Voriconazole, administered orally or parenterally, has been evaluated as primary
or salvage therapy in 520 patients aged 12 years and older with infections caused
by Aspergillus spp., Fusarium spp., and Scedosporium spp.
Invasive Aspergillosis
Voriconazole was studied in patients for primary therapy of invasive aspergillosis
(randomized, controlled study 307/602), for primary and salvage therapy of aspergillosis
(non-comparative study 304) and for treatment of patients with invasive aspergillosis
who were refractory to, or intolerant of, other antifungal therapy (non-comparative
study 309/604).
Study 307/602
The efficacy of voriconazole compared to amphotericin B in the primary treatment
of acute invasive aspergillosis was demonstrated in 277 patients treated for 12
weeks in Study 307/602. The majority of study patients had underlying hematologic
malignancies, including bone marrow transplantation. The study also included patients
with solid organ transplantation, solid tumors, and AIDS. The patients were mainly
treated for definite or probable invasive aspergillosis of the lungs. Other aspergillosis
infections included disseminated disease, CNS infections and sinus infections. Diagnosis
of definite or probable invasive aspergillosis was made according to criteria modified
from those established by the National Institute of Allergy and Infectious Diseases
Mycoses Study Group/European Organisation for Research and Treatment of Cancer (NIAID
MSG/EORTC).
Voriconazole was administered intravenously with a loading dose of 6 mg/kg every
12 hours for the first 24 hours followed by a maintenance dose of 4 mg/kg every
12 hours for a minimum of seven days. Therapy could then be switched to the oral
formulation at a dose of 200 mg Q12h. Median duration of IV voriconazole therapy
was 10 days (range 2-90 days). After IV voriconazole therapy, the median duration
of PO voriconazole therapy was 76 days (range 2-232 days).
Patients in the comparator group received conventional amphotericin B as a slow
infusion at a daily dose of 1.0-1.5 mg/kg/day. Median duration of IV amphotericin
therapy was 12 days (range 1-85 days). Treatment was then continued with other licensed
antifungal therapy (OLAT), including itraconazole and lipid amphotericin B formulations.
Although initial therapy with conventional amphotericin B was to be continued for
at least two weeks, actual duration of therapy was at the discretion of the investigator.
Patients who discontinued initial randomized therapy due to toxicity or lack of
efficacy were eligible to continue in the study with OLAT treatment.
A satisfactory global response at 12 weeks (complete or partial resolution of all
attributable symptoms, signs, radiographic/bronchoscopic abnormalities present at
baseline) was seen in 53% of voriconazole treated patients compared to 32% of amphotericin
B treated patients (Table 4). A benefit of voriconazole compared to amphotericin
B on patient survival at Day 84 was seen with a 71% survival rate on voriconazole
compared to 58% on amphotericin B (Table 6).
Table 6 also summarizes the response (success) based on mycological confirmation
and species.
Table 6
Overall Efficacy and Success by Species in the Primary Treatment of Acute Invasive
Aspergillosis
Study 307/602
Study 304
The results of this comparative trial (Study 307/602) confirmed the results of an
earlier trial in the primary and salvage treatment of patients with acute invasive
aspergillosis (Study 304). In this earlier study, an overall success rate of 52%
(26/50) was seen in patients treated with voriconazole for primary therapy. Success
was seen in 17/29 (59%) with Aspergillus fumigatus infections and 3/6 (50%)
patients with infections due to non-fumigatus species [A. flavus (1/1);
A. nidulans (0/2); A. niger (2/2); A. terreus (0/1)]. Success
in patients who received voriconazole as salvage therapy is presented in Table 7.
Study 309/604
Additional data regarding response rates in patients who were refractory to, or
intolerant of, other antifungal agents are also provided in Table 7. Overall mycological
eradication for culture-documented infections due to fumigatus and non-fumigatus
species of Aspergillus was 36/82 (44%) and 12/30 (40%), respectively, in
voriconazole treated patients. Patients had various underlying diseases and species
other than A. fumigatus contributed to mixed infections in some cases.
For patients who were infected with a single pathogen and were refractory to, or
intolerant of, other antifungal agents, the satisfactory response rates for voriconazole
in studies 304 and 309/604 are presented in Table 7.
Table 7
Combined Response Data in Salvage Patients with Single Aspergillus Species
(Studies
304 and 309/604)
Nineteen patients had more than one species of Aspergillus isolated. Success
was seen in 4/17 (24%) of these patients.
Candidemia in nonneutropenic patients and other deep tissue Candida infections
Voriconazole was compared to the regimen of amphotericin B followed by fluconazole
in Study 608, an open label, comparative study in nonneutropenic patients with candidemia
associated with clinical signs of infection. Patients were randomized in 2:1 ratio
to receive either voriconazole (n=283) or the regimen of amphotericin B followed
by fluconazole (n=139). Patients were treated with randomized study drug for a median
of 15 days. Most of the candidemia in patients evaluated for efficacy was caused
by C. albicans (46%), followed by C. tropicalis (19%), C. parapsilosis
(17%), C. glabrata (15%), and C. krusei (1%).
An independent Data Review Committee (DRC), blinded to study treatment, reviewed
the clinical and mycological data from this study, and generated one assessment
of response for each patient. A successful response required all of the following:
resolution or improvement in all clinical signs and symptoms of infection, blood
cultures negative for Candida, infected deep tissue sites negative for Candida
or resolution of all local signs of infection, and no systemic antifungal therapy
other than study drug. The primary analysis, which counted DRC-assessed successes
at the fixed time point (12 weeks after End of Therapy [EOT]), demonstrated that
voriconazole was comparable to the regimen of amphotericin B followed by fluconazole
(response rates of 41% and 41%, respectively) in the treatment of candidemia. Patients
who did not have a 12-week assessment for any reason were considered a treatment
failure.
The overall clinical and mycological success rates by Candida species in
Study 150-608 are presented in Table 8.
Table 8
Overall Success Rates Sustained From EOT To The Fixed 12-Week Follow-Up Time Point
By Baseline Pathogena,b
In a secondary analysis, which counted DRC-assessed successes at any time point
(EOT, or 2, 6, or 12 weeks after EOT), the response rates were 65% for voriconazole
and 71% for the regimen of amphotericin B followed by fluconazole.
In Studies 608 and 309/604 (non-comparative study in patients with invasive fungal
infections who were refractory to, or intolerant of, other antifungal agents), voriconazole
was evaluated in 35 patients with deep tissue Candida infections. A favorable
response was seen in 4 of 7 patients with intraabdominal infections, 5 of 6 patients
with kidney and bladder wall infections, 3 of 3 patients with deep tissue abscess
or wound infection, 1 of 2 patients with pneumonia/pleural space infections, 2 of
4 patients with skin lesions, 1 of 1 patients with mixed intraabdominal and pulmonary
infection, 1 of 2 patients with suppurative phlebitis, 1 of 3 patients with hepatosplenic
infection, 1 of 5 patients with osteomyelitis, 0 of 1 with liver infection, and
0 of 1 with cervical lymph node infection.
Esophageal Candidiasis
The efficacy of oral voriconazole 200 mg bid compared to oral fluconazole 200 mg
od in the primary treatment of esophageal candidiasis was demonstrated in Study
150-305, a double-blind, double-dummy study in immunocompromised patients with endoscopically-proven
esophageal candidiasis. Patients were treated for a median of 15 days (range 1 to
49 days). Outcome was assessed by repeat endoscopy at end of treatment (EOT). A
successful response was defined as a normal endoscopy at EOT or at least a 1-grade
improvement over baseline endoscopic score. For patients in the Intent to Treat
(ITT) population with only a baseline endoscopy, a successful response was defined
as symptomatic cure or improvement at EOT compared to baseline. Voriconazole and
fluconazole (200 mg od) showed comparable efficacy rates against esophageal candidiasis,
as presented in Table 9.
Table 9
Success Rates in Patients Treated for Esophageal Candidiasis
Microbiologic success rates by Candida species are presented in Table 10.
Table 10
Clinical and mycological outcome by baseline pathogen in patients with esophageal
candidiasis (Study 150-305).
Other Serious Fungal Pathogens
In pooled analyses of patients, voriconazole was shown to be effective against the
following additional fungal pathogens:
Scedosporium apiospermum – Successful response to voriconazole therapy was
seen in 15 of 24 patients (63%). Three of these patients relapsed within 4 weeks,
including 1 patient with pulmonary, skin and eye infections, 1 patient with cerebral
disease, and 1 patient with skin infection. Ten patients had evidence of cerebral
disease and 6 of these had a successful outcome (1 relapse). In addition, a successful
response was seen in 1 of 3 patients with mixed organism infections.
Fusarium spp. – Nine of 21 (43%) patients were successfully treated with
voriconazole. Of these 9 patients, 3 had eye infections, 1 had an eye and blood
infection, 1 had a skin infection, 1 had a blood infection alone, 2 had sinus infections,
and 1 had disseminated infection (pulmonary, skin, hepatosplenic). Three of these
patients (1 with disseminated disease, 1 with an eye infection and 1 with a blood
infection) had Fusarium solani and were complete successes. Two of these
patients relapsed, 1 with a sinus infection and profound neutropenia and 1 post
surgical patient with blood and eye infections.