Update on Azole Antifungals
Dimitrios I. Zonios; John E. Bennett
Semin Respir Crit Care Med. 2008;29(2):198-210. ©2008 Thieme Medical Publishers
Posted 06/11/2008
Abstract and Introduction
Abstract
This is a comprehensive, clinically oriented review of the four commercially available
triazoles: fluconazole, itraconazole, voriconazole, and posaconazole. Emphasis is
placed in pharmacology, drug interactions, adverse events, antifungal activity, and the
evolving perspective of their clinical use. Key clinical trials are briefly discussed, and
specific drug indications summarized. Fluconazole remains a valuable low-cost choice
for the treatment of various fungal infections, including candidiasis and cryptococcosis.
It has relatively few drug interactions and is safe but lacks activity against filamentous
fungi. The use of itraconazole is historically plagued by erratic bioavailability of the oral
capsule, improved with the oral solution. Drug interactions are numerous. Itraconazole
exhibits significant activity against Aspergillus and the endemic fungi. Voriconazole has
revolutionized the treatment of aspergillosis in severely immunocompromised
patients, but its use is compromised by complicated pharmacokinetics, notable drug
interactions, and relatively significant adverse events. Finally, posaconazole is the last
addition to the azole armamentarium with extended antifungal spectrum, significant
activity against the zygomycetes, and, apparently, optimal safety profile. Posaconazole
has a significant role for the prophylaxis of invasive fungal infections in severely
immunocompromised patients. Multiple daily dosing, a need for fatty foods for
absorption, and absence of an intravenous formulation restrict its use to selected
populations.
Introduction
The azole antifungals include two classes, imidazoles and triazoles, which share the
same mechanism of action. Imidazoles have a two-nitrogen azole ring; they are
predominantly used topically and have been replaced for systemic administration by
triazoles, which have three nitrogens in the azole ring. Triazoles have a more favorable
pharmacokinetic profile than imidazoles and do not significantly inhibit human sterol
synthesis. They were introduced almost 30 years ago. Triazoles include fluconazole,
itraconazole, voriconazole, and posaconazole (Figure 1), each of which will be
discussed in detail. Fluconazole and itraconazole were the first azoles in clinical
practice. Newer azoles such as voriconazole and posaconazole have been developed to
overcome the limited efficacy of fluconazole against Aspergillus and other molds and
to improve absorption, tolerability, and drug interaction profile of itraconazole.
Voriconazole is structurally similar to fluconazole and posaconazole to itraconazole.
Figure 1.
Commercially available triazoles.
Mechanism Of Action
Triazoles inhibit the cytochrome P450 enzyme 14-α-sterol-demethylase. This enzyme is
implicated in the biosynthetic pathway of ergosterol, which is an essential molecule of
the fungal cell membrane. Inhibition of this enzyme leads to accumulation of 14-amethylsterols on the fungal surface, which results in arrest of fungal growth. Triazoles
are generally considered fungistatic. Table 1 provides formulations of the commercially
available triazoles.
Pharmacology
Fluconazole
Fluconazole is water soluble and it is very well absorbed from the gastrointestinal
tract.[1] Its absorption is not affected by food or gastric pH. In blood, 12% is protein
bound. Eighty percent is excreted unchanged in the urine; hepatic CYP2C9 enzyme
plays a minor role in its metabolism. Fluconazole diffuses readily in body fluids and
cerebrospinal fluid (CSF) concentration is ∼70% of serum. Terminal plasma elimination
half-life of fluconazole is ∼30 hours after oral administration.[1] The dose should be
halved for creatinine clearance below 50 mL/min, and 100% of the regular dose should
be given after hemodialysis. An initial double dose is recommended as a loading dose
but is not always used.
Itraconazole
Itraconazole is water insoluble, and its bioavailability is variable after oral ingestion.
The capsule is best absorbed with food. The oral solution is better absorbed in the
fasting state[2] and generally achieves higher bioavailability than the capsule.[3]
Unpredictable bioavailability of the oral solution is seen in bone marrow transplants
and human immunodeficiency virus (HIV) patients.[4] Itraconazole is solubilized in the
oral solution and the intravenous form by a hydroxypropyl-β-cyclodextrin. This
pharmacologically inactive oligosaccharide molecule acts as a vehicle for the
hydrophobic drug, which is readily released upon contact to the lipid membrane of the
enteric cells. After absorption, itraconazole is found in equal amounts in plasma as
native drug and the hydroxy-itraconazole metabolite. Unlike metabolites of other
azoles, hydroxyitraconazole has equivalent antifungal activity to the parent compound.
Both molecules are bound more than 99% to plasma proteins. Itraconazole is
metabolized in the liver and is a substrate and strong inhibitor of CYP3A4. Elimination
half-time is ∼30 to 40 hours after both oral and intravenous administration, and
steady-state concentration is reached after 4 days of treatment. Itraconazole does not
penetrate the CSF. Due to the potential accumulation of the hydroxypropyl-βcyclodextrin intravenous vehicle of itraconazole, patients with creatinine clearance of
less than 30 mL/min should not be treated with intravenous itraconazole.
Voriconazole
Voriconazole is poorly soluble, despite structural similarity to fluconazole. Following
oral administration, as either tablet or solution, bioavailability is 96%. Oral absorption
is reduced by 22% when taken with food. Solubility of the intravenous formulation is
achieved by sulfobutyl ether β-cyclodextrin (SBECD), a molecule pharmacologically
similar to hydroxypropyl β-cyclodextrin used for the itraconazole intravenous
formulation. The oral solution does not contain SBECD. Voriconazole is 56% bound to
serum proteins. The volume of distribution is good (4.6 L/Kg), and the drug is
metabolized in the liver, mainly by CYP2C19 and CYP3A4 and to a lesser extent by
CYP2C9.[5] Steady-state concentration without a loading dose is achieved within 5 to 6
days of treatment. Voriconazole penetrates the blood-brain barrier, and CSF level is
∼46% of the serum level. The percentages of voriconazole level in noninflamed
vitreous and aqueous humor are 38.1% and 53.0%, respectively.[6] The major metabolic
pathways in humans involve fluoropyrimidine N-oxidation, fluoropyrimidine
hydroxylation, and methyl hydroxylation. The main metabolite in serum is the inactive
N-oxide.[7] Only 2% of the active drug can be found in urine. Voriconazole exhibits
nonlinear pharmacokinetics due to saturation of metabolism, and small increases in
dose result in exponential increases in blood levels. Optimal therapeutic levels of
voriconazole have not been described, but in phase II/III studies a median trough
voriconazole level of 2.49 µg/mL was found. Although high voriconazole blood levels
have been implicated in increased toxicity[8-10] and low levels to disease progression,[11]
therapeutic and toxic levels of this agent are yet to be determined. Moreover,
correlation between dose and levels is weak, and there is significant inter- and
intrapatient voriconazole level variability.[12] Voriconazole pharmacokinetics are also
affected by, at least, CYP2C19 enzyme genetic variability.[13] Nineteen percent of the
Asian and 2% of the Caucasian population are poor metabolizers in terms of CYP2C19
activity[14] (homozygous for the CYP2C19 allele) resulting in high voriconazole blood
levels. Higher percentages of patients are heterozygous for the CYP2C19 allele, leading
to an intermediate metabolizer phenotype with moderately increased voriconazole
blood levels. Patients with mild to moderate hepatic disease (Child-Pugh class A and B)
should get 50% of the usual maintenance dose. The safety of voriconazole has not
been established for liver cirrhosis and should not be used in this setting. Finally, due
to accumulation of the intravenous voriconazole vehicle SBECD, the drug should be
used with caution in patients with creatinine clearance of < 50 mL/min.
Posaconazole
Posaconazole is available only as a suspension for oral use. Absorption is increased
when taken with food, especially fatty meals,[15] and is not affected by use of antacids.
In detail, the area under the curve (AUC) and maximum concentration (Cmax) was
increased fourfold with a fatty meal and between 2.6 and 2.9 times with a nonfatty
meal, as compared with the fasting state.[15] Moreover, oral absorption is better in
divided daily doses and optimal when administered four times daily.[16] Absorption is
saturated for doses more than 800 mg daily and is diminished in patients undergoing
allogeneic bone marrow transplantation.[17] Posaconazole is more than 98% protein
bound, and its volume of distribution is between 343 and 1341 L, compatible with
good tissue penetration. The mean half-life of posaconazole is more than 20 hours,
and the drug is metabolized in the liver through glucuronidation (phase 2 metabolism)
and excreted primarily in bile (76.9%) and in urine (14%) as unchanged drug or inactive
metabolites. Although posaconazole is not metabolized through liver CYP450 system
enzymes (phase 1 metabolism), it is a moderate inhibitor of CYP3A4,[18] which leads to
increased blood levels of drugs using the CYP3A4 metabolic pathway when
coadministered. There is no need for dose adjustment in patients with moderate to
severe renal disease, and the drug is not cleared with hemodialysis. Posaconazole has
not been adequately studied in patients with hepatic insufficiency and should be used
with caution in this setting.
Drug Interactions
Triazoles have numerous clinically significant drug interactions, the list is constantly
expanding and the majority of those currently identified are presented in Table 2 [19-72]
and Table 3 .[47,48,50-53,56,73-80] Most of these interactions arise from competitive
inhibition of liver oxidative metabolism via rapid reversible binding to CYP450 system
enzymes (phase I metabolism). Triazoles interfere mainly with CYP3A4, CYP2C9, and
CYP2C19 with distinctive affinity ( Table 4 ) and, accordingly, they exhibit slightly
different drug interaction profiles. In addition, itraconazole and posaconazole, but not
fluconazole and voriconazole, are inhibitors of gastric P-glycoprotein.[81] P-glycoprotein
is a transmembrane efflux pump limiting systemic exposure to many drugs by
inhibiting GI absorption. Thus inhibition of P-glycoprotein by azoles may lead to
increased systemic exposure of drugs affected by this transport system. Because
interactions caused by itraconazole have been extensively studied and both
itraconazole and posaconazole inhibit CYP3A4, drugs with known interaction to
itraconazole should be used with caution in posaconazole-treated patients.
Among the most significant common drug interactions of triazoles are drug elevations
of cyclosporine, tacrolimus, and sirolimus, most Ca channel blockers, most
benzodiazepines, many statins and steroids, warfarin, and rifabutin ( Table 2 ).
Carbamazepine, phenobarbital, phenytoin, rifampin, and rifabutin significantly
decrease azole concentrations ( Table 3 ). Increased blood levels of terfenadine,
astemizole, cisapride, pimozide, and quinine can cause Q-Tc prolongation and
predispose to torsades de pointes. Finally, increased cytotoxic chemotherapy-related
toxicity can be caused by concomitant treatment with triazoles (with the exception of
fluconazole) and vinca alkaloids, cyclophosphamide, vinorelbine, and busulfan. In
general, use of an azole should be cautious if an interaction is suspected. The absence
of data to support an interaction does not mean absence of interaction, especially with
the newer azoles.
Adverse Events
Fluconazole
Fluconazole is generally well tolerated. Serious adverse events, mainly liver toxicity,
are rare. Headache, nausea, vomiting, abdominal pain, and diarrhea are among the
most common complaints. Skin rashes can also occur. In patients with prolonged
treatment, headache, alopecia, and anorexia are common as well as eosinophilia and
aspartate aminotransferase (AST) elevation.[82] Alopecia is reversible and dose
dependent, commonly seen in chronic treatment with doses above 400 mg daily. [83]
Liver toxicity can rarely lead to acute hepatic necrosis. Rare adverse events, typically
restricted to a few case reports, are agranulocytosis, thrombocytopenia, toxic
epidermal necrolysis, Stevens-Johnson syndrome, anaphylaxis, Q-T prolongation and
torsades de pointes. Fluconazole is a category C drug; its use should be avoided in
pregnancy due to teratogenicity in animals and a few reports of severe organ
deformities in humans.[84]
Itraconazole
Itraconazole most often causes nausea and vomiting, and these symptoms are dose
dependent. Dividing the dose increases tolerance. Other common adverse events
include AST/ALT (alanine aminotransferase) elevation, hypokalemia, and rash.[85]
Hypokalemia can be severe, especially in high doses (> 400 mg daily) and accompanied
by hypertension and dependent edema.[86] The oral solution is generally less well
tolerated due to the presence of cyclodextrin, which can cause diarrhea and
gastrointestinal discomfort, possibly due to osmotic effect. Serious hepatotoxicity can
lead to liver failure but is rare. Heart failure is caused by a direct negative inotropic
effect and has led to a "black box" warning on the label.[87] Intravenous itraconazole
can cause chemical phlebitis. Use in pregnancy and lactation is contraindicated (class
C).
Voriconazole
Voriconazole is usually well tolerated; the most common adverse events after
voriconazole treatment are visual changes, with an incidence of 20 to 23%.[88,89]
Occurrence of 44.8% has been reported in one study.[90] Typically, the patients report
blurred vision, photopsias, photophobia, and color changes 30 minutes to 1 hour after
dosing. The symptoms are transient and reversible, almost never lead to drug
discontinuation, and tend to dissipate after repeated dosing. As with all azoles,
voriconazole can cause hepatotoxicity, mainly manifested by elevation of AST/ALT,
which, on rare occasion, can be serious or lethal.[91] Both visual changes and
hepatotoxicity have been associated with high voriconazole blood levels.[9] Visual and,
rarely, auditory hallucinations can occur in less than 5% of patients[88] and should be
distinguished from visual changes. The patient is usually alert and has awareness of the
symptoms, which is rarely described as something unpleasant. Hallucinations are most
often reported with the intravenous formulation and tend to disappear with the oral
drug or with continued treatment. Confusion is less common. Skin rashes and cheilitis
can occur after prolonged treatment, mainly due to photosensitivity. Although most
commonly the rash is restricted to facial erythema in sun-exposed areas, more serious
eruptions can occur necessitating discontinuation of the drug.[92] Pseudoporphyria,
toxic epidermal necrolysis, and multifocal facial squamous cell carcinomas have also
been reported.[93-95] Use of sunscreen should be advised, and appropriate guidance for
sun exposure avoidance should be given in chronically treated patients. Q-Tc
prolongation and torsades de pointes should be a consideration in patients with
predisposing factors.[96] Finally, acutely painful extremities and peripheral neuropathy
have been described.[97] Voriconazole is teratogenic in animals and should not be used
during pregnancy (class D).
Posaconazole
The safety profile of posaconazole seems to be more favorable than that of
voriconazole. Common adverse events are headaches and gastrointestinal complaints,
such as nausea, diarrhea, and vomiting (3 to 12% each in several studies).[98-102]
Hepatotoxicity and liver enzyme abnormalities have been reported in less than 2 to 3%
of patients,[101,102] hypokalemia in 3%, and rash in 3%.[99] Q-Tc prolongation was
reported to be as high as 4% in one study.[99] Long-term posaconazole treatment
seems to be equally safe, with no increase or additional adverse events observed. [103]
The safety of posaconazole has not been evaluated in children under 13 years old.
Because skeletal malformations have been reported in posaconazole-treated rats, use
in pregnancy should be avoided (class C drug).
Antifungal Activity-Therapeutic Uses
Approved indications in the United States for the commercially available azoles and
respective doses are presented in Table 5 . An estimation of the relative daily oral cost
of triazole usage is given in Table 6 .
Fluconazole
Fluconazole is active against Candida spp. (except Candida glabrata and krusei),
Cryptococcus neoformans, Blastomyces dermatitidis, Coccidioides spp., Histoplasma
capsulatum, Sporothrix schenckii, and ringworm. It is first-choice treatment for certain
Candida and cryptococcal infections as well as nonmeningeal coccidioidal infections.
Fluconazole as a single dose of 150 mg is effective for the treatment of vaginal
candidiasis. Oropharyngeal and esophageal candidiasis can be treated with 100 to 200
mg daily for 14 to 21 days. A loading dose of 200 to 400 mg can be given the first day.
Fluconazole has an indication and has been shown to be as effective as amphotericin B
for the treatment of candidemia in nonneutropenic patients.[104] One post hoc analysis
indicated that more severely ill patients with candidemia benefited by starting with the
addition of amphotericin B to fluconazole.[105] Guidelines from the Swiss Consortium
do not recommend fluconazole for patients with septic shock due to candidemia.[106]
The emergence of fluconazole-resistant Candida species during prior fluconazole
exposure and the introduction of echinocandins in clinical practice make fluconazole a
less attractive choice. In two studies with patients undergoing bone marrow
transplantation, prophylactic use of fluconazole has been shown to reduce the
incidence of systemic and superficial fungal infections.[107,108] In one of these studies,
fluconazole prophylaxis reduced the need for amphotericin B empirical treatment, and
survival was increased. In these studies, a dose of 400 mg daily has been used,
although one study has concluded that 200 mg may be equally effective.[109] One study
has concluded that fluconazole prophylaxis decreases fungal colonization and invasive
fungal infection in preterm infants.[110] In a recent study, a dose of 6 mg or 3 mg
fluconazole per kg reduced the incidence of colonization and invasive Candida
infections in neonates weighing less than 1500 g at birth compared with placebo. [111]
Overall mortality was the same.
Fluconazole is also used for the treatment of cryptococcal meningitis in HIV- and nonHIV-infected patients. In HIV infection, 400 mg of fluconazole daily is given for 8 weeks
following a 2 week amphotericin B ± flucytosine combination therapy. Fluconazole is
then continued indefinitely at 200 mg daily, or as long as the CD4 count remains below
100/mm3.[112] In the non-HIV-infected and in alert and well-oriented HIV patients
fluconazole can be used as initial treatment.[113] Nonmeningeal cryptococcosis can be
treated with fluconazole in both HIV and non-HIV patients at a dose of 400 mg daily for
6 to 12 months.
Treatment of coccidioidomycosis with fluconazole is indicated for the meningeal form
due to adequate CSF penetration and limited toxicity compared with amphotericin B.
Therapy is lifelong at doses of at least 400 mg daily. Although fluconazole is also
effective for nonmeningeal forms of this disease, itraconazole is preferred due to
possible increased efficacy for skeletal infections.[114]
Itraconazole
Itraconazole is active in vitro and in vivo for Aspergillus fumigatus, Candida spp.,
Cryptococcus neoformans, Trichophyton spp., and the dimorphic fungi (Blastomyces
dermatitidis, Histoplasma capsulatum, Coccidioides spp., Paracoccidioides brasiliensis,
Penicillium marneffei, and Sporothrix schenckii).
Itraconazole is indicated for treatment of non-CNS-invasive aspergillosis[115] and
increases response rates when added to steroid-treated patients with allergic
bronchopulmonary aspergillosis.[116] Itraconazole capsules are the treatment of choice
for indolent cases of blastomycosis and histoplasmosis,[117] nonmeningeal forms of
coccidioidomycosis,[118] and paracoccidioidomycosis.[119] The capsule form is also useful
for the treatment of sporotrichosis and penicilliosis marneffei (although not an
approved indication) and the various dermatophytoses, including onychomycosis of
the toenail and fingernail ( Table 5 ). HIV patients with histoplasmosis and penicilliosis
should receive lifelong maintenance therapy. Itraconazole has no place in the therapy
of cryptococcosis, mainly due to poor CNS penetration and high incidence of relapse.
Intravenous itraconazole has been approved for use in persistently febrile neutropenic
patients when a fungal etiology is suspected. This was based on an open randomized,
controlled, multicenter trial in which intravenous itraconazole (followed by oral) was
compared with conventional amphotericin B and was found to have equivalent efficacy
in a relatively low-risk population and had less toxicity.[120]
The oral itraconazole solution is indicated for the therapy of oropharyngeal and
esophageal candidiasis. Finally, itraconazole suspension prevents invasive fungal
infections when used for prophylaxis in patients with hematological malignancies [121]
and can be a reasonable alternative to fluconazole in this setting.
Voriconazole
Voriconazole is active against most Candida and Aspergillus spp. Like itraconazole,
voriconazole has significant activity against Scedosporium apiospermum
(Pseudallescheria boydii) and is also active against fusariosis. Voriconazole is
reasonably active in vitro against the endemic fungi (Blastomyces dermatitidis,
Coccidioides spp., and Histoplasma capsulatum) as well as Cryptococcus neoformans,
Trichosporon spp., and Acremonium kilensii. Clinical data about efficacy for these
mycoses are insufficient.
Voriconazole has been approved for the treatment of invasive aspergillosis since 2002
and has subsequently replaced amphotericin B for this indication. This conclusion has
been based on a randomized, unblinded study of voriconazole versus amphotericin B
deoxycholate for initial therapy of invasive aspergillosis.[90] In this study, starting
treatment with voriconazole was more efficacious and safer than conventional
amphotericin B (52.8% vs 31.6% successful outcomes). In a secondary end point
analysis voriconazole offered better 12-week survival rates (70.8% vs 57.9%). In a
second key study, voriconazole was compared with liposomal amphotericin B in a
randomized multicenter trial as empirical antifungal treatment in febrile
neutropenia.[88] Voriconazole marginally failed to meet the predefined margin for
noninferiority and hence was not approved for this indication. However, voriconazole
was safer than amphotericin B and was associated with fewer fungal breakthrough
infections (1.9% vs 5%).
The efficacy of voriconazole for the treatment of esophageal candidiasis compared
with fluconazole was evaluated by a large, randomized, double-blind, multicenter trial
in immunocompromised patients.[89] In this study the use of voriconazole at a dose of
200 mg twice daily was as effective as fluconazole but was associated with more
adverse event-related discontinuation of treatment. This dose is also indicated for the
treatment of candidemia and other deep Candida infections in nonneutropenic
patients.[122]
Responses of 45.5% and 30% have been reported for fusariosis and scedosporiosis,
respectively,[123] with evidence of better results for Scedosporium apiospermum than S.
prolificans.[124] This led to approval of voriconazole treatment as salvage therapy for
these indications. Penicilliosis marneffei seems to respond as well.[123]
Voriconazole has an extended spectrum of activity when compared with other azoles
but no efficacy toward the agents of mucormycosis. This has led to a possible increase
in cases of zygomycosis in voriconazole-treated patients; this possibility should be
considered in cases of progressive fungal infections in patients undergoing
voriconazole treatment, especially those in high-risk populations.
Posaconazole
Posaconazole has potent in vitro activity against most Candida and Aspergillus species.
It is also active against Scedosporium spp., Fusarium spp., Histoplasma spp.,
Coccidioides spp., Penicillium marneffei, Sporothrix schenckii, Blastomyces dermatitidis,
Trichosporon spp., and Cryptococcus neoformans as well as several dematiaceous
molds. The most distinctive characteristic, though, when compared with other azoles,
is the improved activity posaconazole exhibits against the zygomycetes.
Posaconazole is approved for prophylaxis against fungal infections in severely
immunocompromised patients, such as hematopoietic stem cell transplant patients
(HSCT), who are at least 13 years of age, with graft versus host disease (GVHD) and
patients with hematologic malignancies and neutropenia due to chemotherapy. This
indication was based on two studies that compared posaconazole with fluconazole and
fluconazole or itraconazole, respectively. The first was a randomized, multicenter,
double-blind, and double-dummy study in HSCT patients with GVHD treated with
either 200 mg posaconazole three times daily or fluconazole 400 mg daily.[101] The
primary efficacy end point was the incidence of proven or probable fungal infections
during the interval between randomization and day 112 in the intention to treat
population. Posaconazole was as effective as fluconazole in prevention of invasive
fungal infections, but posaconazole was superior to fluconazole in prevention of
aspergillosis. The second study was a multicenter, randomized, unblinded study with
evaluators unaware of the treatment assignments in patients receiving chemotherapy
for acute myelogenous leukemia or myelodysplastic syndrome.[99] Patients received
200 mg posaconazole three times daily or either fluconazole suspension 400 mg daily
or itraconazole solution 200 mg twice daily. The therapy was administered for the
duration of neutropenia until occurrence of invasive fungal infection or for 12 weeks
after randomization, whichever came first. The primary end point was occurrence of
proven or probable fungal infection during prophylaxis in the intension-to-treat
population. The use of galactomannan to diagnose most of the aspergillosis
breakthrough cases remains a controversial feature of these two studies. With this
reservation, posaconazole was superior to the comparator for the prevention of
invasive fungal infections.
Posaconazole is also approved for the treatment of patients with oropharyngeal
candidiasis, including those refractory to fluconazole and itraconazole. The dose for
this indication is 100 mg daily or up to 400 mg twice daily for refractory to other
treatment patients. In the respective studies, posaconazole was as effective as
fluconazole[100] in treatment-naive patients or exhibited a satisfactory response in
refractory patients.[98]
Finally, despite the fact that posaconazole has not received an indication for salvage
therapy of refractory fungal infections, several uncontrolled case studies
demonstrated a promising response rate in this setting for zygomycosis,
histoplasmosis, fusariosis, coccidioidomycosis, or patients with chronic granulomatous
disease.[102,125-130]
Table 1. Triazole Formulations
Triazole
Oral
Intravenous
Fluconazole
50,100,150, and 200 mg tabs, oral suspension
Yes
Itraconazole
100 mg caps, oral solution*
Yes†
Voriconazole 50 and 200 mg tabs, oral suspension
Yes
Posaconazole Oral suspension
No
*Caps
and oral solution are not bioequivalent and should not be used interchangeably.
form recently withdrawn from US market.
†Intravenous
Table 2. Drugs With Increased Concentration When Coadministered With
Azole
Drug
Fluconazole Voriconazole Itraconazole Posaconazole
+[20]
+
Alprazolama
+
+
Astemizole
X
+[21]
Alfentanil
+[19]
Buspirone
+
+
+[22]
Busulphan
-[23]
+
+[23]
Caffeine
Carbamazepine
Cisapride
Cyclophosphamide
Cyclosporine
+
+[24]
X
+
X
-[25]
+[26,27]
Digoxin
X
+[28,29]
+[28,30]
-[32]
+[30,33]
+
Dofetilide
+
Efavirenz
X
+
+
Eplerenone
+
+
X
X
Erlotinib
+
Eszopiclone
+
+
+
Gefitinib
+[36]
+[37]
+[38]
+[38]
+[39]
Imatinib
Irinotecan
Losartan
(+)
+
Haloperidol
Ibuprofen
+[34]
(X)
+[35]
Fexofenadine
Glimepiridec]
+[31]
+
Eletriptan
Ergot alkaloids
(X)
+[25]
Docetaxel
Felodipineb]
(+)
+
+[40]
-[40]
Lovastatind
+
+
X[41]
Methadone
+[42]
+[43]
+
(+)
Methylprednisolonee
+
+
+[44]
Midazolama
+[45]
+[46]
X[45]
Nevirapine
+
-[47]
+[48]
Omeprazole
+[49]
Paroxetine
Phenytoin
+[50]
Pimozide
Quinidine
+
Ramelteon
+
+[51]
-[52]
+[53]
X
X
(X)
X
X[54]
(X)
+
Ranolazine
Rifabutin
+
+[55]
X
Risperidonef
Saquinavirg
+
+[58]
+
X
+
Solifenacin
+
Sunitinib
+
+[26]
Terfenadine
Triazolama
+[56]
+[57]
Sirolimus
Tacrolimus
+
+[62]
+[59]
+
+[60]
X
+[61]
(+)
+
X[63]
+
+
(+)
+[65]
Valdenafilh
Vincristinei
+
+[64]
Vinorelbine
+
+[66]
+[68]
+[69]
+[72]
+[71]
Warfarinj
+[67]
Zidovudine
+[70]
Zolpidem
+[71]
(+)
+ = interaction; X = contraindication; - = absence of interaction.
aIncludes most benzodiazepines except: bromazepam, diazepam, temazepam, and
estazolam.
bIncludes most Ca channel inhibitors.
cIncludes glyburide and tolbutamide.
dIncludes simvastatin and atorvastatin but not pravastatin, fluvastatin, and
rosuvastatin.
eIncludes betamethasone, dexamethasone, hydrocortisone, fludrocortisone,
budesonide, and fluticasone, but not prednisolone.
fIncludes ziprasidone.
gPossibly includes all protease inhibitors. Fluconazole does not affect indinavir and
ritonavir.
hIncludes tadalafil, sildenafil.
iIncludes vinblastin.
jIncludes acenocoumarol.
Table 3. Drugs That Decrease Azole Concentration When Coadministered
Drug
Fluconazole Voriconazole Itraconazole Posaconazole
+
-[73]
+
+
Cimetidine
+
+
Didanoside
+[74]
Antacids
-
Carbamazepine
+
X
Efavirenz
X
+
Grapefruit juice
-
-
+[75]
H2 inhibitors
-
-[76]
+[77]
Nevirapine
+
+[47]
Phenobarbital
X
+
-[50]
+[51]
+[52]
+[53]
-
-[48]
+[78]
-
+[79]
X
+
+[56]
Rifabutin
X
+
+
Ritonavir
X
Phenytoin
Proton pump inhibitor
Rifampin
St. John's wort
Sucralfate
+[80]
+
-
+
-
+ = interaction; X = contraindication; - = absence of interaction.
Table 4. Inhibition of CYP450 Enzymes by Triazoles
Triazole
CYP3A4 CYP2C9 CYP2C19
Fluconazole
Moderate
Strong
Moderate
Itraconazole
Strong
-
-
Voriconazole Moderate Moderate
Weak
Posaconazole Moderate
-
-
- = no inhibition.
Table 5. Approved Indications and Doses for Triazoles in the United States
Triazole
Fluconazole
Indication
Dose
Vaginal candidiasis
150 mg one time dose
Oropharyngeal and esophageal
candidiasis
200 mg the first day, then 100 mg
daily
Invasive candidiasis, including
candidemia in nonneutropenic
patients
400 mg IV q24h then 400 mg PO
daily
Urinary Candida infections
50-200 mg daily
Cryptococcosis
400 mg daily
Prophylaxis of HSCT patients treated 400 mg daily
with cytotoxic chemotherapy and/or
radiation
Itraconazole
Aspergillosis
200 mg twice daily for 2 days
followed by 200 mg IV daily for
2 wks then 400 mg PO daily
Blastomycosis
Histoplasmosis
Empirical therapy in febrile
neutropenia
Oropharyngeal candidiasis
200 mg daily (solution)
Esophageal candidiasis
100-200 mg daily (solution)
Onychomycosis (fingernail)
200 mg twice daily for 1 week;
two courses 1 month apart
(capsule)
Onychomycosis (toenail)
200 mg once daily for 12 weeks
(capsule)
Voriconazole Invasive aspergillosis
Scedosporiosis
6 mg/kg twice daily for 1 day,
followed by 4 mg/kg twice daily
(intravenous), then 200 mg twice
daily (oral)
Fusariosis
Candidemia or deep Candida
infections in nonneutropenic patients
Esophageal candidiasis
200 mg twice daily
Posaconazole Prophylaxis against invasive
aspergillosis or candidiasis in
severely immunocompromised
patients
200 mg three times daily
Oropharyngeal candidiasis
100 mg twice daily (first day
loading dose), then 100 mg daily
Treatment failure or oropharyngeal
candidiasis refractory to fluconazole
or itraconazole
400 mg twice daily
HSCT = hematopoietic stem cell transplantation.
Table 6. Daily Cost of Oral Azole Treatment*,†
Triazole
Daily Dose
Cost
Fluconazole
200 mg
$17 ($2 generic)
Itraconazole
200 mg (solution)
$21
Voriconazole
400 mg
$78
Posaconazole
800 mg
$110
*2007
†At
Red Book (average wholesale price).
doses recommended for treatment of esophageal candidiasis.
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Funding Information
This work has been funded by the Intramural Research Program of NIAID.
Reprint Address
John E Bennett, MD, 9000 Rockville Pike, Bldg. 10/11N234, Bethesda, MD 20892. Email: jbennett@niaid.nih.gov
Dimitrios I. Zonios, John E. Bennett, Clinical Mycology Section, Laboratory of Clinical
Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID),
National Institutes of Health, Bethesda, Maryland