
(18%), skin rashes (17%), neurologic disturbances (14%), cardiovascular events
(10%), hematologic disorders (8%), and renal disturbances (4%). Other less
commonly identified ADEs included headache, nausea, vomiting, and diarrhea.
Drug–drug interactions were observed in 7 cases. According to the Naranjo
criteria, 84% of ADEs were classified as possible, 7% as probable, 5% as highly
probable, and 4% as doubtful.
CONCLUSIONS: Most ADEs found in this study are well documented in the
literature, except for cardiac complications, which are rarely reported. Few ADEs
related to drug interactions were observed; however, due to the extensive
metabolism of voriconazole by cytochrome P450 isoenzymes, clinicians should be
aware of potential interactions between voriconazole and other drugs metabolized
through this pathway.
KEY WORDS: adverse drug effects, pharmacovigilance, voriconazole.

Although generally well tolerated, Ann Pharmacother 2007;41:755-63.

voriconazole may be associated with ad- Published Online, 24 Apr 2007, www.theannals.com, DOI 10.1345/aph.1H671
verse events like transient visual distur-
bances, hepatotoxicity, and skin rashes.6
The objective of this analysis was to evaluate the inci- ed to the French Pharmacovigilance Database (FPD) were
dence of the adverse drug effects (ADEs) associated with analyzed.
voriconazole after 4 years of its use in France. All cases of
ADEs secondary to voriconazole use that had been report- Methods

All cases of ADEs reported to the network of the French

Author information provided at the end of the text. pharmacovigilance centers over a period of 4 years, from

www.theannals.com The Annals of Pharmacotherapy n 2007 May, Volume 41 n 755

Downloaded from aop.sagepub.com by guest on October 11, 2013
C Eiden et al.

January 1, 2002, when voriconazole was marketed in subacute toxic effects used to score the increase of the hep-
France, to December 31, 2005, were retrospectively col- atic enzymes are represented in Table 3.9
lected. In 6 cases, abnormal results of liver function tests wors-
According to the law, all prescribers and pharmacists ened with hepatocellular injury and a median decrease in
must report serious ADEs (ie, fatal or life threatening, re-
quires hospitalization or prolongation of hospitalization,
and causes permanent disability, temporary disability, or
incapacity) and unexpected ADEs (not reported in the Table 1. Demographic and Clinical Characteristics
product information) to their regional pharmacovigilance Characteristics Pts. (N = 187)
center. All suspected ADEs are verified, analyzed, validat-
Women, n (%) 65 (34)
ed, and then registered in the FPD. This system is charac- Children (<12 y), n (%) 9 (5)
terized by a network of 31 regional pharmacovigilance Median age, y (range) 49.6 (2–86)
centers, which are located to provide convenient proximity women 47.6 (2–86)
to healthcare professionals, and a causality assessment men 50.7 (3–84)

method designed to evaluate the causal relationship be- Voriconazole indication, n (%)
pulmonary aspergillosis 91 (49)
tween an adverse effect and one or more drugs.7 pneumonia 12 (6)
For each ADE notification, the following data were col- prophylactic treatment 10 (5)
lected: sex, age, voriconazole dosage, route of voriconazole oropharyngeal candidiasis 7 (4)
disseminated candidiasis 6 (3)
administration, associated drugs, and adverse effects (im- other invasive infection 4 (2)
putability, delay before onset, seriousness, and evolution). disseminated aspergillosis 2 (1)
For harmonization of ADE analysis, the causal relation- unknown 45 (24)

ship between voriconazole and the adverse reactions was Fungi involved, n (%)
Aspergillus spp. 96 (51)
evaluated using the Naranjo probability scale.8 Candida spp. 17 (9)
Cryptococcus spp. 2 (1)
other species 2 (1)
Results
unknown 72 (38)

During the study period, a total of 227 reports of ADEs Voriconazole route of
administration, n (%)
that had occurred in 187 patients (178 adults, 9 children) oral 129 (69)
were collected, representing 0.24% of the notifications re- intravenous 42 (22)
ported to the FPD over the same period. The demographic intravenous and then oral 2 (1)
unknown 14 (7)
and clinical characteristics of patients are summarized in
Voriconazole dosage
Table 1. Underlying medical conditions were blood can- (mg/day), n (%)
cers (33%), pulmonary diseases (12%), and cardiac dis- ≤200 7 (4)
201–400 99 (53)
eases (12%). The repartition of all ADEs is reported in
401–600 14 (7)
Figure 1, and characteristics of ADEs are summarized in >600 17 (9)
Table 2. unknown 52 (28)
The adverse events were classified as severe in 55.6% Dosage for each type of ADE, n (%)
hepatobiliary disease oral route 38 (74)
of cases. Twenty-one (11.2%) patients died; 6 (2.9%) median 400 mg/day (150–600) intravenous 9 (18)
deaths were potentially related to the adverse event. unknown 5 (8)
According to Naranjo criteria, 84% of ADEs were clas- visual disturbance oral route 23 (55)
median 400 mg/day (200–800) intravenous 14 (33)
sified as possible, 7% as probable, 5% as highly probable, unknown 5 (13)
and 4% as doubtful. skin diseases oral route 23 (59)
median 400 mg/day (150–800) intravenous 9 (23)
unknown 7 (18)
HEPATOBILIARY DISEASES neurologic disturbance oral route 7 (22)
median 400 mg/day (200–400) intravenous 25 (75)
Hepatobiliary ADEs were described in 52 reports (23% unknown 1 (3)
cardiovascular disorders oral route 8 (36)
of all ADEs). On average, the increase in liver function median 400 mg/day (400–600) intravenous 7 (32)
tests from the upper limit of normal (ULN) was 6.6-fold unknown 7 (36)
blood disturbance oral route 10 (12)
for alanine aminotransferase (ALT; range 1.5 ULN–30 median 400 mg/day (400–800) intravenous 2 (55)
ULN), 5.5-fold for aspartate aminotransferase (AST; 1.5 unknown 6 (33)
ULN–26 ULN), 4.3-fold for alkaline phosphatase (ALP; renal disturbance oral route 6 (67)
median 400 mg/day (372–400) intravenous 2 (22)
1.5 ULN–12 ULN), 25-fold for γ-glutamyltransferase (1.5 unknown 1 (11)
ULN–152 ULN), and 3.5-fold for total bilirubin (1.5
ADE = adverse drug effect.
ULN–9 ULN). Recommendations for grading acute and

756 n The Annals of Pharmacotherapy n 2007 May, Volume 41 www.theannals.com


prothrombin level of 65% (range 29–78%). In all cases,
voriconazole was the suspected drug; however, in 5 cases,
voriconazole had been administered with another drug
(morphine, cytarabine, ciprofloxacin, imatinib, acetamin-
ophen, omeprazole).
In 5 cases, lithiasis occurred, confirmed by abdominal
ultrasonography. In 68% of cases, voriconazole had been
administered with drugs that can be associated with liver
function impairment, such as chemotherapy in 11 cases
(methotrexate, 2 cases; cyclophosphamide, tamoxifen, cis-
platin, bleomycin, imatinib, 2 cases; cytarabine, 3 cases),
antibiotics in 13 cases (cefepime, imipenem, rifampicin,
ciprofloxacin, moxifloxacin, ofloxacin), other antifungal
agents in 6 cases (liposomal amphotericin B, caspofungin),
immunosuppressive drugs in 4 cases (cyclosporine,
tacrolimus, mycophenolate mofetil), and parenteral nutri-
tion (Clinomel) in 1 case. Voriconazole was the only sus-
pected drug in 37% (13) of cases.
VISUAL DISTURBANCES
Visual disturbances were described in 42 reports (18%
of all ADEs). Among the 25 cases of visual hallucinations,
12 were associated with behavior disorders (delirious, in-
coherent speech, agitation, anxiety). Intravenous route of
administration was used in more than 50% (14) of halluci-
nations. Voriconazole was the suspected drug in 76% of
cases. In 14 cases, concomitant drugs were fluoroquino-
lones: ciprofloxacin in 12 cases (1 with the oral route, 9
with the intravenous route, not specified in 2 cases) and
ofloxacin in 2 cases (1 with the oral route and 1 with the
intravenous route).
Figure 1. Pareto diagram of adverse drug effects (ADEs) found in our study. A Pareto diagram is used to determine what characteristic is the major con-
tributor in a process. The diagram is constructed by ranking the data in frequency of occurrence and plotting the bars in descending order.
www.theannals.com
Adverse Effects of Voriconazole
Two cases of optic neuritis were reported. One case of
episcleritis and scleritis was diagnosed, with a favorable
outcome after stopping voriconazole treatment.
SKIN DISEASE
Thirty-nine reports of skin diseases were identified
(17% of all ADEs). These included erythema (38% of skin
ADEs), maculopapular exanthema (17%), urticaria (13%),
bullous eruption (9%), blister (6%), and purpura (4%); a
precise description of the eruption was not indicated in
13% of the reports.
Among these 39 ADEs, 15 were photosensitivity reac-
tions; they were associated with erythema (43% of photo-
sensitivity reactions), bullous eruption (22%), eczema
(5%), desquamation (10%), necrosis (5%), and cheilitis
(5%). In one case, drug-induced lupus was suspected, with
a skin biopsy compatible with toxidermia or acute cuta-
neous lupus. Antinuclear antibodies and anti-Ro/SSA were
negative. Voriconazole treatment was stopped and the pa-
tient was treated with corticosteroids, with a favorable out-
come. In 67% of cases, voriconazole had been adminis-
tered with other drugs that cause skin diseases.
NEUROLOGIC DISTURBANCES
Among 33 cases of neurologic disturbances (14% of all
ADEs), behavior disorders were described in 21 reports
(agitation, dizziness, confusion, anxiety, tremor). Intra-
venous voriconazole was administered in 6 cases. In one
patient, 0.6 –1.5 mg/L had been the usual voriconazole
trough concentration; however, 12 hours after the last dose,
the concentration was 7 mg/L. The patient developed hal-
The Annals of Pharmacotherapy n 2007 May, Volume 41 n 757
 Table 2. Characteristics of ADEs Reported to the French Pharmacovigilance Database

758
Median

n
Time to Median Time Voriconazole
Median Onset to Normalize Stopped,
C Eiden et al.

Cases, Sex Age, y (range), (range), Median Time Positive

Type of ADEs N (%) (F/M) (range) ADEs days days of Treatment Readministration Rechallenge Severitya Outcome

Hepatobiliary 52 (23) 24/28 54 28 cholestasis 10.5 (2–180) 10 (2–30) 29 cases, 14 cases 12 cases not severe 31% unknown 25%
diseases (2–84) 10 acute cytotoxic 13 (7–240) 10 (5–15) 14 days unknown 8% no sequelae 63%
hepatitis (3–549) severe sequelae 4%
2 mixed presentation 37 (11–63) 13.5 (10–17) I: 45% no death related
6 hepatocellular injury 8.5 (2–77) 10 (5–10) II: 6% to ADEs
1 pancreatitis 28 60 III: 6%
5 biliary lithiasis 35 (21–660) 30 (5–30) IV: 4%
Visual 42 (18) 9/27 57 25 visual 3 (immedi- 1 (1–10) 24 cases, 3 cases 1 case not severe 58% unknown 14%
disturbances (8–80) hallucinations ately–244) 6 days unknown 3% no sequelae 78%
14 visual troubles 2 (1–9) 2 (1–122) (1–244) severe no death related

The Annals of Pharmacotherapy

(scotoma) I: 33% to ADEs
2 optical neuritis 46 (2–91) ? II: 3%

n
1 episcleritis scleritis 90 7 III: 3%
Skin diseases 39 (17) 12/25 53 23 cutaneous 9 (1–150) 4 (1–10) 9 cases, 6 cases 2 cases not severe 65% unknown 22%
(3–70) reactions 73.5 (16–240) 20 (4–120) 14 days severe no sequelae 70%
15 photosensitivity 3 (2–4) ? (1–92) I: 32% no death related
reactions III: 3% to ADEs
1 lupus-like reaction 42 7
Neurologic 33 (14) 10/23 54 25 delirious, incoherent 3 (1–42) 3.5 (1–10) 13 cases, 1 case no not severe 52% unknown 10%
disturbances (8–81) speech, agitation 5 days severe no sequelae 80%
(1–14) I: 43% no death related
III: 5% to ADEs

2007 May, Volume 41

4 peripheral 30 (4–90) 30 (1–84) 3 cases, no no not severe 50% unknown 50%
neuropathies 92 days severe 50% no sequelae 50%
1 hemiplegia (35–122)
3 paresthesia
4 seizures 24.5 (8–330) 16 (4–28) 2 cases, 1 case no severe I: 100% unknown 25%
35 days no sequelae 50%
(8–77) Death related to
ADEs: 1 case
(25%)
Cardiovascular 22 (10) 6/11 51 1 malaise, 5.5 (1–28) 1 (immedi- 4 cases, 1 case 1 case not severe 18% no sequelae 53%
disorders (13–72) 3 hypotension, ately– 7 days severe sequelae 18%
2 hypertension, 56 days) (3–35) I: 18% death related to
1 QT interval II: 12% ADEs: 2 cases
prolongation, III: 40% (14%)
3 atrial flutter, IV: 12%
1 ventricular
fibrillation,
2 bradycardia,
2 tachycardia,
2 torsade de pointes,
1 atrioventricular
block, 4 cardiac
arrest
a
Severity: I = hospitalization or prolongation of hospitalization; II = permanent or temporary disability or incapacity; III = life threatening; IV = death.

www.theannals.com
(continued on page 759)
 Adverse Effects of Voriconazole

lucinations, mental confusion, and disorientation. Pharma-

no sequelae 56%

no sequelae 78%
no death related
ADEs: 2 cases
death related to
cogenomic analysis showed that the patient was not a poor

unknown 31%

unknown 22%
Outcome
metabolizer.

to ADEs
Four patients experienced central neurologic disorders

(13%)
such as seizures, and 8 patients experienced peripheral
not severe 13% neurologic disorders like neuropathy, hemiplegia, and

not severe 11%

paresthesias. In 97% of the cases, voriconazole was the
Severitya

suspected drug (in 40% of the cases, voriconazole had

III: 13%

III:11%
IV: 6% been administered with other drugs).
I: 68%

I: 78%
severe

severe CARDIOVASCULAR DISORDERS

Rechallenge
Positive

Cardiovascular disorders were identified in 22 reports

no

no
Table 2. Characteristics of ADEs Reported to the French Pharmacovigilance Database (continued)

(10% of all ADEs). Cardiac medical history (arrhythmia,

tachycardia, aortic valve replacement) was noted only for
4 patients.
Readministration

Five cardiac ADEs were QT interval prolongation/ven-

Severity: I = hospitalization or prolongation of hospitalization; II = permanent or temporary disability or incapacity; III = life threatening; IV = death.
no

no

tricular tachycardia/torsade de pointes. In 21 of the 22 car-

diac ADEs reported, voriconazole was the suspected drug
(in 60% of cases, voriconazole was associated with other
drugs). In the latter case, intravenous infusion of immuno-
Voriconazole

Median Time
of Treatment
Stopped,

globulin (Sandoglobuline) was involved.

21 days

16 days
8 cases,

5 cases,

Fatal outcomes were reported in 25% (n = 5) of cardiac

(2–92)

(3–56)

ADEs. In one case, the death was not linked with the car-
diac adverse event reported. In 2 patients, the cardiac ad-
verse event seems to be associated with death. In one of
Median Time
to Normalize
(range),

10 (1–120)

these patients, the voriconazole trough concentration was 9

4 (2–28)
days

mg/L, which is a toxic level. In the other case, the link be-
tween death and cardiac adverse event was unknown.
18.5 (2–150)

HEMATOLOGIC DISTURBANCES
(range),
Time to
Median

Onset

9 (3–56)
days

Hematologic disorders involved 18 reports (8% of all

ADEs), including anemia, thrombocytopenia, leukopenia,
pancytopenia, bone marrow depression, agranulocytosis,
2 anemia, 2 aplasia,

9 acute renal failure

and eosinophilia. In 87.5% of the cases, voriconazole was

7 thrombopenia,

1 pancytopenia
5 neutropenia,
1 eosinophilia,

the suspected drug (in 50% of cases, voriconazole was ad-

ADEs

ministered with other drugs). In 9 cases, immunosuppres-

sive risk factors (HIV in 3 pts., hemopathy in 5 pts., allo-
graft in 1 pt.) were reported.
(16–72)
Median

(range)
Age, y

(2–71)
57

52

Table 3. Repartition of Grade Toxicity of Hepatic Enzymes9

(F/M)
Sex

5/11

2/7

Cases (n)
Grade AST ALT ALP GGT Bilirubin
Cases,
N (%)

18 (8)

I 14 6 7 3 0
9 (4)

II 8 6 9 6 5
III 6 12 6 7 2
Type of ADEs

disturbances

disturbances

IV 4 5 2 11 3
TOTAL 32 29 24 27 10
Renal
Blood

ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST =

aspartate aminotransferase; GGT = γ-glutamyltransferase.
a

www.theannals.com The Annals of Pharmacotherapy n 2007 May, Volume 41 n 759

C Eiden et al.
RENAL DISTURBANCES
Nine cases of acute renal failure were reported (4% of
all ADEs). In 1 of these, a biopsy showed tubular necrosis
with glomerular lesions (without immunoglobulin A de-
posit). This patient received voriconazole and liposomal
amphotericin B. Intravenous voriconazole was adminis-
tered in 2 cases. Voriconazole was the suspected drug in all
cases (in 33% of cases, voriconazole was administered
with other drugs).
OTHER ADVERSE EFFECTS
Other less commonly observed ADEs were hyperka-
lemia (1 case), hypokalemia (2 cases), and hypoglycemia
(1 case).
DRUG INTERACTIONS
Among all ADEs observed, 7 were related to drug– drug
interactions. In 2 cases, voriconazole had been given with
cyclosporine, leading to cyclosporine toxicity (blood con-
centrations >400 ng/mL) and abdominal pain. In 3 other
cases, tacrolimus toxicity was reported, with trough blood
concentrations greater than 20 ng/mL. In 1 case, hyper-
glycemia was considered possibly related to concomitant
administration of voriconazole and tacrolimus. The final
patient developed an international normalized ratio greater
than 10 with rectal bleeding. This was believed to be the
result of concomitant use of voriconazole and fluindione
(oral vitamin K antagonist), requiring administration of vi-
tamin K.
Discussion
From 2002 to 2005, 227 cases of voriconazole-induced
adverse reactions were reported to the FDP (Table 2). All
ADEs associated with voriconazole collected in our study
are reported in the literature.10-12
The most common ADEs that we found were elevations
in hepatic enzyme levels, disturbances of vision, and skin
rashes. These also are the most frequently reported ADEs
in the literature. However, visual disturbances are the most
common adverse reaction in the literature, followed by
skin rashes and elevations in hepatic enzyme levels.12
In our study, abnormal results of liver function tests
were assessed as serious in 61% of cases, and worsened
with hepatocellular injury (determined by a decrease in
prothrombin level) in 6 cases. In Phase III clinical trials,
the following types and rates of elevations were reported in
a total of 817 patients exposed to voriconazole: ALT
greater than 3 times ULN (11.2% of pts.), AST greater
than 3 times ULN (19.5%), ALP greater than 3 times ULN
(9.8%), and bilirubin greater than 1.5 times ULN (19.5%).2
Most patients have asymptomatic abnormal alterations in
760 n The Annals of Pharmacotherapy n 2007 May, Volume 41
liver function tests. The potential relationship between
voriconazole plasma concentrations and liver function test
abnormalities has been investigated.13 There was a weaker,
but statistically significant, association (p > 0.001) with
risk related to AST, ALP, or bilirubin, but not with ALT
abnormalities. The model predicted a 7–17% increase in
the odds of an abnormal AST, ALP, or bilirubin level for
every 1 mg/L increase in the voriconazole plasma concen-
tration. However, our study did not identify a threshold
plasma concentration above which the risk of liver func-
tion test abnormalities was increased. The incidence of
hepatotoxicity during treatment with oral and intravenous
formulations of voriconazole has been compared in 35 pa-
tients.14 The increase in liver enzyme levels was compara-
ble between the groups. Liver function should be assessed
before the start of voriconazole treatment and within the
first 2 weeks after the initiation of therapy and then every
2– 4 weeks throughout therapy.12
The second most common ADE was abnormal vision.
In clinical trials, these ADEs occurred in about 30% of pa-
tients.3,6,12,15 They are generally considered not damaging
for the retina and visual cortex, and the disturbance of vi-
sion is reversible. Symptoms tend to occur during the first
week of therapy and decrease or disappear despite contin-
ued therapy. In our study, visual disturbances occurred dur-
ing the first week of voriconazole treatment in 18% of cas-
es and led to voriconazole discontinuation in 67% of cases.
In 15% of cases, intravenous administration was switched
to the oral route; in 5% of cases, dosage was reduced; in
3% of cases, the rate of infusion was reduced; and in 5%
of cases, voriconazole was continued. In 14 reports, visual
hallucinations occurred during concomitant treatment with
fluoroquinolones, drugs that can also induce psychiatric
adverse events such as confusion, hallucinations, and agi-
tation.16 Studies have shown that elevated voriconazole
plasma concentrations are associated with neurologic ad-
verse events.11,13,17 With healthy volunteers, both the maxi-
mum plasma concentration and area under the curve were
associated with visual disturbances.13 In addition, one case
of musical hallucinations induced by voriconazole alone
has been reported.18
The frequency of skin rashes reported in our study (17%
of all ADEs) is close to that reported in early clinical and
pharmacologic trials (17.3%).2 In our study, skin rashes
were not considered to be serious in 65% of cases, and we
did not identify severe reactions like Stevens–Johnson syn-
drome or toxic epidermal necrolysis, which have been re-
ported in very few patients.12 However, we observed 15
cases of photosensitivity reactions and 1 suspected lupus-
like reaction. In one study, 5 patients treated with voricona-
zole developed facial erythema and cheilitis, and 1 patient
developed discoid lupus.19 Such adverse effects (cheilitis,
photosensitivity) are reminiscent of those occurring during
www.theannals.com

therapy with systemic retinoids, and elevations in levels of
all-trans retinol and 13-cis retinol were found in these pa-
tients, suggesting that voriconazole may have indirect
retinoid effects associated with skin reactions. One hypothe-
sis is that voriconazole, via inhibition of the cytochrome
P450 pathway, inhibits a step in the metabolic breakdown of
all-trans retinol, leading to increased plasma retinoid levels.20
Neurologic disturbances were reported in 33 cases.
These ADEs were frequent (>1/100) in Pfizer drug trial
safety data.4
Among cases of cardiovascular disorders, 5 involved
QT interval prolongation/ventricular tachycardia/torsade
de pointes. The voriconazole package insert warns about
such adverse reactions on the basis of a few previous cas-
es.21 In the literature, 3 cases of QTc interval prolongation
have been reported.22,23 Risk factors for QT interval prolon-
gation are well documented: female, electrolyte imbalance,
drug interactions, intravenous route of administration, in-
herited long QT interval, excessive dosing of proarrhyth-
mogenic drugs, and heart disease.24 Electrocardiograms
should be performed in patients at risk of cardiac compli-
cations when voriconazole is administered.
Blood toxicity was frequent (>1/100) during the clinical
trials.4 Most of the patients who developed fungal infec-
tions were in immunosuppressed conditions related to dis-
ease or medications. Occurrence of these ADEs seems to
be multifactorial, and the relation with voriconazole is
therefore difficult to assess.
Nine cases of acute renal failure were reported; in 2 of
these, intravenous voriconazole was administered. In clini-
cal trials, acute renal failure was observed in 3.9% of pa-
tients, and populations exposed to voriconazole may be
more susceptible to abnormalities in renal function due to
their underlying conditions (neutropenia, bone marrow
transplantation, sepsis). In patients with impaired renal
function, intravenous voriconazole can lead to accumula-
tion of the vehicle sulfobutyl ether beta cyclodextrin sodi-
um, with resultant renal failure.25
Drug– drug interactions were reported in 2 cases with
cyclosporine and in 4 cases with tacrolimus. Voriconazole
undergoes hepatic metabolism by CYP2C9, CYP2C19,
and CYP3A4. Therefore, coadministration of drugs that
inhibit or induce these isoenzymes may affect concentra-
tions of voriconazole. On the other hand, voriconazole
may inhibit the metabolism of cyclosporine, tacrolimus,
sirolimus, and prednisolone via CYP3A4, as well as the
metabolism of cyclosporine via CYP2C9. Modification of
cyclosporine concentrations by voriconazole has been re-
ported.26,27 Cyclosporine concentrations must be carefully
monitored when administered with voriconazole. Coad-
ministration of voriconazole and tacrolimus resulted in ele-
vated (nearly 10-fold higher) trough tacrolimus blood con-
centrations in a liver transplant patient.28 The dosage of
www.theannals.com
Adverse Effects of Voriconazole
oral tacrolimus has to be adjusted based on the determina-
tion of trough blood concentrations.29
One drug– drug interaction involved fluindione. Coad-
ministration of voriconazole with fluindione can lead to in-
creased risk of hemorrhage. Monitoring of the international
normalized ratio is recommended during concomitant use
of these drugs. The precise mechanism of this interaction is
unclear; however, like warfarin, fluindione could be subject
to the inhibitory effects of voriconazole via CYP2C9.
The limitation of our study was that all ADEs were
spontaneously reported to the FPD. Moreover, the assess-
ment of the link between voriconazole and the complica-
tion observed was made, in some cases, retrospectively.
Some important data are missing, leading to difficulty in as-
sessing causality. Underreporting is a well-known flaw in
spontaneous reporting systems. However, the spontaneous
reporting system of ADEs remains a useful tool in pharma-
covigilance to generate signals of new or rare ADEs. In addi-
tion, we were not able to determine the real incidence of
these ADEs, because the number of patients exposed to
voriconazole during the study period was not determined.
Conclusions
Voriconazole, a second-generation triazole, is generally
well tolerated. Our data show that the profile of ADEs as-
sociated with voriconazole since its approval in France is
close to that observed during clinical trials. Some of these
ADEs, such as neurologic adverse effects (hallucinations,
confusion) and hepatic test abnormalities, are related to
high voriconazole plasma concentrations. At the initiation
of marketing, routine voriconazole therapeutic drug moni-
toring was not recommended. However, according to the
pharmacokinetic characteristics of this drug (potential for
drug– drug interactions, nonlinear pharmacokinetics, poly-
morphic metabolism), therapeutic monitoring for preven-
tion of ADEs could be useful in relevant situations.
To prevent ADEs associated with voriconazole or detect
them early, we recommend therapeutic drug monitoring in
association with monitoring of other clinical and biological
parameters, such as electrocardiogram, electrolytes, and
hepatic function tests.
Céline Eiden PharmD, Resident, Department of Medical Pharma-
cology and Toxicology, Lapeyronie Hospital, Montpellier, France
Hélène Peyrière PharmD PhD, Lecturer in Clinical Pharmacy, De-
partment of Medical Pharmacology and Toxicology, Lapeyronie Hos-
pital
Marylène Cociglio PharmD PhD, Lecturer in Clinical Pharmacol-
ogy, Department of Medical Pharmacology and Toxicology, Lapey-
ronie Hospital
Samira Djezzar MD, Clinical Specialist, Pharmacovigilance Centre,
Fernand Widal Hospital, Paris, France
Sylvie Hansel PharmD PhD, Professor in Clinical Pharmacy, De-
partment of Pharmacy, Lapeyronie Hospital
Jean-Pierre Blayac MD PhD, Professor in Clinical Pharmacolo-
gy, Department of Medical Pharmacology and Toxicology, Lapey-
ronie Hospital
The Annals of Pharmacotherapy n 2007 May, Volume 41 n 761
C Eiden et al.
Dominique Hillaire-Buys MD PhD, Lecturer in Clinical Pharma-
cology, Department of Medical Pharmacology and Toxicology, Lapey-
ronie Hospital
Reprints: Dr. Peyrière, Service de Pharmacologie Médicale et Toxi-
cologie, Hôpital Lapeyronie, 371 avenue du Doyen Gaston Giraud,
34295 Montpellier Cedex 5, France, fax 33-4-67-33-67-51, h-peyriere@
chu-montpellier.fr
We appreciate the assistance of the French pharmacovigilance centers in our work.
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EXTRACTO
ANTECEDENTES: Los efectos adversos más comunes de voriconazol
descritos en ensayos clínicos son trastornos de la visión (30% de los
pacientes), erupciones cutáneas (17% de los pacientes), y elevación de
los niveles de las enzimas hepáticas (un 10% de los pacientes según la
enzima). No obstante, los datos poscomercialización concernientes a la
seguridad de voriconazol son escasos.
OBJETIVO: Describir los efectos adversos producidos por voriconazol tras
haberlo usado durante 4 años y determinar la frecuencia de los mismos.
MÉTODOS: Se analizaron todos los casos de efectos adversos producidos
por fármacos (ADE, adverse drug effects) que incluían el uso de
voriconazol y que se notificaron a la base de datos francesa de
Fármacovigilancia entre el año 2002 y el 2005. En cada uno de los
casos, se registró la siguiente información: edad, sexo, indicación,
enfermedad concomitante, medicación concomitante, y descripción de
los ADE. Se estableció una relación de causalidad entre el voriconazol y
los ADE utilizando la escala de probabilidad Naranjo.
RESULTADOS: Se encontraron un total de 227 casos de ADE en 178
adultos y 9 niños (<12 años). Los hombres constituyeron un 66% de
todos los pacientes. La edad media del paciente era de 49 ± 20 años. Los
ADE descritos fueron alteraciones en las pruebas funcionales del hígado
(23%), trastornos visuales (18%), erupciones cutáneas (17%), trastornos
neurológicos (14%), episodios cardiovasculares (10%), trastornos
hematológicos (8%), y alteraciones renales (4%). Otros ADE
identificados con menor frecuencia fueron cefaleas, nauseas, y vómitos.
Se observaron interacciones farmacológicas en 7 casos. Según los
criterios Naranjo, el 84% de los ADE se clasificaron como posibles, el
7% como probables, el 5% como muy probables, y el 4% como poco
probables.
CONCLUSIONES: La mayoría de los ADE identificados en este estudio se
han comprobado en la literatura, excepto las complicaciones cardíacas,
que se han notificado en contadas ocasiones. Se observaron pocos ADE
relacionados con interacciones farmacológicas; no obstante los médicos
deben estar atentos a la asociación de voriconazol con otros fármacos
debido al intenso metabolismo que sufre este fármaco por el citocromo
P450.
Violeta Lopez Sanchez
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RÉSUMÉ
RATIONNEL: Peu de données sont disponibles concernant la nature et la
sévérité des effets indésirables du voriconazole depuis sa
commercialisation.
OBJECTIF: L’objectif de cette étude a été de décrire les effets indésirables
médicamenteux du voriconazole observés en pratique courante, après 4
années d’utilisation.
MÉTHODES: Tous les cas d’effets indésirables sous voriconazole rapportés
dans la banque nationale française de Pharmacovigilance entre 2002 et
2005 ont été analysés. Pour chaque cas, les données suivantes ont été
répertoriées: âge, sexe, indication, pathologie concomitante, traitements
médicamenteux associés, et effet indésirable.
RESULTATS: Au total 227 observations ont été rapportées, 178 chez des
adultes et 9 chez des enfants (<12 ans). La population masculine
représentait 66% des patients. La moyenne d’âge était de 49 ± 20 ans.
Les pathologies associées étaient dans 33% des cas des hémopathies
malignes, dans 12% des cas des pathologies pulmonaires, et dans 12%
des cas des pathologies cardiaques. Les principaux effets indésirables
observés ont été des anomalies des tests hépatiques (23%), des
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Adverse Effects of Voriconazole
anomalies visuelles (18%), des rashs cutanés (17%), des troubles
cardiovasculaires (10%), des confusions mentales (9%), des anomalies
hématologiques (8%), neurologiques (5%), et rénales (4%). D’autres
effets indésirables moins fréquents ont été rapportés, essentiellement des
céphalées et des troubles gastro-intestinaux. Une interaction
médicamenteuse a été relevée dans 7 cas. La relation entre l’effet
indésirable et le voriconazole a été imputé selon la méthode de Naranjo;
5% des effets indésirables ont été cotés “très probable,” 7% “probable,”
84% “possible,” et 4% “douteux.”
CONCLUSIONS: La majorité des effets indésirables déclarés sont connus et
décrits dans le résumé des caractéristiques du produit ou dans la
littérature, à l’exception des complications cardiaques qui sont rarement
rapportés. Peu d’effets indésirables ont été secondaires à une interaction
médicamenteuse. Cependant le voriconazole étant métabolisé par les
cytochromes P450, les prescripteurs doivent être vigilants quant aux
associations médicamenteuses du voriconazole.
Céline Eiden
The Annals of Pharmacotherapy n 2007 May, Volume 41 n 763