Current Drug Metabolism, 2009, 10, 395-409 395

Drug-Drug Interactions of Triazole Antifungal Agents in Multimorbid Patients and

Implications for Patient Care

Yasmine Nivoix1,2,*, Geneviève Ubeaud-Sequier1,2, Pauline Engel2, Dominique Levêque1 and

Raoul Herbrecht3

1
Pôle Pharmacie-Pharmacologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France ; 2Laboratoire Innovation Thérapeuti-
que, Université de Strasbourg, Strasbourg, France ; 3Service d’Hématologie et d’Oncologie, Hôpitaux Universitaires de Strasbourg,
Strasbourg, France

Abstract: Drug interactions occur frequently with triazole antifungal agents because of their properties as inhibitors of 1 or more phase 1
(cytochrome P450) biotransformation enzymes and, possibly, as inhibitors or substrates of a phase 2 biotransformation enzyme or trans-
porter protein. Multimorbid patients, including those with hematologic malignancies or other cancers, hematopoietic stem cell or organ
transplant recipients, patients infected with the human immunodeficiency virus, and those in the intensive care unit, are at increased risk
for drug interactions because they typically require several concomitant medications. They may also be extremely vulnerable to the clini-
cal signs and symptoms of drug interactions. This review describes clinically significant drug interactions most frequently seen in multi-
morbid patients who receive systemic therapy with triazole antifungals for the prophylaxis or treatment of invasive fungal infections; in-
cluding interactions with corticosteroids, immunosuppressants, anti-infective drugs, benzodiazepines, opioid analgesics, statins, antico-
agulants, anticonvulsants, and drugs affecting gastric pH. The review also describes recommendations concerning contraindications and
dose-modification strategies. The azoles differ markedly in their pharmacokinetic and antifungal properties, safety and tolerability, and
drug-interaction profiles. Many drug interactions can be prevented if clinicians are thoroughly familiar with the pharmacokinetic profiles
of different azoles, follow contraindications and dose-modification recommendations, and switch azoles when possible to achieve the
best combination of clinical efficacy and safety. Therapeutic drug monitoring can help optimize treatment and prevent underdosing or
overdosing of drugs. Education of patients and their families about signs and symptoms of possible drug interactions is also beneficial.
Keywords: Drug interactions, fluconazole, itraconazole, posaconazole, voriconazole.

INTRODUCTION FACTORS AFFECTING TRIAZOLE ABSORPTION: GAS-

Drug-drug interactions occur frequently with the systemic tria-
zole antifungal drugs fluconazole, itraconazole, voriconazole, and
posaconazole. All four antifungals agents are the most commonly
used in a clinical setting for prophylaxis or treatment of systemic
fungal infections. Each of these agents is an inhibitor of 1 or more
phase 1 (cytochrome P450 [CYP]) biotransformation enzymes and
may also be an inhibitor or a substrate of a phase 2 biotransforma-
tion enzyme or transporter protein. Although drug interactions pose
a potential problem in the management of many patients treated
with systemic azoles, they are particularly challenging in multimor-
bid patients, including those with hematologic malignancies or
other cancers, hematopoietic stem cell or organ transplant recipi-
ents, patients infected with human immunodeficiency virus (HIV),
patients cared for in the intensive care unit (ICU), and those man-
aged by internists for complex medical conditions. In addition to
being at increased risk for drug interactions because they typically
require several concomitant medications, multimorbid patients may
be extremely vulnerable to the clinical signs and symptoms of drug
interactions. Further, it may be difficult to differentiate the manifes-
tation of a drug interaction from that of the patient’s underlying
disorders.
This review describes the clinically significant drug interactions
most frequently seen in multimorbid patients who receive systemic
therapy with triazole antifungals for the prophylaxis or treatment of
invasive fungal infections (IFIs). It summarizes recommendations
for avoiding or minimizing the risk for drug interactions with each
azole and differentiates the systemic azoles in terms of their risk
and tolerability profiles. Finally, it presents general strategies for
the prevention and management of azole-related drug interactions
and discusses the role of therapeutic drug monitoring in multimor-
bid patients receiving triazole therapy.
*Address correspondence to this author at the Pôle Pharmacie-
Pharmacologie, Hôpital de Hautepierre, 67098 Strasbourg, France; Tel: +33
388 12 78 03; Fax: +33 388 12 78 10;
E-mail: yasmine.nivoix@chru-strasbourg.fr
TRIC PH AND FOOD
Gastric pH has emerged as a factor that influences triazole ab-
sorption to varying degrees, depending on the agent; hence, it also
affects triazole levels and drug-drug interactions. For fluconazole
and voriconazole, the effect of gastric acidity on absorption is mod-
est and not clinically relevant [1-3] . For itraconazole, gastric pH
does not affect absorption of the oral solution [4], but it does influ-
ence that of the capsule formulation. In healthy volunteers, coad-
ministration of a 100-mg itraconazole capsule with cola (which
lowers gastric pH) was shown to increase itraconazole Cmax and
AUC values by 121% and 80%, respectively [5]. Conversely, ad-
ministration of itraconazole capsules under conditions of elevated
gastric pH decreased itraconazole Cmax and AUC values both by
about 50% [6]. An acidic carbonated beverage administered with
posaconazole has also been shown to increase posaconazole Cmax
and AUC compared with placebo by 92% and 70%, respectively, in
healthy volunteers, whereas higher gastric pH induced through
proton pump inhibitor administration decreased posaconazole Cmax
and AUC by 46% and 32%, respectively [7].
Food also affects the absorption of azoles to varying degrees.
Fluconazole absorption is not dependent on the presence of food
[8]. Coadministration with food increases absorption of itracona-
zole capsules [9] but decreases absorption of itraconazole oral solu-
tion [10]. Fatty food significantly decreases the bioavailability of
voriconazole [3]. In contrast, systemic exposure to posaconazole
increases 3.9-fold and 2.7-fold when this drug is administered with
a high-fat and a nonfat meal, respectively, relative to the fasted state
[11].
TRIAZOLE INTERACTIONS WITH PHASE 1 AND 2
BIOTRANSFORMATION ENZYMES AND TRANSPORTER
PROTEINS
The interactions of the various triazole antifungals with phase 1
(CYP) and 2 (e.g. UDP-glucuronosyltransferase [UGT]) biotrans-
formation enzymes and transporter proteins (e.g. P-glycoprotein [P-
gp] and the human breast cancer resistance protein [BCRP]) are

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396 Current Drug Metabolism, 2009, Vol. 10, No. 4
Table 1. Interactions of Antifungal Azoles with the Major Phase 1 and 2 Biotransformation Enzymes and Transporter Proteins: Azoles Function-
ing as Inhibitors and Substrates
Antifungal Drugs and CYP450 Activity or Phase 2 Enzymes
CYP2C9 CYP2C19
Inhibitor Substrate Inhibitor Substrate Inhibitor
Fluconazole Yes No Yes No Yes
[12-15,20]
Itraconazole Yes No Yes No Yes
[13-16,20]
Voriconazole Yes Yes Yes Yes Yes
[13,14,17,18,20]
Posaconazole No No No No Yes
[14,19,20]
BCRP = breast cancer resistance protein ; CYP = cytochrome P; P-gp = P-glycoprotein ; UGT = uridine diphosphate glucuronosyltransferase.
markedly different. Table 1 summarizes the majority of these dif-
ferences [12-20].
Drug-oxidizing CYP enzymes are localized mainly in the liver,
although they can also be found in the lung and small intestine [21].
In general, CYP inhibition results in reduced drug metabolism fol-
lowed by increased drug levels in the plasma; similarly, induction
of a CYP enzyme may result in low plasma concentrations and lack
of therapeutic effectiveness [21]. A drug with a high affinity for a
CYP isoform is likely to reduce the clearance of any coadminis-
tered low affinity drugs (e.g. terfenadine, cyclosporine) metabolized
by that isoform [22]. It has been estimated that
90% of drug oxida-
tion can be attributed to 6 enzymes: CYP1A2, 2C9/10, 2C19, 2D6,
2E1, and 3A4 [21].
P-glycoprotein is localized on the canalicular surface of hepato-
cytes, and on the apical surface of renal tubular epithelial cells and
intestinal interstitial cells; from these locations, the P-gp transporter
can enhance drug elimination out of cells [23]. Inhibition of P-gp
results in increased systemic exposure and tissue distribution of
drugs that are P-gp substrates, whereas P-gp induction leads to a
decrease in systemic exposure [23]. Similarly inhibition of another
transporter protein, BRCP, which belongs to subfamily G of the
large ATP-binding cassette (ABC) transporter superfamily, would
also result in increased systemic exposure of BRCP substrate drugs
[13]. Fig. (1) shows a schematic diagram of possible sites for drug
interactions with CYP enzymes, the phase 2 biotransformation en-
zyme UGT, and transporter proteins in the liver and small intestine.
Fluconazole undergoes minimal CYP-mediated metabolism
[24]; it exerts noncompetitive or mixed-type CYP inhibition of
CYP2C9, CYP3A4, and CYP2C19 [20]. Fluconazole also interacts
with phase 2 enzyme involved in glucuronidation [24] and is a P-gp
substrate [12].
Itraconazole is a potent inhibitor of CYP3A4 [14,25], and sev-
eral itraconazole metabolites are also CYP3A4 inhibitors [26,27].
Itraconazole is also a CYP3A4 substrate; therefore, CYP3A4 in-
ducers may augment its metabolism. This can lead to undetectable
or subtherapeutic serum concentrations and compromise the treat-
ment of patients with fungal infections.
Itraconazole is both a P-gp substrate and inhibitor [12]; there-
fore, interactions between itraconazole and another CYP3A4 sub-
strate can result from the inhibition of CYP-mediated metabolism,
reduced P-gp–mediated efflux, or a combination of the two.
Voriconazole undergoes extensive hepatic metabolism by
CYP2C19, CYP3A4, and CYP2C9 [17]. Voriconazole and perhaps
some of its metabolites are inhibitors of CYP2C9, CYP2C19 and,
to a lesser extent, CYP3A4 [14].
An interaction between voriconazole and P-gp has not been
described, and it is probable that voriconazole is neither a P-gp
Nivoix et al.
Transporter Protein Activity
CYP3A4 UGT P-gp BCRP
Substrate Inhibitor Substrate Inhibitor Substrate Inhibitor
No Yes No No Yes No
Yes No No Yes Yes Yes
Yes No No Unlikely Unlikely No
No No Yes Yes Yes No data
inhibitor nor substrate. This is supported by evidence in healthy
volunteers that concomitant administration of voriconazole with
digoxin (which is mainly eliminated by renal tubular clearance,
normally mediated by P-gp) did not significantly alter digoxin
pharmacokinetics [28].
Unlike other azoles, posaconazole is not primarily metabolized
by CYP enzymes [14,19,20]; it is mainly metabolized in the liver,
where it undergoes glucuronidation [29]. The limited metabolism of
posaconazole is mediated predominantly through phase 2 biotrans-
formation via UGT enzyme pathways [29]. Like other azoles, posa-
conazole has an inhibitory effect on hepatic CYP3A4 [19].
It is also probable that posaconazole is both a P-gp substrate
and inhibitor [20]. Posaconazole effluxes directly from the systemic
circulation into the gut lumen; multiple peaks in the concentration
plasma-time profile have been observed in some clinical studies,
indicating that the drug effluxed by the MDR1 transporter is reab-
sorbed into the systemic circulation, resulting in greater systemic
bioavailability [30].
Limited data are available on the interactions of the triazole
antifungals with BCRP. Itraconazole is a BCRP inhibitor, but flu-
conazole and voriconazole are not [13]. No published data have
characterized an interaction between posaconazole and BCRP.
SPECIFIC DRUG INTERACTIONS
Allogeneic hematopoietic stem cell transplantation (HSCT)
recipients or immunocompromised patients with acute leukemia or
HIV infection are particularly at risk for developing an IFI [31] and
are often administered triazole antifungals as treatment or prophy-
lactically. The risk of developing an IFI depends on microbial ex-
posure (colonization and history of fungal infection), the patient’s
state of immunocompromise and the extent of organ damage (e.g.
from mucositis or severe GVHD) [31]. Other risk factors include
prolonged or severe neutropenia, older age (>40 years), myeloabla-
tive chemotherapy, low CD34+ stem cell dose (2 106/kg), and
exposure to other pathogens such as cytomegalovirus, corticoster-
oid use, and T-cell suppressors [31-33].
Patients with Cancer or Hematological Malignancies
Many of the clinically significant drug interactions observed in
patients receiving chemotherapy for cancer have been reported in
patients treated with itraconazole. Caution is recommended when
itraconazole is administered with cyclophosphamide [34] or busul-
fan-based conditioning regimens [35]. Itraconazole increases expo-
sure to the active metabolite of cyclophosphamide, 4-hydroxycyclo-
phosphamide, by inhibiting CYP450 detoxification. Fluconazole,
however, demonstrated a protective effect through inhibition of
metabolite formation [34]. Busulfan is mainly metabolized in the
liver by CYP enzymes [35]. Cmax and AUC values of busulfan were
Drug-Drug Interactions of Triazole Antifungal Agents in Multimorbid Patients
increased in patients receiving itraconazole but not in those receiv-
ing fluconazole [35]. Coadministration of vincristine and itracona-
zole should be avoided because of an increased risk of vincristine-
induced toxicity probably due to inhibition of CYP enzymes [36].
Vinca alkaloids are CYP3A4 substrates [3]; therefore, the dose of a
vinca alkaloid coadministered with voriconazole [3] or posacona-
zole [37] should be decreased to prevent neurotoxicity associated
with high vinca alkaloid plasma concentrations.
Hematopoietic Stem Cell or Organ Transplant Recipients
Corticosteroids
Careful monitoring is recommended when itraconazole is co-
administered with glucocorticosteroids. Itraconazole capsules
markedly increase exposure to oral and intravenous (IV) dex-
amethasone, inhaled budesonide, and methylprednisolone [9]. In a
randomized study in healthy volunteers, itraconazole decreased
systemic clearance of methylprednisolone by 60% and increased
both exposure and half-life (t1/2) by over 2-fold, leading to in-
creased adrenal suppression [38]. Another study showed, however,
that itraconazole did not change the pharmacokinetics of predniso-
lone [39]. Therefore, prednisolone, rather than methylprednisolone,
should be used in combination with itraconazole. If methylpredni-
solone is given with itraconazole, a dose reduction of the corticos-
teroid should be considered [39].
Immunosuppressants
The most clinically significant azole-related drug interactions in
HSCT recipients or solid organ transplant recipients occur with
concomitantly administered immunosuppressive drugs. Triazole
antifungals inhibit the metabolism of cyclosporine, tacrolimus, and
sirolimus, which are significantly metabolized by CYP3A4 and also
are metabolized by and inhibit P-gp [3,37,40]. Inhibition of
CYP3A4 and P-gp metabolism leads to increased plasma concen-
trations of the immunosuppressants and an increased potential for
adverse events (AEs) caused by excessive immunosuppression and
toxicity [3,37,40]. The interaction between azoles and immunosup-
pressive therapy is not a class effect, however, because the magni-
tude of the interaction depends on the combination of drugs admin-
istered and patient factors.
Interactions with Fluconazole
The interaction between fluconazole and cyclosporine usually
occurs at a fluconazole dose of at least 200 mg/day [20] but has also
been reported at 100 mg/day [41]. Cyclosporine concentrations
have been observed to increase 2- to 3-fold after 1 week of flucona-
zole treatment [41,42] and to peak on day 4 [43].
In renal transplant recipients receiving fluconazole 100 mg/day,
the mean tacrolimus dose was decreased by 40% to maintain tac-
rolimus mean trough and AUC values at levels similar to those
achieved before fluconazole administration [44]. In solid organ
transplant recipients receiving concomitant fluconazole 100 to 200
mg/day and tacrolimus, a median reduction of 56% in the tac-
rolimus dose was needed to maintain tacrolimus levels below the
upper limit of normal target dose range [45]. Similarly, in a retro-
spective analysis of pediatric solid organ transplant recipients, ad-
ministration of either fluconazole or itraconazole necessitated a
mean tacrolimus dose reduction of 68% 1 month after triazole ini-
tiation [46]. In studies of fluconazole discontinuation in liver trans-
plant recipients, the median tacrolimus level was 40.7% compared
with levels achieved during coadministration [47]. However, in
allogeneic bone marrow transplant recipients, when fluconazole and
either cyclosporine or tacrolimus were administered IV, no clini-
cally significant increases in cyclosporine or tacrolimus levels were
observed at a fluconazole dose of 400 mg/day [48]. Oral flucona-
zole 200 mg/day increased sirolimus trough levels in renal trans-
plant recipients by 3-fold on day 7 [49] and 4.7-fold on day 22 of
fluconazole treatment [50].
Current Drug Metabolism, 2009, Vol. 10, No. 4 397
Interactions with Itraconazole
In vitro studies have shown that itraconazole inhibits cy-
closporine metabolism at least 50 times more potently than flucona-
zole [51], and case studies have documented this interaction [52]. In
renal transplant recipients, concomitant administration of itracona-
zole solution 200 mg twice daily necessitated a 48% reduction in
the mean total daily dose of cyclosporine [53]. A study in lung
transplant recipients showed that coadministration of itraconazole
and cyclosporine resulted in a significant flattening of the cy-
closporine curve and a significantly greater Tmax value [54].
Case reports demonstrate an interaction between itraconazole
and tacrolimus and have documented increased tacrolimus concen-
trations of 1.7- to 6.7-fold [55-58]. In heart and lung transplant
recipients, an average tacrolimus dose reduction of 63% was re-
quired to keep tacrolimus levels within the therapeutic range fol-
lowing initiation of oral itraconazole [59]. Coadministration of
itraconazole prophylaxis at a dose of 100 mg twice daily necessi-
tated a 49% reduction in the cyclosporine dose and a 66% reduction
in the tacrolimus dose in heart and heart-lung transplant patients
[60]. After the discontinuation of prophylaxis with itraconazole 200
mg twice daily, 1 study showed that the mean total daily dose of
tacrolimus needed to be increased by 76% in lung transplant recipi-
ents [61].
Interactions with Voriconazole
In a placebo-controlled study in kidney transplant recipients, a
1.7-fold increase in the cyclosporine AUC was seen during con-
comitant voriconazole administration [62]. An interaction between
voriconazole and cyclosporine has also been reported in an HSCT
recipient [63].
The interaction between voriconazole and tacrolimus has been
documented in several case reports [64-66]. In 1 case, a liver trans-
plant recipient experienced almost a 10-fold increase in tacrolimus
concentration during voriconazole coadministration [67]. When
voriconazole is discontinued, tacrolimus levels should also be care-
fully monitored [3].
In 3 solid organ transplant recipients, administration of vori-
conazole resulted in a 9.6-fold mean increase in the blood sirolimus
concentration [50]. Concomitant administration of voriconazole and
sirolimus is contraindicated [3]. Despite this contraindication, clini-
cians have used voriconazole successfully with sirolimus by reduc-
ing the sirolimus dose by 75% to 90% [66,68].
Interactions with Posaconazole
Posaconazole 200 mg once daily increased cyclosporine expo-
sure, necessitating a 14% to 29% cyclosporine dose reduction in 3
of 4 heart transplant recipients [69]. Administration of posacona-
zole 400 mg twice daily for 8 days significantly increased exposure
to a single dose of tacrolimus, with increases from baseline of
121% for Cmax and 358% for AUC [69]. Concomitant administra-
tion of posaconazole and sirolimus to healthy volunteers resulted in
a 6.7-fold increase in the Cmax and an 8.9-fold increase in the AUC
[70].
Guidelines for the Concomitant Use of Triazole Antifungals and
Immunosuppressants
Based on the data, a number of actions should be implemented
when considering the concomitant use of triazole antifungals and
immunosuppressants. First, decreasing the dose of the immunosup-
pressant upon initiation of the triazole may prevent AEs associated
with high immunosuppressant levels (Table 2) [3,9,37,71]. The
patient should be closely monitored, and therapy should be indi-
vidualized based on target immunosuppressant levels and the inci-
dence of AEs. Importantly, if the decision is made to use a triazole
and immunosuppressant concomitantly, at least 7 to 10 days are
required for immunosuppressant levels to return to baseline follow-
ing triazole discontinuation [20]. In addition, the dose of the immu-
398 Current Drug Metabolism, 2009, Vol. 10, No. 4 Nivoix et al.

Table 2. Recommendations for Dose Reductions of Immunosuppressants During Concomitant Administration of Triazole Antifungals

Recommended Dose Reduction or Guidelines for Concomitant Use of Immunosuppressant and Triazole Drugs
Antifungal Drug
Cyclosporine Tacrolimus Sirolimus
a b
Fluconazole [71] None recommended None recommended None recommendeda
Itraconazole [9] None recommendedc None recommendedc None recommendedc
d d
Voriconazole [3] 50% reduction 67% reduction Contraindicated
Posaconazole [37] 25% reductiond 67% reductiond Contraindicated
a
Careful monitoring of immunosuppressant recommended.
b
Reports of nephrotoxicity; careful monitoring required.
c
Concomitant administration with itraconazole has lead to increased plasma concentrations of immunosuppressant.
d
Reduction of immunosuppressant dose.

Table 3. Interactions Between Drugs Used to Treat HIV Infection and Concomitant Systemic Triazole Therapy

PIs NRTIs NNRTIs

Fluconazole Fluconazole increased exposure to saquinavir: Fluconazole increased exposure to zidovudine in

Cmax  56%, AUC  50% HIV-positive patients: Cmax  84%, AUC  74%,
No dose adjustement necessary t
 128%
Monitor carefully [72]
[73]
Itraconazole May increase plasma concentrations of PIs (such Nevirapine reduced exposure to itraconazole: Cmax
as indinavir, ritonavir and saquinavir)  38%, AUC  61%, t
 31% [74]
Caution [9] Coadministration not recommended [9]
Efavirenz reduced exposure to itraconazole in an
AIDS patient [75]
Voriconazole Voriconazole increased exposure to efavirenz:
Cmax  37%, AUC  43%
Efavirenz decreased exposure to voriconazole:
Cmax  66%, AUC  80% [76]
Contraindicated [3]
Increased exposure to voriconazole with de-
lavirdine [3]
Monitor carefully for drug toxicity on all NNRTIs
[3]
Posaconazole Efavirenz decreased exposure to posaconazole:
Cmax  45%, AUC  50% [79]
Avoid [37]a

Results shown are in healthy volunteers unless otherwise stated.

AEs = adverse events; AIDS = acquired immunodeficiency syndrome; AUC = area under the concentration-time curve; bid = twice daily; Cmax = maximum plasma concentration;
HIV = human immunodeficiency virus; NNRTI = nonnucleoside reverse-transcriptase inhibitors; NRTIs = nucleoside reverse-transcriptase inhibitors; PI = protease inhibitor; t
=
half-life.
a
Unless the benefits outweigh the risk.

nosuppressant should be increased to avoid the risk of subtherapeu-
tic levels and possibly transplant rejection or GVHD development.
Patients with HIV Infection
The azoles have different profiles in terms of their interactions
with nucleoside reverse-transcriptase inhibitors (NRTIs), nonnu-
cleoside reverse-transcriptase inhibitors (NNRTIs), and protease
inhibitors (PIs). NNRTIs are CYP3A4 substrates, inhibitors, or
CYP450 inducers; and PIs are CYP3A4 substrates and inhibitors.
Table 3 summarizes the azoles’ interactions with these drug classes
[3,9,37,72-79].
Interactions with Fluconazole
Fluconazole, an inhibitor of UDP-glucuronosyltransferase,
inhibits the metabolism of zidovudine to zidovudine 5’-O-
glucuronide (GZDV), an inactive glucuronide [80-83]. When vol-
unteers infected with HIV received zidovudine 200 mg 3 times
daily with fluconazole 400 mg/day for 7 days, fluconazole de-
creased the apparent oral serum clearance of zidovudine by 43%
and the apparent oral formation clearance to GZDV by 48%, result-
ing in increases in the AUC (74%), Cmax (84%), and t1/2 (128%) of
zidovudine [72]. Similar effects have been observed in another
study in HIV-positive patients [84]. Patients receiving concomitant
therapy with fluconazole and zidovudine should be monitored
closely to avoid the development of zidovudine toxicity [72]. Al-
though coadministration of fluconazole and the PI saquinavir in-
creases the AUC and C max of saquinavir by 50% and 56%, respec-
tively, dose adjustments are probably not necessary because of the
favorable safety profile of saquinavir [73].
Interactions with Itraconazole
Coadministration of the NNRTI nevirapine (a CYP3A4 in-
ducer) 200 mg/day and itraconazole 200 mg/day to healthy volun-
teers for 7 days resulted in reductions in mean C max, AUC, and t1/2
of itraconazole by 38%, 61%, and 31%, respectively [74]. Because
of the strong inducing effect, concomitant administration of itra-
conazole and nevirapine is not recommended [9]. A patient with
acquired immunodeficiency syndrome (AIDS) and disseminated
histoplasmosis whose antiretroviral regimen included the NNRTI
efavirenz had undetectable itraconazole plasma concentrations
(<0.05 μg/mL) during treatment with itraconazole capsules at 200
mg/day and 200 mg twice daily and with oral itraconazole solution
at an unspecified dose. When efavirenz was discontinued and the
Drug-Drug Interactions of Triazole Antifungal Agents in Multimorbid Patients
patient was switched to a PI-based regimen of atazanavir and rito-
navir, the plasma itraconazole concentration increased to 3 μg/mL
and the Histoplasma antigen level decreased substantially [75].
Concomitant administration of itraconazole and PIs metabo-
lized by CYP3A4, such as indinavir, ritonavir, and saquinavir, may
increase PI plasma concentrations [9]; whereas concomitant ad-
ministration of itraconazole and indinavir, ritonavir [9], or the lopi-
navir/ritonavir coformulation may increase itraconazole plasma
concentrations [85]. Caution is advised when itraconazole and PIs
are given concomitantly [9].
Interactions with Voriconazole
Clinically significant drug interactions occur when voriconazole
is administered with efavirenz and ritonavir, and the potential for
drug interactions exists during coadministration with other NNRTIs
and other PIs (except indinavir) [3,86].
In healthy volunteers, oral efavirenz 400 mg/day decreased the
mean C max and AUC of oral voriconazole (400 mg twice daily for 1
day; 200 mg twice daily for 8 days) by 66% and 80%, respectively,
whereas voriconazole increased the mean Cmax and AUC of
efavirenz by 37% and 43%, respectively [76]. Coadministration of
standard doses of voriconazole with efavirenz is contraindicated
[3]. Because in vitro studies have shown that voriconazole metabo-
lism may be inhibited by delavirdine and in view of human studies
documenting a 2-way drug interaction between voriconazole and
efavirenz, patients should be frequently monitored for drug toxicity
during coadministration of voriconazole and other NNRTIs (e.g.
delavirdine, nevirapine) [3].
In healthy volunteers, high-dose oral ritonavir (400 mg twice
daily for 9 days) decreased the Cmax and AUC of oral voriconazole
(400 mg twice daily for 1 day; 200 mg twice daily for 8 days) by an
average of 66% and 82%, respectively [77]. Low-dose ritonavir
(100 mg bid for 9 days) decreased the Cmax and AUC of the same
dose of voriconazole by an average of 24% and 39%, respectively
[77]. Repeat oral administration of voriconazole to healthy volun-
teers did not have a significant effect on Cmax and AUC of high-
dose ritonavir, but Cmax and AUC of low-dose ritonavir decreased
by 24% and 14%, respectively [77]. Coadministration of voricona-
zole and high-dose ritonavir (400 mg twice daily) is contraindi-
cated, and coadministration of voriconazole and low-dose ritonavir
(100 mg twice daily) should be avoided unless an assessment of the
benefits and risks to the patient justifies its use [3]. In view of re-
sults of in vitro studies suggesting that voriconazole may inhibit
metabolism of PIs (e.g. saquinavir, amprenavir, nelfinavir) and that
PIs (e.g. saquinavir, amprenavir) may inhibit voriconazole metabo-
lism), patients should be monitored frequently for drug toxicity
during the coadministration of voriconazole and PIs other than rito-
navir [3].
Interactions with Posaconazole
Studies have identified no drug interactions between posacona-
zole and NRTIs (zidovudine, lamivudine) or the PI indinavir [37].
Coadministration of posaconazole (400 mg twice daily, days 8 to
14) with the PI atazanavir (300 mg once daily, days 1 to 14) re-
sulted in greater atazanavir exposure than when atazanavir was
administered alone [78]. Posaconazole exposure was similar when
administered with either atazanavir or atazanavir/ritonavir [78].
Clinically significant increase in bilirubin, a common AE associated
with atazanavir, was observed in the majority of subjects [78];
therefore, monitoring for atazanavir-related AEs may be warranted
during posaconazole administration [37]. Coadministration of posa-
conazole and ritonavir resulted in an increase in ritonavir Cmax and
AUC of 49% and 80%, respectively [37]. Additional clinical studies
have demonstrated that no clinically significant effects of posa-
conazole 200 mg once daily on ritonavir; therefore, no dosage ad-
justments are required, although frequent monitoring of AEs and
toxicity is recommended [37].
Current Drug Metabolism, 2009, Vol. 10, No. 4 399
In contrast, 10 days of posaconazole 400 mg twice
daily/efavirenz 400 mg once daily coadministration does not affect
efavirenz exposure after 10 days of sole administration, whereas
posaconazole C max and AUC were decreased by efavirenz in sub-
jects pretreated with posaconazole 400 mg twice daily for 10 days
by 45% and 50% [79]. Efavirenz and posaconazole coadministra-
tion should be avoided unless the benefits outweigh the risk [37].
The Intensive Care and Internal Medicine Patients
Clinically significant drug interactions frequently observed in
intensive care and internal medicine patients during concomitant
systemic triazole therapy are summarized in Table 4 [1,3,7,9,37,
71,87-122].
Interactions with Other Anti-Infective Agents
Drug interactions often occur when rifampin (rifampicin) and
rifabutin are coadministered with triazole antifungals. Rifampin is a
potent inducer of CYP3A4 [123]. Rifabutin is a less potent inhibitor
of CYP3A4 [123] and is metabolized in part by CYP3A4, which
can lead to 2-way drug interactions.
Fluconazole and Anti-Infective Agents
Except for early work in patients with AIDS [124], studies have
shown a clinically significant effect of rifampin on the pharmacoki-
netics of fluconazole in healthy volunteers [125], patients with
AIDS [88], and patients in the ICU [126]. In a study in patients with
AIDS-related cryptococcal meningitis, for example, concomitant
administration of fluconazole 400 mg/day and rifampin 600 mg/day
increased the elimination rate constant of fluconazole by 39%; flu-
conazole reduced t1/2 by 28%, AUC by 22%, and Cmax by 17%; and
increased clearance by 30% (all P <0.05) [88]. Relapses of AIDS-
related cryptococcal meningitis have been reported during coadmin-
istration of fluconazole and rifampin [127]; therefore, an increase in
fluconazole dose should be considered when it is administered with
rifampin [71].
In HIV-infected patients, coadministration of fluconazole 200
mg/day and rifabutin 300 mg/day resulted in significantly increased
plasma concentrations of rifabutin and its equiactive metabolite,
LM565; AUC increases were 82% for rifabutin and 216% for
LM565 (both P <0.05) [89]. Because uveitis has been reported in
patients with AIDS receiving concomitant therapy with fluconazole
and rifabutin [128,129], patients receiving this combination should
be carefully monitored [71].
Itraconazole and Anti-Infective Agents
Coadministration of itraconazole with rifampin results in de-
creased plasma concentrations of itraconazole [9]. A study in
healthy volunteers and patients with AIDS also showed a clinically
significant effect of rifampin on the pharmacokinetics of itracona-
zole [130]. Reduction of itraconazole to clinically undetectable
levels [131], and marked, unintended weight loss [132] have been
reported.
Coadministration of itraconazole with rifabutin results in both a
reduction in itraconazole plasma concentration and an increase in
rifabutin plasma concentration [9]. Coadministration of itraconazole
with either rifampin or rifabutin is not recommended [9].
Voriconazole and Anti-Infective Agents
In healthy volunteers, rifampin 600 mg/day decreased the
steady-state Cmax and AUC of voriconazole (200 mg twice daily for
7 days) by an average of 93% and 96%, respectively [3]. Doubling
the voriconazole dose did not restore adequate voriconazole expo-
sure. Coadministration of voriconazole and rifampin is contraindi-
cated [3].
In healthy subjects, rifabutin 300 mg/day decreased exposure to
voriconazole 200 mg twice daily (mean AUC was decreased by
79%, Cmax by 67%) [3]. During coadministration with rifabutin 300
mg/day, the mean Cmax and AUC of voriconazole at 400 mg twice
daily were approximately 2 times higher than voriconazole alone at
400 Current Drug Metabolism, 2009, Vol. 10, No. 4 Nivoix et al.

Table 4. Interactions Between Drugs used to Treat Intensive Care and Internal Medicine Patients and Concomitant Systemic Triazole Therapy

Anti-infectives Benzodiazepines Opioid Analgesics

Fluconazole Rifampin decreased exposure to fluconazole:
Cmax  17%, AUC  22%, and t  28%, (all P
<0.05) in patients with AIDS-related cryptococ-
cal meningitis [88]
Fluconazole increased exposure to rifabutin:
AUC  82% (P <0.05) in HIV-infected patients
[89]
Itraconazole Rifampin and rifabutin decrease itraconazole
exposure [9]
Coadministration not recommended with either
rifampin or rifabutin [9]
Voriconazole Rifampin decreased exposure to voriconazole:
Cmax  93% and AUC  96%
Contraindicated [3]
Rifabutin decreased exposure to voriconazole:
Cmax  67%, AUC  79%, and posaconazole 
exposure to rifabutin
Contraindicated [3]
Posaconazole Rifabutin decreased exposure to posaconazole:
Cmax  43% (P = 0.005) and AUC  49%
(P = 0.008) Posaconazole  exposure to ri-
fabutin: Cmax  31% (P = 0.016) and AUC  72%
(P <0.001)
Avoid [90]a
Fluconazole increased exposure to midazolam Fluconazole increased exposure to methadone:
and increased psychomotor effects [91,92] Cmax  27% (P = 0.0076), AUC  35% (P =
Fluconazole increased exposure to diazepam: 0.0008),
AUC  2.5-fold (P <0.01), and t  from 31 to and CL  24% (P = 0.0007) [98]
73 hours (P <0.001) [121] Fluconazole increased exposure to IV fentanyl:
CL 16% (P <0.05) [99]
Itraconazole significantly increased exposure to
midazolam: Cmax
 2- to 3-fold (P <0.01), AUC  2 to 10-fold (P
<0.001), and prolonged effects on psychomotor
performance [91,93]
Contraindicated [9]
Small but significant (P <0.05) increases in
temazepam and diazepam but no significant
psychomotor effects [94,95]
Oral voriconazole increased exposure to IV Voriconazole increased exposure to methadone:
midazolam: CL  72% (P <0.001), Cmax  3.8- (R)-methadone Cmax  30.7% and AUC  47.2%
fold (P <0.001), AUC  10.3-fold (P <0.001), [97]
and t  from 2.8 to 8.3 hours (P <0.001) [96] Consider dose reduction of methadone [3]
Profoundly increased psychomotor effects of Voriconazole increased exposure to IV fentanyl:
oral midazolam but only weakly increased the AUC  1.4-fold and CL  23% (P <0.05 for
effects of IV midazolam [96] each) [99]
Voriconazole increased exposure to oral dilti-
azem: AUC  2.2-fold (P <0.05), and t  from
31 to 61 hours (P <0.01).
Psychomotor effects were modest [121]
Posaconazole (200 or 400 mg bid) increased
exposure to oral (2 mg) or IV (0.4 mg) midazo-
lam: Oral Cmax  126%, AUC  362%; IV Cmax 
62%, AUC  524%;
Monitor carefully [37]

Anticonvulsants Anticoagulants HMG-CoA (Statins) PPIs/

H2 Antagonists

Fluconazole Fluconazole increased exposure to
IV or oral phenytoin: AUC  75%
and 88% [71,100]
Consider dose reduction of pheny-
toin [100]
Reports of interactions of flucona-
zole with carbamazepine in patients
[101-103]
Itraconazole Phenytoin decreased exposure to
itraconazole: AUC  >90%, t 
from 22.3 to 3.8 hours [104]
Itraconazole increased AUC of
phenytoin by 10.3% [104]
Possibility of an interaction with
carbamazepine [9]
Voriconazole Phenytoin decreased exposure to
voriconazole: Cmax  50% , AUC 
70% Voriconazole increased
plasma concentrations of phenytoin:
Cmax  67%, AUC  81% [105]
Double voriconazole dose during
coadministration of phenytoin [3]
Concomitant administration of
voriconazole and carbamazepine is
Contraindicated [3]
Warfarin:  prothrombin times
[71,106] and INR values [107]
Monitor carefully: prothrombin
time in patients receiving flucona-
zole and coumarin-type anticoagu-
lants [71]
Warfarin plus voriconazole signifi-
cantly increased prothrombin time
from 8 to 17 seconds ( P = 0.0004)
[108]
Monitor carfully: prothrombin time
in patients and adjust warfarin dose
accordingly [3]
Fluconazole increased exposure to Fluconazole increased exposure to
simvastatin [109,110], atorvastatin omeprazole: AUC  6.3-fold
[111], and fluvastatin; fluvastatin [117]
Cmax  44%
(P <0.05), AUC  84%
(P <0.01), t  80%
(P <0.01) [112]
Itraconazole significantly increased PPIs and H2 antagonists signifi-
exposure (Cmax, AUC, and t) to cantly reduced itraconazole
lovastatin [113], simvastatin [114], absorption [1,87,118]
atorvastatin [115,116], and cerivas-
tatin [115]
Contraindicated: Coadministration
of itraconazole with lovastatin or
simvastatin [9]
Voriconazole inhibits lovastatin No effects seen with cimetidine or
metabolism in vitro [3] ranitidine [119]
Omeprazole decreased exposure
to voriconazole [120]
Reduce omeprazole doses
40
mg BY 50% [3]
Drug-Drug Interactions of Triazole Antifungal Agents in Multimorbid Patients
Anticonvulsants Anticoagulants
Posaconazole Phenytoin decreased exposure to
posaconazole: Cmax  44% (P =
0.012), AUC  52% (P = 0.007)
[122]
Avoid [37]a
Posaconazole increased phenytoin
bioavailability by 16% [37]
Results shown are in healthy volunteers unless otherwise stated.
AUC = area under the concentration-time curve; bid = twice daily; Cmax = maximum plasma concentration; H2 = histamine-2; INR = international normalized ratio; IV = intravenous;
PPI = proton pump inhibitor; t
= half-life.
a
Unless the benefits outweigh the risk.
200 mg twice daily [3]. Coadministration of voriconazole 400 mg
twice daily with rifabutin 300 mg twice daily increased the Cmax
and AUC of rifabutin by 3- and 4-fold, respectively, compared with
rifabutin given alone [3]. Coadministration of voriconazole and
rifabutin is contraindicated [3].
Posaconazole and Anti-Infective Agents
In an open-label, parallel-group, multiple-dose study, coadmin-
istration of posaconazole and rifabutin resulted in reduction of
posaconazole Cmax by 43% (P = 0.005) and AUC by 49% (P =
0.008), as well as an increase in the rifabutin Cmax of 31% (P =
0.016) and AUC of 72% (P <0.001) [90]. Concomitant administra-
tion of posaconazole and rifabutin should be avoided unless the
benefits outweigh the risk; in these cases, patients should undergo
frequent full blood counts and monitoring for AEs associated with
increased rifabutin levels (e.g. uveitis) [37].
Benzodiazepines
Azoles affect the pharmacokinetic parameters of benzodiazepi-
nes metabolized by CYP3A4 (midazolam, triazolam, and alprazo-
lam), which may result in excessive sedative effects. Coadministra-
tion of an azole with diltiazem or temazepam, which do not un-
dergo significant first-pass metabolism, results in less-pronounced
effects.
Fluconazole and Benzodiazepines
In healthy volunteers, oral fluconazole increased the AUC and
reduced the clearance of oral or IV midazolam, while profoundly
increasing its psychomotor effects [91,92]. The mean Cmax of mida-
zolam increased significantly when mechanically ventilated ICU
patients sedated with a stable midazolam infusion received IV flu-
conazole at doses of 200 mg/day; effects were most pronounced in
patients with renal failure (3 of 10 patients) [133]. Coadministration
of oral diazepam 5 mg with oral fluconazole (day 1, 400 mg; day 2,
200 mg) to healthy volunteers increased diazepam AUC by 2.5-fold
(P <0.01) and prolonged t1/2 from 31 hours to 73 hours (P <0.001)
[121].
Itraconazole and Benzodiazepines
Studies in healthy volunteers have consistently shown signifi-
cant increases in the AUC (2- to 10-fold) and Cmax (2- to 3-fold) of
midazolam following coadministration with itraconazole, as well as
prolonged effects on psychomotor performance [91,93]; therefore,
concomitant administration of itraconazole with midazolam or tria-
zolam is contraindicated [9]. Itraconazole coadministration resulted
in small but statistically significant increases in temazepam and
diazepam AUC, but no significant psychomotor effects were ob-
served [94,95]. Therefore, usual doses of temazepam and diltiazem
may be administered during itraconazole therapy.
Current Drug Metabolism, 2009, Vol. 10, No. 4 401
(Table 4) Contd….
HMG-CoA (Statins) PPIs/
H2 Antagonists
No data published but a dose reduc- Cimetidine decreased exposure to
tion of statins should be considered posaconazole: Cmax and AUC 
during coadministration with posa- 39%
conazole [37] Avoid [37]a
Omeprazole decreased exposure
to posaconazole: Cmax  46%,
AUC  32% [7]
Avoid in lower posaconazole
absorption states
Voriconazole and Benzodiazepines
Oral voriconazole (day 1, 400 mg twice daily; day 2, 200 mg
twice daily) reduced the clearance of IV midazolam 0.05 mg/kg by
72% (P <0.001) and increased its t1/2 from 2.8 to 8.3 hours (P
<0.001). Voriconazole also increased oral midazolam (7.5 mg) Cmax
and AUC by 3.8- and 10.3-fold, respectively (P <0.001) [96]. Co-
administration profoundly increased the psychomotor effects of oral
midazolam but only weakly increased the effects of IV midazolam
[96]. Coadministration of oral voriconazole (day 1, 400 mg twice
daily; day 2, 200 mg twice daily) with oral diltiazem 5 mg in
healthy volunteers resulted in a 2.2-fold (P <0.05) increase in dilti-
azem AUC and a prolongation of t1/2 from 31 to 61 hours (P <0.01);
psychomotor effects were modest [121].
Posaconazole and Benzodiazepines
Oral posaconazole (days 1-7, 200 mg twice daily; days 8-14,
400 mg twice daily) increased oral and IV midazolam (day -2, 6, 13
oral 2 mg; day -1, 7, 14 IV 0.4 mg) Cmax and AUC up to 2- and 5-
fold, respectively. The t1/2 of midazolam was also prolonged [134].
During coadministration of fluconazole or posaconazole with
midazolam, and voriconazole with midazolam, triazolam, or alpra-
zolam, the benzodiazepine dose should be reduced [3,37,71].
Opioid Analgesics
Clinically significant interactions have been reported between
fluconazole or voriconazole and the opioid analgesics methadone or
fentanyl.
The increase in methadone exposure following coadministration
with voriconazole may be due to triazole inhibition of CYP3A4,
CYP2C9, and/or CYP2C19 [97]. When volunteers receiving
methadone therapy received voriconazole (day 1, 400 mg twice
daily; days 2-5, 200 mg twice daily), the (R)-methadone AUC in-
creased by 47.2% and Cmax increased by 30.7% [97]. When volun-
teers who were receiving methadone maintenance therapy received
oral fluconazole 200 mg/day for 14 days, methadone AUC in-
creased by 35% (P = 0.0008), Cmax increased by 27% (P = 0.0076),
and oral clearance decreased by 24% (P = 0.0007) [98]. Respiratory
depression has been reported during concomitant therapy with flu-
conazole and methadone [135] Decreasing the methadone dose
during coadministration with voriconazole should be considered
[3].
Fluconazole decreased IV fentanyl clearance by 16% (P <0.05),
whereas voriconazole decreased IV fentanyl clearance by 23% and
increased fentanyl AUC by 1.4-fold (both P <0.05); these changes
may potentiate fentanyl-induced respiratory depression [99]. Fen-
tanyl is primarily metabolized by CYP3A4 [25], and the increase in
fentanyl exposure following coadministration with a triazole likely
results from CYP3A4 inhibition by the triazole.
402 Current Drug Metabolism, 2009, Vol. 10, No. 4
Anticonvulsants
Because the anticonvulsants phenytoin, carbamazepine, and
phenobarbital are potent inducers of the CYP450 system, concomi-
tant administration with azoles can lead to significantly reduced
triazole plasma concentrations. Phenytoin is a CYP2C9 substrate;
therefore, 2-way interactions can also occur. Interactions that in-
crease phenytoin concentrations need to be monitored carefully
because this agent has a narrow therapeutic window.
Fluconazole and Anticonvulsant Therapy
In healthy male volunteers who received oral fluconazole at
doses of 200 mg/day, concomitant administration of IV or oral
phenytoin at doses up to 250 mg resulted in mean increases in the
phenytoin AUC of 75% and 88% [71,100]. Many cases of flucona-
zole-induced symptomatic phenytoin toxicity, including instances
of dizziness, nystagmus, and ataxia, have been reported [136-138].
During concomitant administration of fluconazole and phenytoin,
phenytoin concentrations should be carefully monitored [71] and a
reduction in the phenytoin dose should be considered [100]. Cases
of interactions with carbamazepine have also been reported during
concomitant fluconazole therapy, both asymptomatic and sympto-
matic, including an instance of stupor [101-103], suggesting that a
reduction in the carbamazepine dose should also be considered
during concurrent treatment with fluconazole.
Itraconazole and Anticonvulsant Therapy
When healthy male volunteers received a single 200-mg itra-
conazole dose after 15 days of oral phenytoin 300 mg/day, pheny-
toin decreased the itraconazole AUC by more than 90% and re-
duced the t1/2 from 22.3 to 3.8 hours [104]. Therapeutic failure has
occurred in a patient with a fungal infection during concomitant
treatment with itraconazole and phenytoin [139]. When healthy
male volunteers received a single 300-mg oral dose of phenytoin
after receiving itraconazole 200 mg/day for 15 days, itraconazole
increased the phenytoin AUC by 10.3% but did not affect any other
pharmacokinetic parameter [104]. Although interactions with car-
bamazepine and phenobarbital have not been systematically stud-
ied, concomitant administration of itraconazole and these drugs
would be expected to result in decreased plasma concentrations of
itraconazole [9]. A case report described a patient who experienced
subtherapeutic itraconazole concentrations, first during concomitant
therapy with phenobarbital and subsequently during concomitant
therapy with carbamazepine [140].
Voriconazole and Anticonvulsant Therapy
When oral voriconazole 200 mg twice daily was given with
phenytoin, the mean voriconazole Cmax was decreased by 50% and
the mean AUC by 70% [105]. These decreases were corrected by
increasing the voriconazole dose to 400 mg twice daily during co-
administration of phenytoin 300 mg/day [105]. Oral voriconazole
400 mg twice daily increased exposure to oral phenytoin 300
mg/day compared with placebo (AUC increased by 81% and Cmax
by 67%) [105]. Concomitant administration of voriconazole and
carbamazepine is contraindicated because of the potential for sig-
nificantly decreased voriconazole levels [3].
Posaconazole and Anticonvulsant Therapy
In healthy volunteers randomized to receive posaconazole 200
mg/day, phenytoin 200 mg/day, or the same doses of both agents
for 10 days, posaconazole exposure at steady state was significantly
decreased in the presence of phenytoin (AUC decreased by 52% [P
= 0.007] and Cmax by 44% [P = 0.012]) [122]. Conversely, concomi-
tant administration of posaconazole and phenytoin resulted in a
15.5% increase in the relative oral bioavailability of log-
transformed phenytoin Cmax and AUC values at steady state [122].
The combination of posaconazole and phenytoin should be avoided,
if possible, and frequent monitoring of phenytoin levels should be
performed if the drugs are coadministered [37].
Nivoix et al.
Anticoagulants
The pharmacologically active enantiomer of warfarin—S-
warfarin—is metabolized almost exclusively by CYP2C9.[141]
Clinically significant interactions have been reported during coad-
ministration of warfarin with fluconazole, itraconazole, and vori-
conazole [3,9,141].
Fluconazole and Anticoagulants
Healthy volunteers and patients have experienced marked in-
creases in prothrombin times [71,106] and international normalized
ratio (INR) values [107] during concomitant therapy with flucona-
zole and warfarin. Various bleeding events, including intraocular
hemorrhages [142], gastrointestinal bleeding [143], and spinal
epidural hematoma [144], have been reported in association with
prothrombin time increases in patients receiving concurrent flu-
conazole and warfarin. A stepped-dose warfarin reduction schedule
has been proposed for patients who require concomitant flucona-
zole therapy [145], and careful monitoring of prothrombin time in
patients receiving fluconazole and coumarin-type anticoagulants is
recommended [71].
Itraconazole and Anticoagulants
Intractable bleeding and generalized bruising were reported in a
woman who had an INR >8 following the addition of itraconazole
200 mg twice daily to a stable 5-mg dose of warfarin [146]. The
authors proposed that itraconazole probably potentiated the effect
of warfarin [146].
Voriconazole and Anticoagulants
Administration of a single dose of warfarin 30 mg to healthy
volunteers who received voriconazole 300 mg twice daily for 12
days significantly increased the prothrombin time (from 8 to 17
seconds [P = 0.0004]) [108]. If voriconazole and warfarin are co-
administered, close monitoring of prothrombin time or other antico-
agulation test results is recommended, and the warfarin dose should
be adjusted accordingly [3].
Posaconazole and Anticoagulants
Because posaconazole is not a CYP2C9 inhibitor, coadministra-
tion of posaconazole and warfarin is not expected to cause a drug
interaction.
3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) Reductase
Inhibitors (Statins)
Azoles can increase the plasma concentrations of statins that are
CYP3A4 substrates (lovastatin, simvastatin, atorvastatin), possibly
leading to myopathy or rhabdomyolysis.
Fluconazole and Statins
Increased plasma concentrations associated with CYP3A4 inhi-
bition resulted in rhabdomyolysis during concomitant administra-
tion of fluconazole and simvastatin [109,110] or atorvastatin [111].
Fluconazole inhibition of CYP2C9 increased fluvastatin AUC in
healthy volunteers by 84% (P <0.01), t1/2 by 80% (P <0.01), and
Cmax by 44% (P <0.05) [112].
Itraconazole and Statins
Studies in healthy volunteers showed significant increases in
the Cmax, AUC, and t1/2 of the statin during coadministration of
itraconazole with lovastatin [113], simvastatin [114], atorvastatin
[115,116], and cerivastatin [115]. Coadministration of itraconazole
with lovastatin or simvastatin is contraindicated [9]. Rhabdomyoly-
sis has been reported in 2 heart transplant recipients: one received
itraconazole in combination with simvastatin and cyclosporine
[147], the other with simvastatin, cyclosporine, and gemfibrozil
[148].
Voriconazole and Statins
Voriconazole inhibits lovastatin metabolism in human liver
microsomes [3]. During administration of voriconazole with a statin
Drug-Drug Interactions of Triazole Antifungal Agents in Multimorbid Patients
metabolized by CYP3A4, patients should be monitored frequently
for statin-related AEs and toxicity; statin dose adjustment may be
needed [3].
Posaconazole and Statins
Based on experience with the other azoles, dose reduction of
statins metabolized through CYP3A4 should be considered during
coadministration with posaconazole [37].
Proton Pump Inhibitors (PPIs) and Histamine-2 (H2) Antago-
nists
As previously described, gastric pH has different effects on the
various azoles; in addition, the azoles have different effects on the
metabolism of PPIs and H2 antagonists.
Fluconazole and PPIs/H2 Antagonists
Omeprazole is a CYP2C19 inhibitor and CYP2C19 and
CYP3A4 substrate [3]. The AUC of omeprazole increased 6.3-fold
in healthy volunteers who received fluconazole; this interaction
may have led to an increased effect of omeprazole [117].
Itraconazole and PPIs/H2 Antagonists
Coadministration of the itraconazole capsule formulation with
PPIs or H2 antagonists significantly decreased itraconazole absorp-
tion [1,87,118]. Although coadministration of omeprazole did not
have a significant effect on the pharmacokinetics of itraconazole
oral solution, subjects showed wide variability in itraconazole ab-
sorption, with Cmax and AUC differing as much as 3-fold [4].
Voriconazole and PPIs/H2 Antagonists
No clinically significant effects on voriconazole steady-state
pharmacokinetics were observed when voriconazole was coadmin-
istered with the H2 antagonist cimetidine [119], a nonspecific
CYP450 inhibitor, or ranitidine [119]. At steady state, omeprazole
increased voriconazole AUC by 41% and Cmax by 15% [120]. When
voriconazole therapy is initiated in patients already receiving ome-
prazole at a dose of
40 mg, the omeprazole dose should be re-
duced by 50% [3].
Posaconazole and PPIs/H2 Antagonists
Coadministration of posaconazole 200 mg/day for 10 days with
cimetidine 400 mg twice daily for 10 days resulted in decreases of
39% for both the Cmax and the AUC of posaconazole [37]. Con-
comitant administration of posaconazole and cimetidine should be
avoided unless the benefits outweigh the risk [37]. No clinically
relevant effect on posaconazole bioavailability or plasma concentra-
tions was observed when posaconazole was administered with other
H2 antagonists or PPIs; therefore, no posaconazole dose adjust-
ments are required when posaconazole is used concomitantly with
these products [37]. However, a recent, preliminary study has
shown that coadministration of posaconazole and the PPI esome-
prazole (40 mg once daily) decreased posaconazole Cmax and AUC
by 46% and 32%, respectively [7]. These results suggest that PPIs
should be avoided at lower posaconazole absorption states.
Other Clinically Important Interactions
Because of the potential for QT prolongation and, possibly,
torsades de pointes, coadministration of quinidine with itracona-
zole, voriconazole, and posaconazole is contraindicated [3,9,37].
Increased plasma concentrations of calcium channel blockers
that are metabolized by CYP3A4 may occur during coadministra-
tion with azoles. Therefore, a calcium channel blocker dose reduc-
tion should be considered during concomitant use with itraconazole,
voriconazole, and posaconazole [3,9,37].
The hypoglycemic effects of sulfonylureas may be exaggerated
during administration with oral azoles; therefore, blood glucose
concentrations should be measured frequently and patients closely
monitored for signs and symptoms of hypoglycemia [3,9,37,71].
Current Drug Metabolism, 2009, Vol. 10, No. 4 403
Itraconazole increases the serum concentration of digoxin in
healthy volunteers. Mean serum digoxin AUC(0-72h) was ap-
proximately 50% higher (P <0.001) and renal clearance of digoxin
about 20% lower (P <0.01) when digoxin was coadministered with
itraconazole versus placebo [149]. Renal tubular clearance is effec-
tively inhibited by coadministration of itraconazole, resulting in
increased serum digoxin levels and digoxin toxicity [150]. The
interaction between itraconazole and digoxin can be attributed to
inhibition of P-gp–mediated renal secretion of digoxin by itracona-
zole. Patients should be closely monitored for signs and symptoms
of digoxin toxicity. Similarly, coadministration of digoxin and
posaconazole was shown to increase digoxin plasma concentra-
tions; monitoring of digoxin plasma concentrations is therefore
recommended when posaconazole and digoxin are taken concomi-
tantly [37]. In contrast, concomitant administration of voriconazole
with digoxin has not been observed to significantly alter any of the
digoxin pharmacokinetics parameters at steady state [28].
MAIN DIFFERENCES BETWEEN THE AZOLES AND
THEIR PRACTICAL SIGNIFICANCE
The azoles differ markedly in their pharmacokinetic and anti-
fungal properties (Table 5) [2,3,9,26,37,71,151-160], safety and
tolerability, and drug-interaction profiles.
Fluconazole is a water-soluble agent that offers a good pharma-
cokinetic profile characterized by excellent oral bioavailability, a
long t1/2, and urinary excretion as an active drug [155]. Fluconazole
is generally well tolerated; commonly reported AEs are nausea,
headache, skin rash, vomiting, abdominal pain, and diarrhea [71].
Fluconazole engages in less-extensive drug-drug interactions than
other azoles [155]. Because fluconazole pharmacokinetics are
markedly affected by reduced renal function, the fluconazole dose
needs to be reduced in patients with renal impairment [71]. The
main restrictions in the use of fluconazole for prophylaxis and
treatment of IFIs are limitations in its spectrum of activity. Al-
though it is active against Candida spp (except C krusei) and other
yeasts, fluconazole lacks activity against moulds [152,153].
The capsule formulation of itraconazole displays erratic phar-
macokinetics [161,162], and both oral formulations (particularly the
capsule) are poorly absorbed, so that routine measurement of serum
levels is advisable [161]. Commonly reported AEs in patients with
IFIs treated with itraconazole are nausea, rash, vomiting, edema,
and headache [9]. A pharmacokinetic study in patients with renal
impairment demonstrated that itraconazole bioavailability was
slightly reduced in patients with uremia and that AUC values
showed a wide intersubject variation. No statistically significant
change in AUC was seen when itraconazole was administered to
patients with cirrhosis, although a significant reduction in mean
Cmax (47%) and a 2-fold increase in t1/2 were observed [9]. Patients
with hepatic impairment should be carefully monitored when taking
itraconazole, and the prolonged elimination t1/2 of itraconazole ob-
served in patients with cirrhosis should be considered when decid-
ing to initiate therapy with other agents metabolized by CYP3A4
[9]. Itraconazole has a broader spectrum of activity than flucona-
zole, demonstrating activity against yeasts, including Candida and
Cryptococcus spp; dermatophytes; and some moulds, including
Aspergillus spp and dimorphic fungi [154].
Voriconazole displays excellent oral bioavailability (>90%)
[155]; its major pharmacokinetic limitation is a complex drug-
interaction profile. The AEs most commonly reported in voricona-
zole clinical trials were visual disturbances, fever, rash, vomiting,
nausea, diarrhea, and headache [3]. Visual disturbances were re-
ported in approximately 21% of patients during clinical trials and
may be associated with higher plasma concentrations and/or doses
[3]. A limitation to the use of voriconazole in some multimorbid
patients is the presence of cyclodextrin in the IV formulation, which
accumulates in patients with renal dysfunction [163]. Although no
adjustment is needed for oral dosing in patients with mild to severe
404 Current Drug Metabolism, 2009, Vol. 10, No. 4 Nivoix et al.

Table 5. Pharmacokinetic and Antifungal Properties of the Systemic Triazole Antifungals

Parameter Fluconazole[2,71,152,153] Itraconazole[9,26,151,154] Voriconazole[3,155-157] Posaconazole

[30, 37,154,158-160]

Tmax, h
t
, h
Steady state, days
Protein binding, %
Dose-dependent plasma concen-
trations, mg
Metabolism/ excretion
Renal elimination (%)
Bioavailability, %
Antifungal activity
Volume of distribution (L/kg)
Apparent clearance (mL/min)
Pharmacokinetic parameters shown are in healthy volunteers unless otherwise stated.
Tmax = time to maximum plasma concentration, t
= half-life.
2.4-3.7 (immuno-compromised
patients)
37.2 ± 5.5 (AIDS patients)
31.4 ± 4.7 (healthy volunteers)
5-10
11-12
25-100 (linear)
Mainly (~90%) eliminated in
urine as unchanged drug
80
>90 (of suspension)
Active against Candida spp
(except C krusei and some C
glabrata) and other yeasts.
Not active against moulds
0.7-0.8
17-19
1.0 (IV); 3.9 (oral) 1.7-3.0 (patients with hemato-
logical malignancies, solid
tumors, or bone marrow trans-
plants); high intersubject varia-
tion
35 (IV); 21 (oral) 4.71-8.18
14 4-7 (patients)
4 (healthy volunteers)
99.8 58
50-200 (nonlinear) None
Almost completely metabolized Extensively metabolized: 2%
by CYP3A4 excreted as unchanged drug in
urine/feces, 98% excreted as
metabolites
<1 <2
55 (oral) >96
Active against yeasts (including Broad spectrum of activity
Candida and Cryptococcus against Candida spp (including
spp), dermatophytes, some C krusei), Aspergillus spp, some
moulds (including some Asper- Scedosporium spp, and
gillus spp), dimorphic fungi Fusarium spp.
Not active against the Zygomy-
cetes
10.7 2 25
381 100-333
~3-5
35
7-10
>98
50-800 (linear)
>70% excreted unchanged in
feces; remainder mainly me-
tabolized in liver by glucuroni-
dation and transformation into
other metabolites
<1
8-47
Broad spectrum of activity
against yeast (including Can-
dida spp and Cryptococcus
spp), moulds (including Asper-
gillus spp, Scedosporium apio-
spermum, some Fusarium spp,
the Zygomycetes), and Der-
matophytes
192-363

renal impairment, IV voriconazole should be avoided in patients
with moderate or severe renal impairment (creatinine clearance <50
mL/min) unless an assessment of the benefits and risks to the pa-
tient justifies its use [3]. Standard loading dose regimens should be
used, but the maintenance dose of voriconazole should be halved in
patients with mild to moderate hepatic cirrhosis (Child-Pugh classes
A and B) [3]. No pharmacokinetic data are available for patients
with severe cirrhosis (Child-Pugh class C). Voriconazole has a
broad spectrum of activity, including most pathogenic yeasts and
various filamentous fungi, such as Aspergillus spp and, to a cer-
tain extent, Scedosporium spp and Fusarium spp [155]. However,
voriconazole lacks activity against the Zygomycetes, and break-
through zygomycosis has been reported during voriconazole ther-
apy [164-166].
Posaconazole is well absorbed after oral administration and is
extensively distributed to many tissue sites [37,158]. Posaconazole
is best absorbed in 2 to 4 divided doses given with food or a nutri-
tional supplement [167]. T1/2 is approximately 35 hours, C max is
achieved in about 5 hours, and steady state is attained within 7 to
10 days [158,159,167]. Commonly reported AEs are fever, diar-
rhea, nausea, vomiting, abdominal pain, and headache [37]; large
comparative studies have shown that posaconazole has a
safety/tolerability profile similar to that of fluconazole [168,169].
Because it is not extensively metabolized by CYP450 isozymes
[30] and does not have a significant effect on CYP2C8/9, CYP1A2,
CYP2D6, or CYP2E1 activity at clinically relevant concentrations
[19], posaconazole does not engage in many of the drug interactions
observed with fluconazole, itraconazole, and voriconazole. No
posaconazole dose adjustment is required in patients with mild to
moderate renal impairment [37]. In patients with severe renal insuf-
ficiency, the mean AUC was similar to that in patients with normal
renal function, but the range of AUC estimates was highly variable.
Therefore, patients with severe renal impairment should be moni-
tored closely for breakthrough fungal infections [37]. Pharmacoki-
netic data in subjects with hepatic impairment were not sufficient to
determine whether posaconazole dose adjustment is necessary in
patients with hepatic dysfunction [37]. A recent study showed that
regardless of the degree of hepatic impairment, there was consider-
able overlap in exposure of posaconazole with that in healthy sub-
jects, suggesting that dose adjustment of posaconazole in patients
with hepatic impairment is not necessary [170]. In addition to dem-
onstrating activity against the most frequently isolated yeast and
mould pathogens, including Candida spp and Aspergillus spp
[154], posaconazole is also active against most Zygomycetes, as
well as some Candida and Aspergillus isolates (including A ter-
reus) that exhibit resistance to other azoles [154].
GENERAL MEASURES FOR PREVENTING AND MANAG-
ING DRUG INTERACTIONS IN HIGH-RISK PATIENTS
Because of their activities as inhibitors or substrates of biotrans-
formation enzymes and transporter proteins, significant drug inter-
actions can often occur between triazole antifungals and other drugs
needed to treat underlying disorders in multimorbid patients. Clini-
cians who prescribe systemic azoles for multimorbid patients
should be thoroughly familiar with the pharmacokinetic profiles of
the different azoles, as well as pharmacokinetic differences among
the various formulations of the same triazole. Clinicians should also
heed published recommendations concerning contraindications and
Drug-Drug Interactions of Triazole Antifungal Agents in Multimorbid Patients
dose-modification strategies. However, the extent of a drug interac-
tion varies markedly among individuals. This variability is related
to interindividual differences in CYP3A4 tissue content, preexisting
medical conditions, race, diet, and possibly age [171]. Clinicians
should, therefore, be especially cautious about prescribing concomi-
tant medications associated with possible drug interactions to pa-
tients with severe comorbidities.
Therapeutic drug monitoring may help to optimize treatment
and prevent drug underdosing or overdosing. Patients requiring
treatment with a systemic triazole benefit from therapeutic drug
monitoring if they will be receiving concomitantly a drug known to
engage in clinically significant interactions with a particular tria-
zole. Routine therapeutic drug monitoring is advisable for patients
receiving itraconazole, especially the capsule formulation [161].
Measurement of voriconazole serum levels, especially during oral
therapy, may be useful to assess potential toxicity or adequate drug
exposure, especially in patients with progressive infection [172]. It
may also be beneficial to monitor drug levels in patients with renal
or hepatic insufficiency during triazole therapy [3,9,37,71]
To ensure that drug interactions are managed promptly, health
care providers, patients, patients’ families, and caregivers should be
educated about the signs and symptoms that might be experienced
and which of these might require immediate medical attention. As
long as the antifungal spectrum of activity is appropriate, drug in-
teractions can often be managed by switching from one triazole to
another triazole with a more benign drug-interaction profile or to
another type of antifungal entirely. Sometimes changing to a differ-
ent formulation of the same triazole (e.g. from the capsule to the
oral solution of itraconazole) is effective. If dose modification of a
triazole is deemed necessary, therapeutic drug monitoring should be
initiated and the patient monitored closely for breakthrough IFIs
and AEs.
CONCLUSION
Our growing understanding of the molecular determinants of
the pharmacokinetic profiles of fluconazole, itraconazole, voricona-
zole, and posaconazole has made it possible to predict clinically
significant drug-drug interactions with increasingly greater accu-
racy. The results of numerous well-designed clinical pharmacoki-
netics studies complement our insights into the roles played by
phase 1 and 2 biotransformation enzymes and transporter proteins
in azole-related drug interactions. Case reports documenting clini-
cal manifestations of drug interactions in multimorbid patients also
contribute. Today, many drug interactions in multimorbid patients
can be prevented if clinicians are thoroughly familiar with the
pharmacokinetic profiles of the different triazole antifungals, follow
recommendations concerning contraindications and dose-
modification strategies, make appropriate use of therapeutic drug
monitoring, and switch azoles when possible to achieve the best
combination of clinical efficacy and safety.
FINANCIAL DISCLOSURES
No sources of funding were used to assist in the preparation of
this review. Dr Herbrecht has received grant support from Pfizer
and has served as a consultant for Gilead, Pfizer, Schering-Plough,
Merck Sharp and Dohme, Astellas, and Novartis. The remaining
authors have no conflicts of interest that are directly relevant to the
content of this review.
ABBREVIATIONS:
ABC = ATP-binding cassette
AIDS = Acquired immunodeficiency syndrome
BCRP = Breast cancer resistance protein
CYP = Cytochrome P450
H2 = Histamine-2
HIV = Human immunodeficiency virus
Current Drug Metabolism, 2009, Vol. 10, No. 4 405
HMG-CoA = 3-Hydroxy-3-methylglutaryl coenzyme A
HSCT = Hematopoietic stem cell transplantation
ICU = Intensive care unit
IFI = Invasive fungal infection
INR = International normalized ratio
IV = Intravenous
NNRTI = Nonnucleoside reverse-transcriptase inhibitors
NRTI = Nucleoside reverse-transcriptase inhibitors
P-gp = P-glycoprotein
PPI = Proton pump inhibitors
t
= Half-life
UGT = UDP-glucuronosyltransferase
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