International Journal of A n timicr ob ial Agents 3 (1993) 147-170 147

© 1993 Elsevier Science Publishers BV 0924-8579193l$24.00

A N T A G E 00075

Fluconazole (Diflucan®): a review

M a r k Zervos a and Fran~oise M e u n i e r b

aWilliam Beaumont Hospital, Royal Oak, MI, USA
bEORTC Central Office - - Data Center, Brussels, Belgium

(Accepted 15 June 1993)

Introduction [2], particularly those in neutropenic patients with

cancer [3,4] and in patients with AIDS [5,6].
Increasing numbers of fungal infections are occur- The most common fungal infection in both im-
ring in patients who are severely immunocompro- munocompromised and immunocompetent hosts is
mised because of underlying illness or chemotherapy candidiasis, although aspergillosis occurs frequently
[1]. Such infections are frequently life-threatening in neutropenic cancer patients and cryptococcosis in
AIDS patients. Histoplasmosis and coccidioidomy-
cosis, mycoses endemic in the Americas - - although
Correspondence to: F. Meunier, M.D., Ph.D., Director, not seen frequently - - are more likely to disseminate
EORTC Central Office - - Data Center, Avenue E. Mounier 83, in immunocompromised patients [4]. Histoplasma
Bte 11, 1200 Brussels, Belgium. capsulatum is becoming an important opportunistic
148

pathogen in patients with AIDS, even among those OH

living in nonendemic areas [7].
~ N ~ N_ CH2
Mycoses have been the most difficult to treat of all
microbial infections [1,8], in part because of the lack
of reliable diagnostic methodologies and the limited F
number of therapeutic agents available. Amphoter-
icin B is effective against a number of mycoses; how-
ever, it must be given parenterally and is often poorly
tolerated [9-11]. Also, resistance to amphotericin B,
including strains of Candida albicans, C. lusitaniae,
Fig. 1. Chemical structure of fluconazole.
and C. guillermondii, has been reported [11-16].
Although previously available azole drugs are bet-
ter tolerated than amphotericin B, their value in the
treatment of disseminated infections in immuno-
compromised patients is limited [17,18]. tests of in vitro susceptibility of clinical yeast isolates
This review presents an overview of the key prop- [33]. However, the correlation of test results with
erties of fluconazole (Diflucan®), a well-tolerated clinical efficacy remains to be established. Thus, in
bis-triazole agent which provides antifungal activity vivo data currently provide the best assessment of
against a number of localized and disseminated my- the therapeutic activity of fluconazole.
coses. The development of resistance during fluconazole
administration is under investigation. Emergence of
resistant strains of Candida spp. during therapy with
Chemistry azoles has been reported with both ketoconazole [34]
and fluconazole [35]. The selection of new species
Fluconazole is the first member of a new subclass (e.g., C. krusei) as fluconazole-resistant pathogens in
of synthetic triazole antifungal agents (Fig. 1). It was the setting of prophylactic or therapeutic admini-
selected for development because of its optimum stration in immunocompromised cancer patients
combination of antifungal activity, pharmacokinetic has been observed [36-38]. However, recent pro-
profile, and aqueous solubility [19]. spective, randomized placebo-controlled evalua-
Fluconazole is a white crystalline solid which is tions of fluconazole prophylaxis in patients with leu-
slightly soluble in water and saline. Its solubility in kemia or those undergoing bone marrow transplan-
water is approximately 6 mg/ml [20]. tation have shown no significant increase in the inci-
dence of C. krusei infection (unpublished data on
file, Pfizer; [39-43]).
Microbiology and pharmacology The definite role of fluconazole in the recent in-
creased incidence of C. krusei infections remains
In vitro antifungal activity controversial because these infections have been ob-
served by several investigators even in patients who
Fluconazole is active in vitro against a variety of have not been exposed to fluconazole [44]. Merz et
fungi and yeasts, including Cryptococcus neofor- al. [45] have also reported an increased incidence of
mans and Candida spp. [21-25]. However, most C. krusei infections prior to fluconazole use in their
fungi show a higher apparent sensitivity to flucon- own hospital.
azole in vivo than in vitro. This phenomenon is Nevertheless, fluconazole should not be recom-
shared by other azole antifungal agents and empha- mended for patients who are colonized with C. krusei
sizes the limitations of in vitro antifungal susceptibil- or for patients with documented infection caused by
ity testing [26-32]. C. krusei. Local epidemiological factors observed in
A macrobroth dilution method has been de- several units with higher incidence of C. krusei may
scribed recently, with improved reproducibility in reveal a common source for those infections.
 149

In vivo antifungal activity albicans in vitro, ketoconazole was found to be up to

16 times more active, indicating the poor reliability
Fluconazole has been evaluated extensively in a of quantitative in vitro comparisons.
variety of animal models of fungal infection and In a model of disseminated candidiasis in persis-
found to be effective. Both normal and immunosup- tently granulocytopenic rabbits [47], timing of anti-
pressed animals were challenged with major oppor- fungal therapy included preventive treatment
tunistic and endemic fungal organisms - - including (started 3 days before challenge), early treatment (24
Candida spp., Aspergillus spp., Cryptocoecus neofor- h after challenge), and delayed treatment (6 days
mans, Blastomyces dermatitidis, Coccidioides immi- after challenge). At the dosages employed, flucon-
tis, Histoplasma capsulatum, and dermatophytes. azole was comparable to amphotericin B for preven-
Although optimal therapeutic dosages were not de- tion of disseminated candidiasis and equivalent to
termined in these studies, the data indicate the rela- amphotericin B plus flucytosine for early treatment
tive activity of active drugs at the dosages employed. of these infections.
Other animal studies have shown fluconazole to
Candidiasis be effective in disseminated candidiasis [31,48,49],
renal candidiasis [50,51], Candida endophthalmitis
Compared to ketoconazole in a model of acute [52,53], vaginal candidiasis [54], and non-C, albicans
disseminated candidiasis in mice and rats [46], EDs0 candidal infection [29].
values with fluconazole were up to 100 times lower in
mice and at least 20 times lower in rats (Table 1). The Aspergillosis
activity of oral or intravenous fluconazole in pre-
venting death of mice 2 days postinfection was com- Disseminated aspergillosis was induced in mice by
parable to that of intravenous amphotericin B, al- intravenous injection of spores of A.flavus or A.fu-
though the polyene showed more prolonged protec- migatus. EDs0 values with fluconazole were up to
tion. 20-fold lower than those with ketoconazole against
A further study in a rat model [30] confirmed that the A.flavus infection [55]. Oral fluconazole was less
fluconazole was some 20 times more active than active against the A. fumigatus infection, although
ketoconazole against infections caused by isolates of ketoconazole was ineffective at doses up to 100 mg/
C. albicans. In this same study, however, when flu- kg twice daily.
conazole and ketoconazole were tested against C. In a different animal model, Patterson et al. [55]

TABLE 1
Efficacy of fluconazole, ketoconazole, and amphotericin B against systemic infections with Candida albicans in normal mice and rats

Mean EDs0 + s.d. (n > 3) (mg/kg)*

Mice Rats

Treatment** Route 2 days PI 5 days PI 2 days PI 5 days PI

Fluconazole p.o. 0.08 + 0.02 0.7 + 0.5 0.22 + 0.01 0.32 + 0.01
i.v. 0.06 + 0.04 1.2 + 0.2 ND ND
Ketoconazole p.o. 9.5 + 1.2 >20 4.9 + 1.0 >10
Amphotericin B i.v. 0.07 + 0.02 0.14 + 0.05 ND ND

PI=postinfection; p.o. = oral; i.v. = intravenous; ND = not done.

*EDs0 based on preventing death at 2 days or 5 days postinfection.
**Dose ranges: fluconazole, 0.01 to 2.0 mg/kg; ketoconazole, 1.0 to 20 mg/kg (mice), or 1.0 to 10 mg/kg (rats); amphotericin B, 0.01 to
0.5 mg/kg. Dosing frequency: Oral doses at 1, 4, and 24 h postinfection; intravenous doses at 1 and 4 h postinfection.
Adapted from Richardson et al. [46].
150

evaluated the efficacy offluconazole in experimental TABLE 2

invasive aspergillosis. Rabbits were immunocom- Efficacy of fluconazole, ketoconazole, and amphotericin B on
promised by treatment with cyclophosphamide and numbers of viable cryptococci in the brain, lungs, and spleen of
challenged intravenously with A. fumigatus. While intracranially infected mice sacrificed 10 days postinfection
fluconazole had demonstrated limited activity
CFU/g tissue
against this organism in vitro, the drug was active in
the animal model. Fluconazole decreased mortality Treatment Dose Brain Lungs Spleen
and reduced the tissue burden of Aspergillus. Fur- (mg/kg)
ther, measurement o f blood antigen levels showed and
that fluconazole significantly reduced antigenemia route
when used postinfection.
Control 0 1.5 x 108 4.3 × 10 6 4.3 × 10 6
In other experiments, the prophylactic effects of Fluconazole 5 p.o. 1.6 x 10 3 5.2 x 10" 2.5 x 102*
fluconazole were measured against lethal and suble- Ketoconazole 50p.o. 6.4 + 105 2.1 × 10 4 2.7 x 104
thal challenges of A.fumigatus in the same immuno- Amphotericin B 3 i.p. 1.7 × 103 2.9 x 102 2.9 x 102**
suppressed animal model [56]. Fluconazole was
begun 48 h prior to challenge and continued daily CFU = colony-forming units; p.o. = oral; i.p. = intraperi-
toneal.
throughout the experiment. At 60 mg/kg per day,
*Only one from fivepositive cultures.
fluconazole was protective against a lethal challenge **Only three from fivepositive cultures
and significantly prolonged survival compared with Adapted from Troke et al. [54].
untreated controls. However, fluconazole did not
sterilize tissues. At dosages of 60 and 120 mg/kg per
day, fluconazole prophylaxis begun 48 h prior to
sublethal challenge sterilized liver and kidney tissues neoformans [54], survival was significantly longer
and significantly reduced colony counts in lung. with oral fluconazole compared to placebo or keto-
conazole, although at the dosages employed ampho-
Cryptococcosis tericin B given intraperitoneally was more effective
than fluconazole (Fig. 2). In animals sacrificed 10
In a model of disseminated cryptococcosis in days postinfection, fluconazole was as effective as
which mice were injected intracranially with Cr. amphotericin B and significantly more effective than
ketoconazole in reducing the numbers of viable
cryptococci in the brain, lungs, and spleen (Table 2).
In similar experiments [57], amphotericin B was
superior to fluconazole in prolonging survival in
I00
\ normal mice but the two agents were comparable in
80- athymic mice. In both types of animals with crypto-
coccosis, fluconazole was more effective than keto-
m
60-
\ \. conazole. Fluconazole and itraconazole have been
40- shown to be comparably effective in an immuno-
compromised rabbit model ofcryptococcal meningi-
20- tis [50].

'
5
I
I0
I
20
' I
3O
' I
4O Blastomycosis
A A A A
I I Days postinfection
Therapy
Mice challenged intranasally with Blastomyces
Fig. 2. Survival of mice with intracranial cryptococcosistreated dermatitidis developed a lethal infection, and 80% of
with placebo (~); oral fluconazole 5 mg/kg twice daily (A); oral
ketoconazole 50 mg/kg twice daily (o); intraperitoneal ampho- untreated animals died within 15 days [58]. Various
tericin B 3 mg/kg (,,) administered once daily as indicated by A. oral doses of fluconazole and ketoconazole were
Adapted from Troke et al. [54]. compared during 22 days of therapy and 2 months of
 151

too _1 -:,q
.~ ;.- ~li L
100 \ \ __. ~:~ ~ Control
/ (~ o-- Fluconazole
80-
8o- i:1 : °, ° 1 ~)~ 20 mg/kg
"~ ~ O-- Ketoconazole
m
>~
t/J
~"
:ii
[l
"

!', 1
,

''
:
D--

'TL
I

- ql
60-

40
& \
i~'(~
~)\ ~
,~
60 mg/kg
O - - Amphotericin B
3 mg/kg
3 times per wk

20

II II I[--] ~. . . . ,
\
0
i

• 1'0 2'o 3'o 40 so ~'o

~'o ~o 3~ ~o Days pastchallenge
Survival time (Bays) after inteetion with B. dermatitidi$
Fig. 5. Survival ofnu/nu congenitally athymic mice after intrana-
c = 100 mg/kg fluconazole o - - -o 10 mg/kg ketoconazole
o---,, 10 mg/kg fluconazole ..... 100 mg/kg ketoconazole sal challenge with 105 Histoplasma capsulatum, and treatment
= = 1 mg/kgfluconazole • ..... • No treatment from day 2 through day 44 with water (control), fluconazole 20
I I Treatment mg/kg per dose twice daily, ketoconazole orally 60 mg/kg per
dose twice daily, or amphotericin B 3 mg/kg three times per week
Fig. 3. Responses to various doses of fluconazole or ketocon- intraperitoneally. Adapted from Graybill et al. [61].
azole in mice infected with Blastomyces dermatitidis (LDso).
Adapted from Stevens et al. [58].

observation (Fig. 3). Fluconazole 10 mg/kg per day nite or probable infections, seven showed favorable
was significantly superior to ketoconazole 100 mg/ initial responses. However, relapse occurred upon
kg per day in prolonging life. interruption of treatment.

Co c c idio ido m y c o s is Histoplasmosis

Fluconazole, ketoconazole, and amphotericin B Disseminated histoplasmosis was established in

have been compared in a murine model of coccidi- athymic mice by intranasal injection of Histoplasma
oidal meningitis [59]. All three agents significantly capsulatum [61]. Oral fluconazole was equivalent to
prolonged survival compared to untreated controls oral ketoconazole or intraperitoneal amphotericin B
(Fig. 4). Fluconazole was also evaluated in naturally in prolonging survival compared to control mice
acquired coccidioidomycosis in Japanese macaque (Fig. 5). Kobayashi et al. [62,63] found that flucon-
monkeys [60]. Of nine assessable animals with deft- azole given orally for 6 consecutive days compared
100--/~ . . . . . . . .

Control
80-
Fluconazote
60 mg/kg
60- Fluconazole
20 mg/kg
Ketoconazole
40-
Amphotericin B

20-

0
6 10 14 18 22 26 30 34 38 42 46
Days postehallenge
Fig. 4. Survival of groups of 10 mice challenged intracerebrally stwith Coccidioides immitis and treated from day 1 through day 36 with
water (control), fluconazole, ketoconazole, or amphotericin B. All mice that succumbed had brain cultures positive for C. immitis.
Survivors were not cultured. Adapted from Graybill et al. [591.
 152

favorably with amphotericin B given intraperitone- pg]mL

ally in the treatment of histoplasmosis in normal and
1.5-
neutropenic mice.

Dermatophytosis
E
(n
Dermal infection with Trichophyton mentagro- g~-
1.0, I

phytes, T. rubrum, or Microsporum canis was in-

duced in guinea pigs in a model of dermatophytosis
[46]. Percentage reduction in lesion severity with flu- ;%
conazole 10 mg/kg per day was significantly greater 0.5.
than that with ketoconazole 20 mg/kg per day for E
each of the three infections.

Fusarium infection
2'4 48 7'2 9'6
Fluconazole, SCH 39304, itraconazole, and am- Hours postdose
photericin B were compared in a murine model of
disseminated Fusarium solani infection [64]. Azoles Fig. 6. Mean plasma concentrations of fluconazole over time
were administered oraliy twice daily at a dosage of 50 following administration of intravenous (u) and oral (e) doses of
50 mg to 12 healthy volunteers in a randomized, crossover study.
mg/kg. Median survival time with fluconazole was
Data on file, Pfizer Inc.
comparable to that with SCH 39304 and signifi-
cantly superior to that with itraconazole or intraper-
itoneal amphotericin B at 1 mg/kg per day. lase is a cytochrome P-450 linked monooxygenase.
Since cytochrome P-450 is present in mammalian or-
Mechanism of action gans and mediates reactions involving cholesterol,
adrenal steroid, and estrogen biosynthesis - - as well
Fluconazole is a highly selective inhibitor of la- as those responsible for drug metabolism - - the se-
nosterol C-14 demethylase, an enzyme which con- lectivity of fluconazole for fungal enzymes is an im-
verts lanosterol into ergosterol, an essential sterol in portant consideration [65].
fungal cell membranes. Lanosterol C-14 demethy- Fluconazole did not antagonize the activity ofam-
photericin B in a rabbit model of invasive aspergil-
TABLE 3 losis [66] and its activity was at least additive to that
Pharmacokinetic profile of fluconazole
of flucytosine in athymic mice infected intracere-
brally with Cr. neoformans [67]. However, no en-
Parameter Approximate hancement of activity was seen with the combination
mean (range) of fluconazole and flucytosine in a model of crypto-
coccosis in normal mice [68]. The concomitant use of
Cmaxafter single dose of 400 mg p.o. (mg/l) 6.7 (4.1-8.1)
fluconazole and flucytosine in patients with crypto-
tmax (h) 1-2
Plasma half-life (h) 30 (20-50) coccosis has been reported recently [69,70].
Apparent volume of distribution (1/kg) 0.7 (0.65-0.75)
Plasma protein binding (%) 11-12
Oral bioavailability (%) > 90 Pharmacokinetics
Total body clearance (ml/min per kg) 0.2-0.3
Renal clearance (ml/min per kg) 0.15-0.30
Analytical methods
Cma x --- maximum plasma concentration; tmax = time to achieve
maximum plasma concentration; p.o. = oral. For the assay of fluconazole in biologic fluid and
Adapted from Brammer et al. [72] and Dudley [73]. tissue, a high-performance liquid chromatographic
 153

'~ 1.25" daily to a patient with documented malabsorption of

T~.
ketoconazole has been described [76].
1.00.
Stable bone marrow transplant patients receiving
"~ 0.75"
twice-daily doses ofcyclosporine who were adminis-
w
tered fluconazole 100 mg/day for 14 days showed
'~ 0.50 - slight increases in cyclosporine plasma levels and
A U C values which did not reach statistical signifi-
"~ 0.25j cance [77]. However, higher fluconazole doses (200
mg daily for 14 days) were associated with significant
,5 o.oo increases in cyclosporine A U C values in renal trans-
Time after dose (h) plant patients [78]. Increased cyclosporine levels
Fig. 7. Concentrations offluconazolein plasma of human volun- were not associated with clinical evidence of cy-
teers followingadministration of 50-mgoral capsules in the fed closporine toxicity when fluconazole 100 mg/day
(o) and fasted (i) states. Data are mean values from 12 volun- was added to the therapeutic regimen of a renal
teers. Adapted from Brammer and Tarbit [20]. transplant patient receiving cyclosporine 100 mg/
day, however [79].
In healthy volunteers, 7-day multidose studies
without a loading dose [20] have demonstrated that
method has been developed [71]. Its sensitivity is fluconazole usually reaches 90% of steady-state lev-
-< 0.2 mg/1. els after 4 or 5 days of oral or intravenous admini-
The pharmacokinetic profile of fluconazole is stration (Fig. 9). These results are consistent with a
summarized in Table 3 [72, 73]. drug exhibiting an elimination half-life of about 30 h
[72]. Administration of a loading dose on day 1 of
Absorption twice the usual daily dose produces plasma levels
close to steady-state levels by the second day [80].
The pharmacokinetic properties of fluconazole
after oral or intravenous administration in healthy Distribution
volunteers are similar (Fig. 6). Fluconazole is rapidly
absorbed after oral dosing, providing plasma levels The apparent volume of distribution of flucon-
over 90% of those achieved after intravenous admin- azole is approximately 0.71/kg after intravenous [80]
istration [20]. There is no evidence, therefore, of first- or oral [81 ] dosing, a value close to that for total body
pass drug metabolism. Peak plasma levels after oral water. Fluconazole has a low affinity for plasma pro-
dosing occur within 1 or 2 h in the fasting state, and
oral absorption of fluconazole is not affected by
food (Fig. 7). As shown in Fig. 8, plasma levels are 4.0
proportional to dose. _m 3.5
Absorption of fluconazole is not significantly af-
i~ 3.0 -
fected by agents that increase gastric pH, such as
2.5-
Maalox® [74] or cimetidine [75]. In a randomized,
~'~ 2.0-
four-way crossover study, the effects of cimetidine-
~ • 15-
induced increases in gastric pH on the bioavailability
,o-
of oral doses of fluconazole 200 mg or ketoconazole Q.
0.5--
400 mg were evaluated in healthy male volunteers
[75]. The pharmacokinetic disposition of flucon- O0
0.5 1.0 1.5 2.5 3.0
0.0 ' ' ' 2'0. '
azole was unaffected by elevations in gastric pH pro- Oose level (mg/kg)
duced by cimetidine. In contrast, mean A U C and Fig. 8. Linear relationship between peak plasma concentration
C m a x values for ketoconazole were reduced 95%. of fluconazoleand dose level.Adapted from Brammer and Tar-
Good absorption of fluconazole given orally once bit [20].
154

2.0- (approximately 30 h) allows once-daily dosing. Since

1,8- fluconazole is cleared by renal mechanisms, appro-
~ 1.6" priate reductions in dosage should be made in pa-
~ 1.4- tients with renal impairment [87]. Because of its ex-
1.2-
cellent bioavailability, dosage adjustments with flu-
~ 0.8-
conazole are unnecessary when changing from an
g 0.6 intravenous to an oral route of administration (or
0.4 vice versa).
0.2 The usual clinical dosage ranges from 50 to 400 mg
g given once daily. In clinical trials, the highest dosage
Bay o! dosing administered was 2400 mg/day; no adverse effects
Fig. 9. Concentrations of fluconazole in plasma of human volun-
were noted [88].
teers immediately before dosing during oral (o) and intravenous Clinical pharmacology studies have confirmed the
(=) administration of 50 mg daily for 7 consecutive days. Data selectivity of fluconazole for fungal as opposed to
are mean values (_+ s.d.) from 10 volunteers. Adapted from mammalian cytochrome P-450 linked enzymes.
Brammer and Tarbit [20]. Doses of 50 mg/day had no clinically important ef-
fect on the cortisol response to ACTH or the levels of
gonadal hormones in healthy female volunteers, re-
teins and is not extensively bound to tissue proteins gardless of oral contraceptive usage. Healthy male
or fat; plasma protein binding has been estimated at subjects demonstrated small and inconsistent effects
11% to 12% [81]. In both clinical and animal experi- in testosterone levels [89] and in the adrenal response
mental studies, fluconazole penetrates well into to ACTH after administration of fluconazole in
body fluids and tissues (Table 4), including skin and doses up to 400 mg/day (unpublished data on file,
nails, blister fluid and blister skin, sputum [82], saliva Pfizer).
[20], cerebrospinal fluid (CSF) [71,83], eye fluids
[84,85], and prostate [86]. In patients with fungal
meningitis, fluconazole levels in CSF during therapy Pharmacy
have been approximately 80% of corresponding lev-
els in plasma [71,83]. Fluconazole is excreted in In the United States, fluconazole (Diflucan ®) is
human milk at concentrations similar to those in
plasma (unpublished data on file, Pfizer).
TABLE 4
Elimination and metabolism
Distribution of flucouazole in human tissues and fluids

Renal elimination is the predominant route of Tissue or fluid Ratio of fluconazole tissue
clearance for fluconazole [80,81]. Approximately (fluid)/plasma concentration*
80% of a single oral 50-mg dose is excreted un-
changed in urine, an elimination route which reflects Cerebrospinal fluid** 0.5-0.9
fluconazole's metabolic stability and relative polar- Saliva 1
Sputum 1
ity [20]. An additional 11% is recovered in urine as Blister fluid 1
the glucuronide and N-oxide metabolites at a ratio of Urine l0
3:1. Two percent is recovered as unchanged drug in Normal skin 10
feces; the fate of 7% of the dose is unknown [73]. Nails 1
Blister skin 2

*Relative to concurrent concentrations in plasma in subjects

Clinical pharmacology with normal renal function.
** Independent of degree of meningeal inflammation.
The prolonged elimination half-life of fluconazole Data on file, Pfizer Inc.
 155

available as tablets or powder for oral administra- der for oral suspension, and solution for intravenous
tion and as a solution for intravenous use. Diflucan use are also available.
tablets contain 50, 100, or 200 mg offluconazole and
the following inactive ingredients: microcrystalline Dosage and administration
cellulose, dibasic calcium phosphate anhydrous, po-
vidone, croscarmellose sodium, FD&C Red No. 40 Since oral absorption is rapid and almost com-
aluminum lake dye, and magnesium stearate. Di- plete, the daily dose of fluconazole is the same for
flucan powder for the oral suspension is contained in oral and intravenous administration (Table 5).
35-ml bottles containing 350 mg and 1400 mg of Di-
flucan per bottle. Diflucan for infusion is an isoos-
motic, sterile, nonpyrogenic solution of fluconazole Drug interactions
in a sodium chloride diluent. Each ml contains 2 mg
offluconazole and 9 mg of sodium chloride. The pH Potential drug interactions with fluconazole
ranges from 4.0 to 8.0. Injection volumes of 100 ml [90,91] are an important consideration as many pa-
and 200 ml are packaged in glass and in Viaflex ®Plus tients receiving antifungal therapy are seriously ill
plastic containers. and likely to receive other medications as well. Table
Diflucan tablets should be stored below 30°C. 6 summarizes key drug interaction data with flucon-
Diflucan injections in glass bottles should be stored azole.
between 30°C and 5°C and protected from freezing. Fluconazole increased the prothrombin time after
Diflucan injections in Viaflex ® Plus plastic contain- warfarin administration. A single dose of warfarin
ers should be stored between 25°C and 5°C and pro- 15 mg given to normal volunteers after 14 days of
tected from freezing. Brief exposure up to 40°C does fluconazole 200 mg/day produced a 12% increase in
not adversely affect the product. the prothrombin time response (area under the
Outside of the United States, fluconazole (Di- prothrombin time-time curve). One of 13 subjects
flucan ®) is available as gelatin capsules containing experienced a two-fold increase in prothrombin time
50, 100, 150, or 200 mg offluconazole. A syrup, pow- response. Careful monitoring of prothrombin time

TABLE 5
Fluconazole dosing regimens

Indication Daily dose* Duration

Oropharyngeal
candidiasis 50-100 mg/day 1-2 weeks

Esophageal 50-100 mg/day 2 4 weeks, or at least

candidiasis (up to 400 mg/day) 2 weeks after resolution

Systemic 200-400 mg/day --> 4 weeks, or at least

candidiasis 2 weeks after resolution

Cryptococcal meningitis
Acute therapy 200400 mg/day at least 6-8 weeks depending on response; or 10-12
weeks after CSF becomes negative

Suppressive
therapy in AIDS 200 mg/day

See text for alterations in patients with impaired renal function.

*An initial loading dose of twice the daily dose should be given.
156

in patients receiving fluconazole and coumarin-type of cyclosporine concentrations in patients receiving

anticoagulants is recommended. fluconazole and cyclosporine is recommended.
Fluconazole increased the plasma concentrations Fluconazole increased the plasma concentrations
of phenytoin. Concomitant administration of oral and reduced the metabolism of tolbutamide, gly-
fluconazole (200 mg) at steady state with phenytoin buride, and glipizide. In placebo-controlled cross-
at steady state resulted in an average increase of 75% over studies, normal volunteers received the sulfon-
of phenytoin AUC values in normal volunteers. ylurea alone and following treatment with flucon-
Careful monitoring of phenytoin concentrations in azole 100 mg/day for 7 days. Fluconazole was associ-
patients receiving fluconazole and phenytoin is rec- ated with significant increases in Cmaxand AUC of
ommended. the sulfonylurea; several subjects experienced symp-
Fluconazole has been infrequently associated toms consistent with hypoglycemia. When flucon-
with an increase in cyclosporine concentrations in azole is used concomitantly with these or other sul-
renal transplant patients with or without impaired fonylurea oral hypoglycemic agents, blood glucose
renal function. Stable bone marrow transplant pa- concentrations should be carefully monitored, and
tients receiving twice-daily doses of cyclosporine the dose of the sulfonylurea should be adjusted as
who were administered fluconazole 100 mg/day for necessary.
14 days demonstrated slight increases in cy- Rifampin enhances the metabolism of concur-
closporine Cmax,Cmm,and AUC values which did not rently administered fluconazole. Administration of
achieve statistical significance. Careful monitoring a single oral 200-mg dose of fluconazole after
chronic rifampin administration produced a 25% de-
crease in AUC and a 20% shorter half-life offlucon-
TABLE 6 azole in normal volunteers. Depending on clinical
circumstances, consideration should be given to in-
Fluconazole drug interactions
creasing the dose of fluconazole when it is adminis-
Drug/class Results tered with rifampin.

Cimetidine No significant change in fluconazole absorp-

tion Therapeutic use
OC No significant pharmacokinetic change in es-
trogen or progesterone components In the United States, fluconazole has been found
useful for the treatment of oropharyngeal and eso-
Rifampin Significant decrease in fluconazole's AUC and phageal candidiasis; disseminated candidal infec-
half-life tions, including urinary tract infection, peritonitis,
and pneumonia; and cryptococcal meningitis.
Warfarin Slight but significant increase in AUC
prothrombin time In addition to the above indications, fluconazole
has been used in a number of countries for the treat-
Tolbutamide Significant increase in AUC of tolbutamide ment of acute or recurrent vaginal candidiasis; der-
and prolongation of half-life matomycosis, including infection caused by Tinea
pedis, T. corporis, T. cruris, T. versicolor, and Can-
Testosterone No significant changes in testosterone levels
dida spp.; and for prevention of fungal infections in
ACTH No change in adrenal response patients with malignancy who are predisposed to
such infection because of cytotoxic chemotherapy or
Cyclosporin A Increased cyclosporin levels may occur de- radiotherapy.
pending on dose and patient population Fluconazole was evaluated in formal clinical trials
which involved over 5000 patients treated for a vari-
Phenytoin Phenytoin metabolism inhibited
ety of fungal infections, including cryptococcal men-
Adapted from Lazar and Wilner [91]. ingitis in HIV-infected patients and various forms of
OC = oral contraceptive; ACTH = adrenocorticotrophic hormone. mucosal or systemic candidiasis, mainly in immuno-
 157

compromised patients. The prophylactic efficacy of patients in each group had clinically quiescent dis-
fluconazole in preventing fungal infection in im- ease but persistently positive or only one negative
munocompromised cancer patients was also as- CSF culture.
sessed. In the study reported by Larsen et al. [93], 10
weeks of oral fluconazole 400 mg once daily was
Cryptococcal meningitis compared with intravenous amphotericin B (0.7 mg/
kg daily for 1 week, then three times weekly for 9
Clinical efficacy of fluconazole in acute crypto- weeks) combined with oral flucytosine (150 mg/kg
coccal meningitis has been studied in over 300 HIV- daily) in AIDS patients treated for an initial episode
infected patients. Comparative trials (Table 7) in- of acute cryptococcal meningitis. Treatment failed
cluded previously untreated patients and those who for eight of 14 fluconazole recipients compared to
had relapsed after successful antifungal therapy [92- none of six patients given amphotericin B plus flucy-
95]. tosine. However, the frequency and severity of toxic
In a 10-week randomized multicenter trial, Saag et side effects were higher with the combination regi-
al. [92] compared oral fluconazole 200 rag/day with men.
intravenous amphotericin B in a minimum dosage of Nine AIDS patients with evidence of nonmenin-
0.3 mg/kg per day with or without flucytosine. Suc- geal cryptococcal infection were treated with flucon-
cessful outcomes - - clinical improvement or com- azole 400 mg/day plus flucytosine 150 mg/kg per day
plete resolution of symptoms along with two consec- [69]. The positive pretreatment blood culture of one
utive negative CSF cultures - - were obtained in 34% patient became negative 3 days after initiation of
of fluconazole-treated patients and in 40% of pa- therapy. All CSF cultures after 2 weeks of treatment
tients given amphotericin B. Approximately 25% of remained negative, and flucytosine was discontin-

TABLE 7
Comparative clinical trials of fluconazole in cryptococcal meningitis

Reference Type of infection Treatment regimen* Favorable response**

No. (%)

Saag et al. [92] Acute F 200 p.o. x 70 78/131 (60%)

(AIDS) A > 0.3 mg/kg i.v. x 70 42/63 (67%)

Larsen et al. Acute F 400 p.o. × 70 6/14 (43%)***

[93] (AIDS) A 0.7 mg/kg i.v. x 21, 6/6 (100%)
5 FC 150 mg/kg p.o. x 70

Bozzette et al. Suppression of relapse F 100~200 p.o. × 164 av 33/34 (97%)***

[94] (AIDS) PL p.o. x 117 av 17/27 (63%)

Powderly et al. Suppression of relapse F 200 p.o. × 279 med 109/111 (98%)***
[95] (AIDS) A 1 mg/kg week i.v. x 140 med 64/78 (82%)

F = fluconazole; A = amphotericin B; 5 FC = flucytosine; PL = placebo; p.o. = oral; i.v. = intravenous; av = mean; med = median.
*Unless otherwise stated, treatment regimen refers to drug dosage in mg/day, route of administration, and maximum duration of
therapy in days.
**Favorable response among evaluable patients denotes cure or improvement in acute studies or absence of relapse at any site in
suppression studies.
***Significant difference between treatments (P < 0.05); Fisher's exact test (Larsen et al.; Powderly et al.), Mantel-Haenszel method
(Bozzette et al.).
158

TABLE 8
Comparative clinical trials of fluconazole in candidiasis

Reference Type of infection Treatment regimen* Favorable clinical response*

No. (%)

Multicentre Vaginal F 150 p.o. x 1 141/152 (93%)***

Trial [98] C 200 V x 3 113/135 (84%)
Herzog and Vaginal F 150 p.o. x 1 38/47 (81%)
Ansmann [99] E 50 V x 6 39/49 (80%)
Svensson Vaginal F 150 p.o. x 1 79/98 (81%)***
[100] E 150 V x 1 56/84 (67%)
Kutzer et al. Vaginal F 150 p.o. x 1 65/76 (86%)
[101] K 400 p.o. x 5 63/72 (88%)
Rees Vaginal F 150 p.o. x 1 138/164 (85%)
[102] 1 400 p.o. x 1 120/142 (85%)
Stein et al. Vaginal F 50 p.o. x 3 70/86 (81%)
[103] C 200 p.o. x 3 72/86 (84%)
Sobel Recurrent vaginal F 150 p.o. or 25/43 (58%)***
[104] PL monthly x 12 15/47 (32%)
Pons et al. Oropharyngeal F 100 p.o. x 14 146/151 (97%)
[105] (AIDS) C 50 T x 14 127/135 (94%)
Hathorn et al. Oropharyngeal F 100 p.o. x 7 205/214 (96%)***
[106] (cancer) C 50 T x 14 71/91 (78%)
De Wit et al. Oropharyngeal F 150 p.o. x 1 21/24 (88%)
[1071 (AIDS) F 50 p.o. x 7 26/27 (96%)
De Wit et al. Oropharyngeal F 50 p.o. x 28 17/17 (100%)***
[108] (AIDS) K 200 p.o. x 28 12/16 (75%)
Meunier et al. Oropharyngeal F 100 p.o. + 28/32 (88%)
[109] (cancer) K 400 p.o. + 32/36 (89%)
Swinne Oropharyngeal F 150 p.o. or 7/8 (88%)***
[110] (suppression of relapse, AIDS) PL weekly x 26 ++ 3/8 (38%)
Leen et al. Oropharyngeal F 150 p.o. or 5/9 (56%)***
[111] (suppression of relapse, AIDS) PL weekly +24 ++ 0/5 ( )
Laine et al. Esophageal F 100 p.o. x 56 68/72 (94%)***
[112] (AIDS) K 200 p.o. x 56 61/71 (86%)
Lake-Lewin et al. Esophageal F 200 p.o. x 28 12/13 (92%)
[113] (cancer) A 0.34).6 mg/kg 10/12 (83%)
i.v. x 28

F -- fluconazole; C = clotrimazole; E = econazole; K = ketoconazole; I = itraconazole; PL = placebo; A = amphotericin B;

p.o. = oral; V = intravaginal; T = troche; i.v. -- intravenous.
*Unless otherwise stated, treatment regimen refers to drug dosage in rag/day, route of administration, and maximum duration of
therapy in days.
**Favorable clinical response among evaluable patients denotes cure or improvement in acute studies or absence of relapse in suppres-
sion studies.
***Significant difference between treatment groups (P < 0.05), Fisher's exact test except logistic regression analysis (Multicentre Trial)
and Mantel-Haenszel method (Hathorn et al., Laine et al.).
+Fluconazole was administered for a median duration of 13 days and ketoconazole for 12.5 days.
++Fluconazole 50 mg was given once daily for up to 28 days prior to suppression study.

u e d a f t e r 4 w e e k s . A f t e r 10 w e e k s , t h e f l u c o n a z o l e vation period of 6 to 9 months. Although two pa-

d o s a g e w a s r e d u c e d t o a m a i n t e n a n c e level o f 200 tients developed other opportunistic infections,
mg/day. All nine patients survived during the obser- none developed cryptococcal meningitis.
 159

Recently, Jones et al. [70] reported the treatment sis) has been established by the randomized compar-
of acute cryptococcal meningitis with oral flucon- ative trials shown in Table 8 [98-113]. In addition,
azole 400 mg/day combined with oral flucytosine 150 fluconazole was evaluated in noncomparative trials
mg/kg per day in 15 evaluable patients. CSF culture (unpublished data on file, Pfizer) involving over 500
conversion occurred in 11 patients (median time, 21 patients, nearly all of whom were immunocompro-
days), with the remainder culture-positive after 70 mised. Of 209 patients with AIDS in the noncom-
days of therapy. Two patients died, with one death parative trials, 76% were infected with oropharyn-
due to cryptococcosis. Fluconazole was well toler- geal candidiasis. Of the 311 non-AIDS patients, 60%
ated, while flucytosine was associated with gastroin- had oropharyngeal candidiasis and the remainder
testinal complaints and neutropenia. had disseminated or deep visceral infections.
Two randomized multicenter trials evaluated flu-
conazole for suppression of relapse of AIDS-associ- Vaginal candidiasis
ated cryptococcal meningitis after successful pri-
mary therapy with amphotericin B (Table 7). Flu- Single oral doses of fluconazole (150 mg) have
conazole 200 mg/day was compared with placebo been effective and well tolerated in women with
[94], or amphotericin B 1 mg/kg per week [95]. In vulvovaginal candidiasis [98,114]. In comparative
each trial, fluconazole was significantly superior for studies (Table 8), a single oral dose of fluconazole
maintenance therapy than the comparative agent 150 mg was significantly more effective in relieving
(placebo or amphotericin B). Further, fluconazole clinical symptoms than intravaginal clotrimazole
was well tolerated; treatment-related side effects 200 mg for 3 days [98] or intravaginal econazole 150
were more frequent with weekly administration of mg for one day [100]. Stein et al. [103] found that
amphotericin B than with daily doses of fluconazole 3-day regimens of either fluconazole 50 mg/day or
[95]. clotrimazole 200 mg/day were similarly effective
Fluconazole has been effective for persistent cryp- (Table 8).
tococcal prostatic infection in AIDS patients [86]. Clinical response with a single oral dose of flucon-
Fourteen patients who had completed standard am- azole was similar to that with intravaginal econazole
photericin B therapy with or without flucytosine had 50 mg for 6 days [99], oral ketoconazole 400 mg for 5
sterile cultures of blood and CSF at the time that days [101], or oral itraconazole 400 mg in 1 day [102].
urine cultures following prostatic massage grew In the itraconazole comparison, Candida spp. were
Cryptococcus neoformans. Fluconazole was given absent in vaginal cultures of 81% of fluconazole re-
orally at 100 to 400 mg/day for a median duration of cipients and 71% of itraconazole recipients at the
30 weeks. Seven of 14 patients responded, with sus- first follow-up visit (P = 0.03) and in 59% and 49%,
tained suppression of cryptococcuria and absence of respectively, at the second visit 26 to 50 days after
systemic or CNS relapse. The other seven continued treatment (P = 0.07).
to shed Cr. neoformans after a median of 29 weeks of In patients with recurrent vaginal candidiasis
treatment; meningitis recurred in two of these nonre- [104], once-monthly suppressive therapy with flu-
sponders despite negative cryptococcal antigen titers conazole 150 mg was significantly superior to pla-
in serum and CSF. cebo in reducing the frequency of infection over a
Successful management of AIDS-associated cryp- 12-month period.
tococcal meningitis with fluconazole in patients pre-
viously unresponsive to amphotericin B therapy has Oropharyngeal candidias&
been reported [96,97].
In immunocompromised cancer patients with
Candidiasis oropharyngeal candidiasis (Table 8), clinical re-
sponse with fluconazole 100 mg/day was signifi-
The efficacy offluconazole in various types ofcan- cantly superior to that with clotrimazole 10-mg tro-
didiasis (vaginal or recurrent vaginal candidiasis, ches five times daily [106] and comparable to oral
oropharyngeal candidiasis, or esophageal candidia- ketoconazole 400 rag/day [109]. For oropharyngeal
160

candidiasis in AIDS patients, fluconazole 100 mg/ (at autopsy, one patient had pulmonary aspergillosis
day was comparable in clinical efficacy to clotrima- as well as disseminated candidiasis).
zole 10-mg troches five times daily [105,115], and flu- Clinical experience with fluconazole in dissemi-
conazole 50 mg/day was significantly superior to nated candidiasis has been gained in noncompara-
ketoconazole 200 mg/day [108]. Pons et al. [105] tive clinical trials and in small groups of patients,
showed that fluconazole recipients were signifi- including those who failed or could not tolerate con-
cantly more likely to remain free of candidiasis 2 ventional therapy. Fluconazole has been effective in
weeks after the conclusion of treatment. patients with deep-seated or disseminated forms of
Fluconazole has been found effective in AIDS pa- candidiasis [121-124] including chronic dissemi-
tients with oropharyngeal candidiasis unresponsive nated candidiasis (also known as hepatosplenic can-
to other agents, including nystatin, clotrimazole, didiasis) - - a form of disseminated infection which
and ketoconazole [116,117]. Single-dose treatment occurs in leukemic patients after cytotoxic chemo-
with fluconazole 150 mg in HIV-positive patients therapy [120].
has shown promise [118]. An initial clinical success Oral fluconazole at 200 to 400 rag/day was fre-
rate of 100% after 4 days was followed by recurrence quently successful both clinically and radiologically
of signs and symptoms of oral candidiasis in 10 of 23 in patients with active hepatosplenic candidiasis who
patients evaluated during a 6-week period. How- had failed or could not tolerate amphotericin B ther-
ever, all responded again to a second 150-mg dose. In apy [125,126]. Of 16 patients who completed the
double-blind studies [110,111], weekly fluconazole study conducted by Anaissie et al. [125], eight
(150 mg) was significantly more effective than pla- achieved and maintained a complete clinical, bio-
cebo in suppressing relapse of oropharyngeal can- chemical, and radiological response. Six had a par-
didiasis over a 6-month period in patients with tial response, with a favorable clinical outcome, nor-
AIDS. malization of liver function tests and ultrasound
studies, but persistence of lesions on CT scan. Fever
Esophageal candidiasis resolved in all six patients treated by Kauffman et al.
[126]. CT scans showed resolution in four patients,
In two comparative studies of esophageal candidi- improvement in one other.
asis (Table 8), fluconazole 100 mg/day was compara- Robinson et al. [127] described the treatment of
ble in clinical efficacy to ketoconazole 200 mg/day in seven patients with culture-documented dissemi-
patients with AIDS [112] and to amphotericin B 0.3 nated or visceral candidiasis; a 400-mg loading dose
to 0.6 mg/kg per day in patients with cancer [113]. In of fluconazole was followed by the usual dosage of
the study of AIDS patients, endoscopic cures 5 days 200 mg once daily. Infections included candidemia,
after completion of therapy were observed in 91% of peripancreatic abscesses, and peritonitis. Clinical
the fluconazole group and 52% of the ketoconazole improvement was obtained in five of the seven pa-
group (P < 0.001]. tients treated. Meunier [128] administered intrave-
nous doses of fluconazole (100 to 300 mg/day) for a
Disseminated candidiasis period of 4 to 32 days to eight cancer patients with
nine episodes of candidemia. Six of the eight evalua-
Nosocomial candidiasis and candidemia are now ble cases were considered cured.
major threats to immunocompromised patients, Oral or intravenous fluconazole was administered
particularly neutropenic patients with cancer at 100 to 200 mg once daily to five transplant patients
[119,120]. Other risk factors include steroid or anti- with six episodes of life-threatening candidal infec-
biotic therapy, recent abdominal surgery, concomi- tions, including peripancreatic abscesses (three epi-
tant diabetes, presence of central venous catheters, sodes), splenic abscess, pyelonephritis, and peritoni-
and use of total parenteral nutrition. A recent review tis (one episode each) [129]. Two patients had had
of 55 cancer patients for whom blood samples were pancreas and kidney transplants, and the remainder
positive for yeasts [119] showed that 23 (42%) died, liver transplants. Despite maintenance of high-dose
including 15 of 28 patients with C. albicans infection immunosuppressive therapy, all patients survived
 161

and had a complete clinical response. All but one Prophylaxis of fnngal infection
patient had a mycological cure as well; one diabetic
patient who had candidal pyelonephritis following Candida spp. are increasingly important noso-
kidney transplant responded with initial clearance of comial pathogens in i m m u n o c o m p r o m i s e d patients,
C. albicans from blood and urinary tract, followed including those with cancer, those who have had
by asymptomatic recurrence o f c a n d i d u r i a after ces- organ transplants or extensive surgery, and patients
sation o f treatment. in intensive care units. In a prospective study
These results in disseminated candidiasis suggest [25,133,134], patients admitted to the bone marrow
that fluconazole is a useful addition to the currently transplantation and medical intensive care units o f a
available antifungal agents. Comparative clinical tri- tertiary care hospital were cultured to determine
als with other drugs used in the treatment of these candidal colonization rates. Exogenous acquisition
infections are awaited with interest. of Candida s p p . - including C. lusitaniae [133] - -
was demonstrated.
Other candidal infection The prophylactic efficacy of fluconazole has been
established in patients with malignancies who were
Successful fluconazole therapy of candidal pros- at risk of fungal infection (Table 9) [39-43,135]. Flu-
thetic valve endocarditis [130], renal candidiasis fol- conazole 50 mg daily for 28 days was significantly
lowing a failed transplant [122], and Candida perito- more effective than placebo [43] or oral polyenes
nitis complicating continuous ambulatory perito- (Philpott-Howard et al., personal communication)
neal dialysis [131,132] has been reported. for prevention ofcandidiasis in patients with cancer.

TABLE 9
Comparative clinical trials of fluconazolein prophylaxis of fungal infection

Reference Clinical setting Treatment regimen* Favorable

clinical response**
No. (%)

Goodman et al. Bone marrow F 400 p.o. x 70 159/179 (89%)***

[39] transplantation PL p.o. x 70 90/177 (51%)

Winston et al. Leukemia F 400 p.o. x 70 111/124 (90%)***

[40] (neutropenia) PL p.o. x 70 102/133 (77%)

Anaissie et al. Leukemia F 400 p.o. 22/44 (92%)

[41] (neutropenia) A 0.5 mg/kg i.v.3 x/w 18/21 (86%)

Rozenberg-Arska Leukemia F 50 p.o. 24/25 (96%)

et al. [42] (rieutropenia) A 400 p.o.q.i.d. 24/25 (96%)

Bodey et al. Cancer F 50 p.o. x 28 57/58 (98%)***

[43] PL p.o. x 28 39/54 (72%)

Meunier et al. Cancer F 200 p.o. x 16 (median) 26/30 (87%)

[135] A p.o. 400 o.d. + 10 t.i.d. 23/29 (79%)

F = fluconazole;A = amphotericin B; PL = placebo; p.o. = oral; i.v. = intravenous.

*Unless otherwise stated, treatment regimen refers to drug dosage in mg/day, route of administration, and maximum duration of
therapy in days.
**Absence of fungal infection in evaluable patients; absence of oropharyngeal candidiasis in Bodey et al.
***Significantdifferencebetween treatments (P < 0.05); Fisher's exact test.
162

In 45 neutropenic adults with leukemia [41], oral In those undergoing intensive chemotherapy for
fluconazole 400 mg once daily and intravenous am- acute leukemia [40], failure of prophylaxis (proven
photericin B 0.5 mg/kg three times per week were or suspected systemic infection) occurred earlier and
similarly effective in preventing fungal infection. more frequently with placebo (P = 0.098). Proven
Both drugs were 100% effective in preventing thrush, systemic fungal infection occurred in 10 placebo re-
while five disseminated infections were noted - - two cipients and in five fluconazole recipients. Empirical
with fluconazole (T. glabrata, A. terreus) and three amphotericin B therapy was used earlier and more
with amphotericin B ( C. albicans [one], Aspergillus frequently in the placebo group (P = 0.03).
spp. [two]). In a comparison of fluconazole 50 mg/ In patients about to undergo allogeneic or autolo-
day and oral amphotericin B (200-rag suspension, gous bone marrow transplantation [39], fluconazole
200-mg tablets four times daily) in 50 adult patients effectively prevented both superficial and dissemi-
with acute leukemias undergoing remission induc- nated fungal infections, including systemic infec-
tion chemotherapy [42], two fungal infections were tions with all strains of Candida except C. krusei.
documented - - disseminated aspergillosis in a pa- Although there was no significant difference in over-
tient given fluconazole and oropharyngeal candidia- all mortality between the groups, death was attri-
sis in one patient given amphotericin B. Fluconazole buted to fungal infection in 10 patients in the placebo
effectively prevented yeast colonization of the oro- group compared with one in the fluconazole group
pharynx but was less effective than amphotericin B (P < 0.001). Use of empirical amphotericin B was
in preventing colonization of the lower gastrointesti- significantly delayed with fluconazole (P < 0.004).
nal tract. As reported by Chandrasekar et al. [137,138], flu-
In a large, prospective, randomized trial, flucon- conazole prophylaxis in comparison to placebo
azole 50 rag/day was compared to oral polyenes (at markedly reduced amphotericin B requirements and
least 4 x 106 units/day nystatin or 2 g/day amphoter- suppressed C. albicans colonization in neutropenic
icin B in multiple daily doses) in 511 patients at high patients undergoing bone marrow transplantation
risk of neutropenia because of chemotherapy, radio- or chemotherapy for acute leukemia.
therapy, or bone marrow transplantation [136]. Oro- Milliken et al. (personal communication) com-
pharyngeal candidiasis was observed in four flucon- pared two antifungal prophylactic regimens in 99 pa-
azole and 22 polyene-treated patients (P < 0.001). tients undergoing cytotoxic marrow ablation for
Systemic fungal infections were documented in six treatment of malignancy. One consisted of oral flu-
fluconazole-treated and nine polyene-treated pa- conazole 200 mg once daily; the other was a polyene
tients. regimen consisting ofnystatin (200 000 units suspen-
Prophylaxis with fluconazole 200 mg once daily or sion every 4 h, 500 000-unit tablet every 12 h) plus
amphotericin B administered as one 400-mg capsule amphotericin B (one 10-rag lozenge and two 100-mg
plus one 10-mg tablet to suck every 8 h was evaluated tablets every 6 h). Treatment began 1 week before the
in 59 granulocytopenic patients [135]. Prophylaxis start of cytotoxic therapy and continued for a mini-
was initiated within 2 days of granulocytopenia or mum of 4 weeks, either until the neutrophil count
immediately after administration of antineoplastic reached 1 x 109[1 o r t o a maximum of 8 weeks. Fun-
therapy for a median duration of 16 days in each gal surveillance cultures were obtained weekly from
group. Documented fungal infections occurred in swabs of the oral cavity and genitalia, as well as from
four patients receiving fluconazole and six receiving samples of urine, stool, and blood. Systemic ampho-
amphotericin B. No invasive candidiasis caused by tericin B could be substituted for study medication in
C. albicans was observed, however. Fluconazole was the event of severe mucositis or for persistent fever of
better tolerated, and had to be discontinued in only unknown origin unresponsive to two changes of
one of 30 patients compared with five of 29 discon- broad-spectrum antibiotics.
tinuations with amphotericin B. Surveillance cultures were persistently negative
Two multicenter placebo-controlled studies eval- for 29 fluconazole recipients (59%) and 23 polyene
uated fluconazole 400 rag/day for antifungal pro- recipients (46%). Seven patients in the fluconazole
phylaxis in severely neutropenic patients (Table 9). group and nine in the polyenes group had one or
 163

more positive cultures but no evidence of fungal in- in doses of 200 to 400 mg/day [145]. Cure or improve-
fection. Thus a favorable prophylactic response was ment was noted in 15 of 23 evaluable patients treated
obtained in 36 of 49 fluconazole recipients (73%) for a mean duration of 6 months. No relapses were
compared to 32 of 50 polyene recipients (64%) seen among responders during a mean off-therapy
(P > 0.1). However, systemic amphotericin B was interval of 7 months.
administered more frequently in the polyene group Active cutaneous and lymphangitic sporotricho-
- - either for severe mucositis (nine patients - - flu- sis in 13 patients with Sporothrix schenckii-positive
conazole, eight - - polyene) or for persistent fever lesions responded to fluconazole 400 mg/day [146].
(seven - - fluconazole, 16 - - polyene; P = 0.06). Mycological cure was obtained in 11 of 13 patients
With one exception, all fungal infections were oro- treated for a mean duration of 180 days.
pharyngeal candidiasis (six - - fluconazole, 13 ---
polyene; P = 0.078); one polyene recipient devel- Other studies
oped C. albicans urinary tract infection.
Pediatric patients
Endemic mycoses
Although not yet approved for pediatric use, flu-
Amphotericin B remains the drug of choice in the conazole appears to be safe and effective in children.
treatment of endemic mycoses in severely ill patients, Viscoli et al. [147] treated 34 episodes of candidiasis
especially immunocompromised patients with dis- in 24 immunocompromised children with either oral
seminated infections [139,140]. However, flucon- or intravenous fluconazole in dosages of 6 to 12 mg/
azole has been effective for deep mycoses in im- kg per day given for a median of 12 days. In four
munocompetent hosts. As reported by the Flucon- episodes, isolation of Candida spp. from at least
azole Pan-American Study Group [88], favorable re- three colonization sites (defined as multiple Candida
sponses to therapy were obtained in coccidioidomy- colonization) in the setting of persistent or relapsing
cosis (14 of 16 patients), paracoccidioidomycosis (27 fever after a prolonged period of antibacterial ther-
of 28), histoplasmosis (eight of eight), and sporo- apy was considered suggestive of candidiasis and
trichosis (13 of 19). treated accordingly. Overall, 30 episodes were cured
In coccidioidomycosis, oral therapy with keto- with clinical resolution and mycological eradication
conazole or fluconazole may be useful in patients - - including 16 of 17 episodes of severe oropharyn-
with chronic, nonprogressive infections. Pulmonary geal candidiasis, eight of nine urinary tract infec-
and nonmeningeal disseminated infections [141,142] tions, three of four multiple colonizations in persis-
as well as meningeal infections [84,142-144] have re- tently febrile cancer patients, two fungemias due to
sponded to fluconazole. For nonmeningeal infec- C.parapsilosis, and one episode of Candida otitis. All
tion, Galgiani et al. [142] obtained successful re- patients survived. Of the four episodes not respond-
sponses - - any improvement within 4 months and at ing to treatment, one involved a subhepatic abscess
least 50% improvement by 8 months - - in 61% of 71 due to C. krusei. Ten of the 30 responders relapsed
patients given oral doses of 200 to 400 mg/day. Of 38 after discontinuation of therapy.
patients with coccidioidal meningitis treated with Fluconazole was administered to 214 pediatric pa-
400 mg/day, one patient failed to respond, four died tients, aged 2 days to 16 years, for proven or sus-
(three AIDS, one stroke), one was lost to follow-up, pected fungal infection and also on a prophylactic
while all others were clinically stable on therapy. basis as part of an open, uncontrolled compassion-
Tucker et al. [144] obtained responses in five of eight ate-use trial [148]. Children received average daily
evaluable patients with meningitis given fluconazole doses ranging from 0.16 to 16 mg/kg. The duration
as sole therapy in doses of 50 to 400 mg/day. Two of therapy ranged from 1 to 340 days.
patients who discontinued treatment after an initial In patients with documented fungal infection
response both relapsed. (presence of a baseline pathogen), clinical cure or
For blastomycosis, the N I A I D Mycoses Study improvement was achieved in 86% (83/97) ofevalua-
Group found fluconazole to be moderately effective ble patients. Mycological eradication was achieved
164

in 79% (73/92) of evaluable patients. In 95 patients or 15 mg/kg per day for 12 months showed that the
no pathogen was documented, although most of liver was a target organ in all three species. Changes
these children received fluconazole for prophylaxis consisted of increases in relative organ weight and
or to treat a suspected fungal infection based on clin- fatty deposition, occasionally accompanied by trans-
ical signs and symptoms alone. Related or possibly aminase elevations; the magnitude of these changes
related adverse events occurred in 6% (13/214) of the in all cases was mild.
patients, six of whom were withdrawn from therapy.
These studies suggest that fluconazole may repre- Teratogenicity studies
sent an alternative to amphotericin B in the treat-
ment ofcandidiasis in children. However, compara- Fetotoxicity studies [152] showed that fluconazole
tive trials are needed to assess efficacy and optimal was neither embryotoxic nor teratogenic in rabbits
dosage - - particularly in neonates. and rats at doses up to 25 mg/kg per day, levels at
which maternal toxicity or hormonal disturbances
Aspergillosis were noted. Rats showed an increased incidence of
supernumerary ribs (an anatomical variant) at the
For aspergillosis, fluconazole has shown protec- higher doses in these studies. Fetal effects and de-
tive and therapeutic effects in animal models [55] at layed parturition demonstrated in rats were consis-
dosages greater than those evaluated clinically. Clin- tent with the estrogen-lowering properties offlucon-
ical cure of an immunocompetent patient with As- azole in this species (unpublished data on file,
pergillus pneumonia has been reported [149].. Pfizer).
Dermatomycosis

A few studies have evaluated fluconazole therapy Human toxicity and high-risk patient groups
in patients with dermatophytosis. One trial [150] as-
sessed doses of 50 mg daily for up to 28 days in 32 Special precautions
patients, most of whom had tinea pedis due to T.
rubrum. Mycological and clinical remission was In combined clinical trials and marketing experi-
noted in 87% of patients, with only marginal de- ence outside the United States prior to U.S. market-
creases in response 4 weeks after treatment ended. ing, patients with serious underlying disease (pre-
Weekly doses of fluconazole 150 mg were clinically dominantly AIDS or malignancy) rarely developed
and mycologically effective over a 1-month period in serious hepatic reactions or exfoliative skin disor-
mild to moderate tinea infections [151 ]. ders during treatment with fluconazole (unpub-
lished data on file, Pfizer). Two of these hepatic reac-
tions and one exfoliative skin disorder (Stevens-
Toxicology Johnson syndrome) were associated with a fatal out-
come. Because most of these patients were receiving
Animal toxicity studies multiple concomitant medications, including many
known to be hepatotoxic or associated with exfolia-
Fluconazole was found to have a very low poten- tive skin disorders, the causal association of these
tial for acute toxicity after oral or intravenous ad- reactions with fluconazole therapy is uncertain. Pa-
ministration of high doses to mice and rats [152]. In tients who develop abnormal liver function tests dur-
chronic toxicity studies, rats given intraperitoneal ing fluconazole therapy should be monitored for the
doses of 5, 25, or 75 mg/kg per day for 6 months development of more serious hepatic injury. If clini-
showed mild hepatic changes, including slight hepa- cal signs and symptoms consistent with liver disease
tocellular hypertrophy and fatty deposition at the develop which may be attributable to ftuconazole,
higher doses. Studies in mice, rats, and dogs given therapy should be discontinued. Immunocompro-
oral doses as high as 30 mg/kg per day for 6 months mised patients who develop rashes during treatment
 165

should be monitored closely and the drug discontin- Occasional abnormalities in hematologic, he-
ued if lesions progress. patic, and renal function were observed in all treat-
ment groups in comparative clinical trials with flu-
Special patient groups conazole (unpublished data on file, Pfizer). Gener-
ally, fluconazole was associated with a low incidence
There are no adequate and well-controlled studies of abnormalities in comparison to the systemically
of fluconazole in pregnant women. Adverse fetal ef- administered drugs amphotericin B and ketocon-
fects have been seen in animals only at high dose azole, and the overall incidence of liver function ab-
levels associated with maternal toxicity. These find- normalities considered clinically significant was of
ings are not considered relevant to fluconazole used the same magnitude with fluconazole and placebo.
at therapeutic doses. However, fluconazole should
be used in pregnancy only if the potential benefit
justifies the possible risk to the fetus. Fluconazole is Conclusion
secreted in human milk at concentrations similar to
those in plasma. Hence, its use in nursing mothers is The product of a research program to develop a
not recommended. safe broad-spectrum antifungal with the flexibility of
In elderly patients with no evidence of renal im- both oral and intravenous dosing, fluconazole is the
pairment, normal dosage recommendations should first of a new subclass of synthetic triazoles. Like
be adopted. other azoles, fluconazole acts by inhibiting the enzy-
In patients with renal impairment (creatinine matic synthesis of ergosterol, the fungal cell mem-
clearance < 40 ml/min), normal doses should be brane sterol. Fluconazole is active in vitro against a
given on days 1 and 2 of treatment, and thereafter the variety of fungi and is active in vivo in animal models
dosage intervals should be modified in accordance of candidiasis and cryptococcosis. Fluconazole has
with creatinine clearance (CC) as follows: CC 21 to also demonstrated activity in models of aspergillosis,
40 ml/min, dosage interval 48 h; CC 10 to 20 ml/min, blastomycosis, coccidioidomycosis, and histoplas-
dosage interval 72 h; patients receiving regular dialy- mosis. The pharmacokinetic profile offluconazole is
sis, one dose after every dialysis session. characterized by good penetration into body fluids
and tissues, including CSF, and long half-life, which
allows once-daily dosing. Fluconazole is well toler-
Side effects ated in the clinical setting, where it has been used
effectively in a number of important mycoses, in-
The incidence of adverse events in over 4000 pa- cluding candidiasis (vaginal, oropharyngeal, eso-
tients treated with fluconazole in clinical trials of 7 phageal, and disseminated forms), cryptococcal in-
days or more was 16% (unpublished data on file, fections in immunocompromised patients, and in
Pfizer). Treatment was discontinued in 1.5% of pa- several of the endemic mycoses. Prophylaxis of fun-
tients due to clinical adverse events and in 1.3% of gal infection-- chiefly candidiasis - - in patients with
patients due to laboratory test abnormalities. Clini- malignancies has also been demonstrated. In view of
cal adverse events were reported more frequently in the increasing numbers of fungal infections in im-
HIV-infected patients (21%) than in non-HIV pa- munocompromised patients, fluconazole is a valua-
tients (13%); however, the pattern of side effects and ble addition to the antifungal armamentarium.
proportion of patients discontinuing therapy due to
clinical adverse events were comparable in the two
groups. The following clinical adverse events oc-
curred at an incidence of 1% or greater in 4048 pa-
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