Nephrol Dial Transplant (2003) 18: Editorial Comments
Nephrol Dial Transplant (2003) 18: 2227–2231
DOI: 10.1093/ndt/gfg363
Dosing guidelines for fluconazole in patients with renal failure
Lucile Cousin, Marie Le Berre, Vincent Launay-Vacher, Hassane Izzedine and Gilbert Deray
Department of Nephrology, Pitie-Salpetriere Hospital, Paris, France
Keywords: CAPD; CVVH; fluconazole; haemodialy-
sis; renal insufficiency
Introduction
Fluconazole is a widely used drug that inhibits the
synthesis of fungal cell membranes [1,2]. Its elimination
is predominantly via renal excretion with most of the
dose recovered in urine as an unchanged and active
drug. As a result, drug pharmacokinetics are altered in
patients with renal failure and it is essential to establish
guidelines on how to handle this drug in those patients.
Furthermore, in dialysis patients, the removal of the
drug in the dialysate has to be elucidated to determine
whether fluconazole should be administered after the
session or not. A review of the literature was thus
performed and analysis of the retrieved data permitted
to establish dosage adjustment guidelines for flucona-
zole in patients with renal failure.
Pharmacokinetics
The oral bioavaibility of fluconazole is >90%, which
enables us to administer it with similar doses by i.v. and
oral routes. Neither food nor gastric pH modifications
have a significant effect on its oral absorption [3,4].
Fluconazole has low plasma protein binding (11%) and
its apparent volume of distribution is 0.8 l/kg [5], which
-glutamyl
approximates total body water. The primary route of
elimination is via renal excretion. Eighty per cent of an
administered dose is recovered in urine as unchanged
and active drug and 11% as the glucuronide and
N-oxide metabolites, which are both inactive and
probably come from metabolism in the liver by cyto-
chrome P450 3A4 enzymes [6–8]. Over the range of
100–400 mg orally, the variation of fluconazole max-
imum plasma concentration (Cmax) and area under the
concentration–time curve (AUC) are proportional to
the administered dose, whereas the elimination half-life
Correspondence and offprint requests to: Dr Vincent Launay-Vacher,
Department of Nephrology, Pitie-Salpetriere Hospital, 47–83,
boulevard de l’Hopital, F-75013 Paris, France. Email: vincent.
launay-vacher@psl.ap-hop-paris.fr
Nephrol Dial Transplant 18(11) ß ERA–EDTA 2003; all rights reserved
2227
Downloaded from https://academic.oup.com/ndt/article-abstract/18/11/2227/1845678 by guest on 30 April 2019
(30 h) and the time of maximal concentration remain
constant (0.5–6 h). This indicates the linearity of the
pharmacokinetics of fluconazole for oral doses ranging
from 100 to 400 mg [3]. After doses of 200 and 400 mg,
the plasma concentrations of fluconazole were, respec-
tively, 4.6 and 9 mg/l at steady state, which is reached
4–5 days after administration of multiple doses and
in
2 days when given a loading dose representing
the double of the maintenance dose: 400 or 800 mg,
respectively. This pharmacokinetic profile enables us to
obtain good results against sensitive or usually sensitive
strains, as the minimum inhibitory concentrations
(MICs) 90 of fluconazole are 1 mg/l for Candida
albicans [9] and 16 mg/l for Candida glabrata [9,10]
and Cryptococcus neoformans [11] (Table 1). In clinical
practice, recommended efficient concentrations of
fluconazole are 7–8 mg/l for Candida’s infections and
15–20 mg/l for severe infections [12].
Toxicity
Fluconazole is generally well tolerated. The main side
effects are nausea, headache, skin rash, abdominal
pain, vomiting and diarrhoea. The overall incidence
of these adverse effects was 16% among 4000 patients
treated by fluconazole [5]. Furthermore, fluconazole
has been suggested to be potentially hepatotoxic.
However, in comparative studies vs placebo, the pattern
of abnormal aspartate amino transferase, alanine
amino transferase, alkaline phosphatase,
transferase and bilirubine values did not suggest that
fluconazole treatment was associated with an increased
risk for hepatotoxicity, although a marked elevation of
some of theses enzymes occurred in
1% of patients
[5]. It is thus important to adjust dosage in patients
with renal insufficiency in order to avoid these side
effects.
Patients with renal failure
Fulonazoles pharmacokinetics are altered in patients
with renal insufficiency as its elimination is predomi-
natly via the kidney. Indeed, studies showed that the
elimination half-life may increase to up to 98 h in
patients with a creatinine clearance of <20 ml/min
2228
whereas it is
30 h in patients with normal renal
function [13]. Dosage reduction of fluconazole is thus
mandatory in patients with renal impairment, i.e.
patients with a creatinine clearance of <60 ml/min.
In patients whose creatinine clearance is between 10
and 60 ml/min, it is recommended to reduce fluconazole
maintenance doses by 50%, by halving the unitary dose
or by doubling the dosing interval. The adaptation only
concerns the maintenance dose and not the loading
dose, which should be the same as for patients with
normal renal function, as usually performed for most
drugs. In the indication of vaginal or perineal candi-
diasis, a single oral dose of 150 mg is recommended. In
Nephrol Dial Transplant (2003) 18: Editorial Comments
administration should be performed after the session
on haemodialysis days, as demonstrated previously
[16,17]. The exact CLER being unknown, it is thus not
possible to calculate the exact value of FHD. However,
the total body clearance of fluconazole in healthy
volunteers with normal renal function is 17.9 ± 7.9
ml/min [13]. It can therefore be assumed that FHD will
certainly be >25%. Indeed for a FHD value of <25%,
fluconazole’s total body clearance should increase from
17.9 ml/min in patients with normal renal function to
>318 ml/min in patients with end-stage renal disease,
which is unlikely to occur. Subsequently, haemodialysis
is likely to significantly impair the pharmacokinetics of

Downloaded from https://academic.oup.com/ndt/article-abstract/18/11/2227/1845678 by guest on 30 April 2019

this case, as the administration is not repeated and peak
toxicity is only minor, there is no need to reduce the
single dose in patients with renal failure (Tables 2–4).
Haemodialysis patients
Fluconazole is dialysable [14,15]. Moreover, data from
the study of Oono et al. [15] evaluated the haemodial-
ysis clearance (CLHD) of fluconazole. In this study on
five haemodialysis patients, the authors determined the
extraction ratio of fluconazole during a haemodialysis
session of 3–4 h. The single-pass extraction ratio of the
dialyser was 59% and the blood flow was 180 ml/min.
Consequently, fluconazole’s CLHD, calculated with the
formula: CLHD ¼ extraction rate  blood flow, was
106 ml/min. CLHD should then be compared with
fluconazole’s extra-renal clearance (CLER), which
represents the total body clearance of the drug in the
same patients on a non-haemodialysis day, in order to
calculate the value of FHD (drug fractional clearance
by haemodialysis) with the formula: FHD ¼ CLHD/
(CLHD þ CLER) [16,17]. If FHD is >25%, haemodial-
ysis clearance should be considered as significant as
compared with total body clearance of the drug and the
fluconazole and it seems wise to administer the drug
after the session on haemodialysis days to replenish
depleted stores. Oono et al. [15] recommended that
fluconazole should be given at the end of each
haemodialysis session, thrice a week, at a dose of
100 mg intravenously or orally for oral or digestive
candidiasis and 200 mg intravenously or orally in severe
infection. Moreover, they indicated that fluconazole
serum concentrations monitoring would be an interest-
ing tool to assess efficacy. In another study concerning
five patients with severe renal failure after kidney
transplantation [18], the authors recommended the
dose of 200 mg of fluconazole, intravenously or orally,
after each haemodialysis session for the treatment of
systemic mycoses. In these two studies, the authors
did not discuss the loading dose. Finally, the most
complete study of the pharmacokinetics of fluconazole
in patients with renal impairment was performed by
Berl et al. [19]. This study involved 40 patients with
different degrees of renal insufficiency that were divided
into four groups of 10 patients according to the level of
their renal function, which was appreciated by the value
of creatinine clearance (CLCR). The average values of
CLCR were 107 (CLCR >50 ml/min), 38 (CLCR between
21 and 50 ml/min), and 14.8 ml/min (CLCR between 11

Table 1. Fuconazole MICs

Organisms Candida albicans Candida glabrata Cryptococcus neoformans

MICs (mg/l) 1 16 16

Table 2. Dosage of fluconazole per os in patients with renal failure (Candidiasis)

Creatinine clearance Fluconazole dosage

(ml/min)
Oropharyngeal candidiasis Vaginal candidiasis

First dose Maintenance doses Single dose

60–30 50 mg 50 mg every 48 h or 25 mg every 24 h 150 mg

30–10 50 mg 50 mg every 48 h or 25 mg every 24 h 150 mg
HD 50 mg after a 50 mg thrice a week after 150 mg after a
haemodialysis session each haemodialysis session haemodialysis session
CAPD 50 mg 50 mg every 24 h 150 mg
CVVHD 50 mg 50 mg every 24 h (depending on plasma concentrations) 150 mg

HD, haemodialysis; CAPD, continuous ambulatory peritoneal dialysis; CVVHD, continuous veno-venous haemodialysis.
Nephrol Dial Transplant (2003) 18: Editorial Comments 2229

400 mg every 24 h (depending on plasma concentrations)

and 20 ml/min) for groups 1, 2 and 3, respectively.

200 mg intraperitonally every 48 h during a 12-h dwell

Group 4 included subjects on chronic haemodialysis
(three times per week). The authors concluded that
there was no need for reducing the loading dose to the
degree of renal impairment and that determination of

or 200 mg orally and then 100 mg/day

the appropriate first dose should only be based on

400 mg every 48 h or 200 mg every 24 h

400 mg every 48 h or 200 mg every 24 h
the therapeutic indication. On the other hand, the
maintenance doses should be adjusted according to the

400 mg thrice a week after each

creatinine clearance of the patient. In patients on
chronic haemodialysis, fluconazole should be admin-
istered at doses ranging from 100 to 400 mg after

haemodialysis session
each haemodialysis session, thrice a week, after a
Maintenance doses

loading dose of 100 to 800 mg, administered after an

Downloaded from https://academic.oup.com/ndt/article-abstract/18/11/2227/1845678 by guest on 30 April 2019

haemodialysis session and depending on the indication
(Tables 2–4).

Patients on peritoneal diaysis

haemodialysis session

Most available studies of fluconazole in peritoneal

Systemic candidiasis

dialysis or continuous ambulatory peritoneal dialysis

(CAPD) focused on the treatment of fungal peritonitis.
HD, haemodialysis; CAPD, continuous ambulatory peritoneal dialysis; CVVHD, continuous veno-venous haemodialysis.
800 mg after a

Two routes of administration were studied: orally or

100–200 mg

intraperitoneally. In this latter case, the drug was

First dose

introduced into one of the exchange bags. In a pros-

800 mg
800 mg

800 mg

pective study concerning five patients on peritoneal

dialysis and receiving a single 200 mg dose of i.p.
fluconazole, the authors concluded that the dose of
200 mg intraperitonally every 48 h during a 12-h

200 mg every 48 h should be sufficient to obtain efficient

100–200 mg every 48 h or 50–100 mg every 24 h
100–200 mg every 48 h or 50–100 mg every 24 h

dwell or 200 mg orally and then 100 mg/day

100–200 mg every 24 h (depending on plasma

serum concentrations of fluconazole [20]. Indeed, they

showed that fluconazole was well absorbed by this
route with a bioavailability of 96%. A simulation of
100–200 mg thrice a week after each

fluconazole serum concentrations, after repeated

200 mg doses every 48 h gave minimal and maximal
serum concentrations of 6 and 9 mg/l, respectively [20].
Levine et al. [21] recommended only oral admin-
Table 3. Dosage of i.v. fluconazole in patients with renal failure (Candidiasis)

haemodialysis session

istrations consisting of a 200 mg loading dose and

maintenance doses of 100 mg daily. This study con-
Maintenance doses

concentrations)

cerned two patients on CAPD with a Candida’s

peritonitis (Tables 1–3). The authors suggested that
fluconazole should be considered as the treatment of
choice in cases of fungal peritonitis in patients receiving
Oesophageal or urinary candidiasis

CAPD and they reminded that fungal infections are

frequent and account for between 1 and 15% of
peritonitis episodes in CAPD patients.
haemodialysis session

Finally, in CAPD patients, as oral and peritoneal

100–200 mg after an

fluconazole bioavailabilities are similar (90 and 96%,

Fluconazole dosage

respectively) the drug may be administered orally,

intravenously or intraperitoneally depending on the
100–200 mg
100–200 mg

100–200 mg

100–200 mg

indication and the clinical constraints.

First dose

Patients on continuous renal

replacement therapy
Creatinine clearance

In three studies [22–24] and a subsequent analysis of

two of them [25], the authors recommended to admin-
CVVHD
(ml/min)

ister the usual dose of fluconazole in patients under-

CAPD
60–30
30–10

going continuous renal replacement therapy, whatever

HD

the procedure used. Indeed, fluconazole is dialysable

2230
Table 4. Dosage of i.v. fluconazole in patients with renal failure (Cryptococosis)
Creatinine clearance (ml/min) Fluconazole dosage
Induction (6 to 8 weeks)
60–30 200 mg every 24 h
30–10 200 mg every 24 h
HD 200 mg thrice a week after each
haemodialysis session
CAPD 200 mg intraperitonally during a
12-h dwell or 200 mg orally
CVVHD 400 mg every 24 h (depending on
plasma concentrations)
HD, haemodialysis; CAPD, continuous ambulatory peritoneal dialysis; CVVHD, continuous veno-venous haemodialysis.
and the authors showed that during continuous renal
replacement therapy in a patient with end-stage renal
failure, the total body clearance of fluconazole was the
same as the total body clearance observed in healthy
subjects. Consequently, neither the loading dose nor the
maintenance doses should theoretically be modified
in patients undergoing continuous renal replacement
therapy. However, the elimination rate of fluconazole
varies considerably depending on the procedure used
and on factors, which may influence the quality of drug
extraction (type and size of the membrane, blood flow,
dialysate flow rate, rate of ultrafiltration, etc.). In one
study, the authors reported that it was necessary to
increase the dose of fluconazole even above the usual
doses of the patient with normal renal function due to
the huge removal of fluconazole by haemodiafiltration
[26]. Consequently, in patients undergoing continuous
renal replacement therapy, whatever the procedure
used, it is recommended to start treatment with usual
doses of fluconazole and to control serum concentra-
tions of the drug in order to further adjust the dose
if fluconazole serum concentrations are too low [27]
(Tables 2–4).
Conclusion
The pharmacokinetics of fluconazole is altered in
patients with renal impairment and dosage adjust-
ments are thus necessary in such patients. In all cases,
there is no need to modify the loading dose of the
drug but maintenance doses should be reduced accord-
ing to the prescribing guidelines established from the
literature.
Conflict of interest statement. None declared.
References
1. Thomas AH. Suggested mechanisms for the antimycotic
activity of the polyene antibiotics and the N-substituted
imidazoles. J Antimicrob Chemother 1986; 17: 269–279
2. Van den Bossche H, Willemsens G, Cools W, Marichal P,
Lauwers W. Hypothesis on the molecular basis of the
Nephrol Dial Transplant (2003) 18: Editorial Comments
Maintenance
200 mg every 48 h or 100 mg every 24 h
200 mg every 48 h or 100 mg every 24 h
100 mg thrice a week after each
haemodialysis session
200 mg intraperitonally every 48 h during
a 12-h dwell or 100 mg/day orally
200 mg every 24 h (depending on plasma concentrations)
Downloaded from https://academic.oup.com/ndt/article-abstract/18/11/2227/1845678 by guest on 30 April 2019
antifungal activity of N-subsituted imidazoles and triazoles.
Biochem Soc Trans 1983; 11: 665–667
3. Zimmermann T, Yeates RA, Laufen H, Pfaff G, Wildfeuer A.
Influence of concomitant food intake on the oral absorption of
two triazole antifungal agents, itraconazole and fluconazole.
Eur J Clin Pharmacol 1994; 46: 147–150
4. Blum RA, D’Andrea DT, Florentino BM et al. Increased
gastric pH and bioavailability of fluconazole and ketoconazole.
Ann Intern Med 1991; 114: 755–757
5. Grant SM, Clissold SP. Fluconazole. A review of its
pharmacodynamic and pharmacokinetic properties, and ther-
apeutic potential in superficial and systemic mycoses. Drugs
1990; 39: 877–916
6. Dudley MN. Clinical pharmacology of fluconazole.
Pharmacotherapy 1990; 10: S141–S145
7. Brammer KW, Coakley AJ, Jezequel SG, Tarbit MH. The
disposition and metabolism of [14C]fluconazole in humans.
Drug Metab Disp 1991; 19: 764–767
8. Humphrey MJ, Jevons S, Tarbit MH. Pharmacokinetic
evaluation of UK-49.858, a metabolically stable triazole
antifungal agent, in animals and humans. Antimicrob Agents
Chemother 1985; 28: 648–653
9. Morera Y, Torres-Rodriguez JM, Catalan I, Granadero A,
Josic Z, Alvarez-Lerma F. Candiduria in patients with urethral
catheter admitted in intensive care unit. Etiology and in vitro
susceptibility to fluconazole. Med Clin 2002; 118: 580–582
10. Safdar A, Chaturvedi V, Koll BS, Larone DH, Perlin DS,
Armstrong D. Prospective, multicenter surveillance study of
Candida glabrata: fluconazole and itraconazole susceptibility
profiles in bloodstream, invasive, and colonizing strains and
differences between isolates from three urban teaching hospitals
in New-York City (Candida Susceptibility Trends Study, 1998
to 1999). Antimicrob Agents Chemother 2002; 46: 3268–3272
11. Fernandez Andreu CM, Pimentel Turino T, Martinez Machin
G, Gonzalez Miranda M. Determination of the minimum
inhibitory concentration of fluconazole against Cryptococcus
neoformans. Rev Cubana Med Trop 1999; 51: 55–57
12. Ikemoto H, Watanabe K, Mori T. Clinical study of fluconazole
on deep-seated fungal infections. Jap J Antibiotics 1989; 42:
63–116
13. Debruyne D, Ryckelynck JP. Clinical pharmacokinetics of
fluconazole. Clin Pharmacokinet 1993; 24: 10–27
14. Toon S, Ross CE, Gokal R, Rowland M. An assessment of the
effects of impaired renal function and haemodialysis on the
pharmacokinetics of fluconazole. Br J Clin Pharmacol 1990; 29:
221–226
15. Oono S, Tabei K, Tetsuka T, Asano Y. The pharmacokinetics
of fluconazole during haemodialysis in uraemic patients. Eur J
Clin Pharmacol 1992; 42: 667–670
16. Launay-Vacher V, Storme T, Izzedine H, Deray G.
Pharmacokinetic changes in renal failure. Presse Med 2001;
30: 597–604
Nephrol Dial Transplant (2003) 18: Editorial Comments
17. Izzedine H, Launay-Vacher V, Baumelou A, Deray G. An
appraisal of anti-retroviral drugs in haemodialysis. Kidney Int
2001; 60: 821–830
18. Bren A, Kandus A, Lindic J, Varl J. Fluconazole in the
treatment of fungal infections in kidney-tranplanted patients.
Transplant Proc 1992; 24: 2765–2766
19. Berl T, Wilner KD, Gardner M et al. Pharmacokinetics of
fluconazole in renal failure. J Am Soc Nephrol 1995; 6: 242–247
20. Dahl NV, Foote EF, Searson KM et al. Pharmacokinetics of
intraperitoneal fluconazole during continuous cycling peritoneal
dialysis. Ann Pharmacother 1998; 32: 1284–1289
21. Levine J, Bernard DB, Idelson BA, Farnham H, Saunders C,
Sugar AM. Fungal peritonitis complicating continuous ambu-
latory peritoneal dialysis: successful treatment with fluconazole,
a new orally active antifungal agent. Am J Med 1989; 86:
825–827
22. Valtonen M, Tiula E, Neuvonen PJ. Effect of continuous veno-
venous haemofiltration and haemodiafiltration of fluconazole
2231
in patients with acute renal failure. J Antimicrob Chemother
1997; 40: 695–700
23. Wolter K, Marggraf G, Dermouni H, Fritschke E. Elimination
of fluconazole during continuous veno-venous haemodialysis
(CVVHD). Eur J Clin Pharmacol 1994; 47: 291–292
24. Nicolau DP, Crowe H, Nightingale CH, Quintiliani R: Effect
of continuous arteriovenous hemodiafiltration on the pharma-
cokinetics of fluconazole. Pharmacotherapy 1994; 14: 502–505
25. Pittrow L, Penk A. Dosage adjustment of fluconazole during
continuous renal replacement therapy (CAVH, CVVH,
CAVHD, CVVHD). Mycoses 1999; 42: 17–19
26. Kishino S, Koshinami Y, Hosoi T et al. Effective fluconazole
therapy for liver transplant recipients during continuous
hemodiafiltration. Ther Drug Monit 2001; 23: 4–8
27. Muhl E, Martens T, Iven H, Rob P, Bruch HP. Influence of
Downloaded from https://academic.oup.com/ndt/article-abstract/18/11/2227/1845678 by guest on 30 April 2019
continuous veno-venous haemodiafiltration and continuous
veno-venous haemofiltration on the pharmacokinetics of
fluconazole. Eur J Clin Pharmacol 2000; 56: 671–678