CLINICAL PHARMACOLOGY
Mode of Action
Fluconazole is a highly selective inhibitor of fungal
cytochrome P-450 sterol C-14 alpha-demethylation. Mammalian
cell demethylation is much less sensitive to fluconazole
inhibition. The subsequent loss of normal sterols correlates
with the accumulation of 14 alpha-methyl sterols in fungi
and may be responsible for the fungistatic activity of
fluconazole.
Pharmacokinetics and Metabolism
The pharmacokinetic properties of fluconazole are similar
following administration by the intravenous or oral routes.
In normal volunteers, the bioavailability of orally administered
fluconazole is over 90% compared with intravenous administration.
Bioequivalence was established between the 100 mg tablet
and both suspension strengths when administered as a single
200 mg dose.
Peak plasma concentrations (Cmax) in fasted normal volunteers
occur between 1 and 2 hours with a terminal plasma elimination
half-life of approximately 30 hours (range 20-50 hours)
after oral administration.
In fasted normal volunteers, administration of a single
oral 400 mg dose of fluconazole leads to a mean Cmax of
6.72 mcg/ml (range: 4.12 to 8.08 mcg/ml) and after single
oral doses of 50-400 mg, fluconazole plasma concentrations
and AUC (area under the plasma concentration-time curve)
are dose proportional.
Administration of a single oral 150 mg tablet of fluconazole
to ten lactating women resulted in a mean Cmax of 2.61
mcg/ml (range: 1.57 to 3.65 mcg/ml).
Steady-state concentrations are reached within 5-10 days
following oral doses of 50-400 mg given once daily. Administration
of a loading dose (on day 1) of twice the usual daily
dose results in plasma concentrations close to steady-state
by the second day. The apparent volume of distribution
of fluconazole approximates that of total body water.
Plasma protein binding is low (11-12%). Following either
single- or multiple-oral doses for up to 14 days, fluconazole
penetrates into all body fluids studied (see TABLE 1).
In normal volunteers, saliva concentrations of fluconazole
were equal to or slightly greater than plasma concentrations
regardless of dose, route, or duration of dosing. In patients
with bronchiectasis, sputum concentrations of fluconazole
following a single 150 mg oral dose were equal to plasma
concentrations at both 4 and 24 hours post dose. In patients
with fungal meningitis, fluconazole concentrations in
the CSF are approximately 80% of the corresponding plasma
concentrations.
A single oral 150 mg dose of fluconazole administered
to 27 patients penetrated into vaginal tissue, resulting
in tissue:plasma ratios ranging from 0.94 to 1.14 over
the first 48 hours following dosing.
A single oral 150 mg dose of fluconazole administered
to 14 patients penetrated into vaginal fluid, resulting
in fluid:plasma ratios ranging from 0.36 to 0.71 over
the first 72 hours following dosing (see TABLE 1).
| TABLE 1 |
| Tissue or Fluid |
Ratio of FluconazoleTissue
(Fluid)/Plasma Concentration* |
| Cerebrospinal fluid† |
0.5-0.9 |
| Saliva |
1 |
| Sputum |
1 |
| Blister fluid |
1 |
| Urine |
10 |
| Normal skin |
10 |
| Nails |
1 |
| Blister skin |
2 |
| Vaginal tissue |
1 |
| Vaginal fluid |
0.4-0.7 |
| * Relative
to concurrent concentrations in plasma in subjects
with normal renal function. |
| † Independent
of degree of meningeal inflammation. |
In normal volunteers, fluconazole is cleared primarily by
renal excretion, with approximately 80% of the administered
dose appearing in the urine as unchanged drug. About 11%
of the dose is excreted in the urine as metabolites.
The pharmacokinetics of fluconazole are markedly affected
by reduction in renal function. There is an inverse relationship
between the elimination half-life and creatinine clearance.
The dose of fluconazole may need to be reduced in patients
with impaired renal function (see DOSAGE AND ADMINISTRATION).
A 3-hour hemodialysis session decreases plasma concentrations
by approximately 50%.
In normal volunteers, fluconazole administration (doses
ranging from 200 mg to 400 mg once daily for up to 14
days) was associated with small and inconsistent effects
on testosterone concentrations, endogenous corticosteroid
concentrations, and the ACTH-stimulated cortisol response.
Pharmacokinetics in Children:
In children, the following pharmacokinetic data [MEAN (%
cv)] have been reported (see TABLE 2A and TABLE 2B).
| TABLE 2A |
| Age Studied |
Dose (mg/kg) |
Clearance (ml/min/kg) |
| 9 Months-13 Years |
Single-Oral |
0.40 (38%) |
| |
2 mg/kg |
N=14 |
| 9 Months-13 Years |
Single-Oral |
0.51 (60%) |
| |
8 mg/kg |
N=15 |
| 5-15 years |
Multiple IV |
0.49 (40%) |
| |
2 mg/kg |
N=4 |
| 5-15 years |
Multiple IV |
0.59 (64%) |
| |
4 mg/kg |
N=5 |
| 5-15 years |
Multiple IV |
0.66 (31%) |
| |
8 mg/kg |
N=5 |
| TABLE 2B |
| Half-life |
Cmax |
Vdss |
| (Hours) |
(mcg/ml) |
(l/kg) |
| 25.0 |
2.9 (22%) N=16 |
-- |
| 19.5 |
9.8 (20%) N=15 |
-- |
| 17.4 |
5.5 (25%) N=5 |
0.722 (36%) N=4 |
| 15.2 |
11.4 (44%) N=6 |
0.729 (33%) N=5 |
| 17.6 |
14.1 (22%) N=8 |
1.069 (37%) N=7 |
Clearance corrected for body weight was not affected
by age in these studies. Mean body clearance in adults
is reported to be 0.23 (17%) ml/min/kg.
In premature newborns (gestational age 26 to 29 weeks),
the mean (% cv) clearance within 36 hours of birth was
0.180 (35%, N=7) ml/min/kg, which increased with time
to a mean of 0.218 (31%, N=9) ml/min/kg six days later
and 0.333 (56%, N=4) ml/min/kg 12 days later. Similarly,
the half- life was 73.6 hours, which decreased with time
to a mean of 53.2 hours six days later and 46.6 hours
12 days later.
Microbiology
Fluconazole exhibits in vitro activity against Cryptococcus
neoformans and Candida spp. Fungistatic activity has also
been demonstrated in normal and immunocompromised animal
models for systemic and intracranial fungal infections
due to Cryptococcus neoformans and for systemic infections
due to Candida albicans.
In common with other azole antifungal agents, most fungi
wshow a higher apparent sensitivity to fluconazole in
vivo than in vitro. Fluconazole administered orally and/or
intravenously was active in a variety of animal models
of fungal infection using standard laboratory strains
of fungi. Activity has been demonstrated against fungal
infections caused by Aspergillus flavus and Aspergillus
fumigatus in normal mice. Fluconazole has also been shown
to be active in animal models of endemic mycoses, including
one model of Blastomyces dermatitidis pulmonary infections
in normal mice; one model of Coccidioides immitis intracranial
infections in normal mice; and several models of Histoplasma
capsulatum pulmonary infection in normal and immunosuppressed
mice. The clinical significance of results obtained in
these studies is unknown.
Concurrent administration of fluconazole and amphotericin
B in infected normal and immunosuppressed mice showed
the following results: a small additive antifungal effect
in systemic infection with C. albicans, no interaction
in intracranial infection with Cr. neoformans, and antagonism
of the two drugs in systemic infection with Asp. fumigatus.
The clinical significance of results obtained in these
studies is unknown.
There have been reports of cases of superinfection with
Candida species other than C. albicans, which are often
inherently not susceptible to Diflucan (e.g., Candida
krusei). Such cases may require alternative antifungal
therapy.
CLINICAL STUDIES
Cryptococcal Meningitis: In
a multicenter study comparing fluconazole (200 mg/day)
to amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal
meningitis in patients with AIDS, a multivariate analysis
revealed three pretreatment factors that predicted death
during the course of therapy: abnormal mental status,
cerebrospinal fluid cryptococcal antigen titer greater
than 1:1024, and cerebrospinal fluid white blood cell
count of less than 20 cells/mm3. Mortality among high
risk patients was 33% and 40% for amphotericin B and Diflucan
patients, respectively (p=0.58), with overall deaths 14%
(9 of 63 subjects) and 18% (24 of 131 subjects) for the
2 arms of the study (p=0.48). Optimal doses and regimens
for patients with acute cryptococcal meningitis and at
high risk for treatment failure remain to be determined.
(Saag, et al, N Engl J Med 1992;326:83-9).
Vaginal Candidiasis: Two adequate
and well-controlled studies were conducted in the U.S.
using the 150 mg tablet. In both, the results of the fluconazole
regimen were comparable to the control regimen (clotrimazole
or miconazole intravaginally for 7 days) both clinically
and statistically at the one month post-treatment evaluation.
The therapeutic cure rate, defined as a complete resolution
of signs and symptoms of vaginal candidiasis (clinical
cure), along with a negative KOH examination and negative
culture for Candida (microbiologic eradication), was 55%
in both the fluconazole group and the vaginal products
group (see TABLE 3A and TABLE 3B).
| TABLE 3A |
| Fluconazole PO 150 mg tablet |
|
| Enrolled |
448 |
| Evaluable at Late Follow-up |
347 (77%) |
| Clinical cure |
239/347 (69%) |
| Mycologic erad. |
213/347 (61%) |
| Therapeutic cure |
190/347 (55%) |
| TABLE 3B |
| Vaginal Product qhs x 7
days |
|
| Enrolled |
422 |
| Evaluable at Late Follow-up |
327 (77%) |
| Clinical cure |
235/327 (72%) |
| Mycologic erad. |
196/327 (60%) |
| Therapeutic cure |
179/327 (55%) |
Approximately three-fourths of the enrolled patients
had acute vaginitis (<4 episodes/12 months) and achieved
80% clinical cure, 67% mycologic eradication and 59% therapeutic
cure when treated with a 150 mg fluconazole tablet administered
orally. These rates were comparable to control products.
The remaining one-fourth of enrolled patients had recurrent
vaginitis (³4 episodes/12 months) and achieved 57%
clinical cure, 47% mycologic eradication and 40% therapeutic
cure. The numbers are too small to make meaningful clinical
or statistical comparisons with vaginal products in the
treatment of patients with recurrent vaginitis.
Substantially more gastrointestinal events were reported
in the fluconazole group compared to the vaginal product
group. Most of the events were mild to moderate. Because
fluconazole was given as a single dose, no discontinuations
occurred (see TABLE 4).
| TABLE 4 |
| Parameter |
Fluconazole PO |
Vaginal Products |
| Evaluable patients |
448 |
422 |
| With any adverse event |
141 (31%) |
112 (27%) |
| Nervous System |
90 (20%) |
69 (16%) |
| Gastrointestinal |
73 (16%) |
18 (4%) |
| With drug-related event |
117 (26%) |
67 (16%) |
| Nervous System |
61 (14%) |
29 (7%) |
| Headache |
58 (13%) |
28 (7%) |
| With drug-related event
(cont.) |
|
|
| Gastrointestinal |
68 (15%) |
13 (3%) |
| Abdominal pain |
25 (6%) |
7 (2%) |
| Nausea |
30 (7%) |
3 (1%) |
| Diarrhea |
12 (3%) |
2 (<1%) |
| Application site event |
0 (0%) |
19 (5%) |
| Taste Perversion |
6 (1%) |
0 (0%) |
Pediatric
Oropharyngeal candidiasis: An
open-label, comparative study of the efficacy and safety
if fluconazole (2-3 mg/kg/day) and oral nystatin (400,000
I.U. 4 times daily) in immunocompromised children with
oropharyngeal candidiasis was conducted. Clinical and
mycological response rates were higher in the children
treated with fluconazole.
Clinical cure at the end of treatment was reported for 86%
of fluconazole treated patients compared to 46% of nystatin
treated patients. Mycologically, 76% of fluconazole treated
patients had the infecting organism eradicated compared
to 11% for nystatin treated patients (see TABLE 5).
| TABLE 5 |
| |
Fluconazole |
Nystatin |
| Enrolled |
96 |
90 |
| Clinical Cure |
76/88 (86%) |
36/78 (46%) |
| Mycological eradication* |
55/72 (76%) |
6/54 (11%) |
| * Subjects
without follow-up cultures for any reason were considered
nonevaluable for mycological response. |
The proportion of patients with clinical relapse 2 weeks
after the end of treatment was 14% for subjects receiving
fluconazole and 16% for subjects receiving nystatin. At
4 weeks after the end of treatment the percentages of patients
with clinical relapse were 22% for Diflucan and 23% for
nystatin.
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