Ketoconazole and Fluconazole Drug Interactions

Anne M. Baciewicz, PharmD, Frank A. Baciewicz, Jr, MD

This
article reviews potential drug interactions that exist between ketoconazole or flu-
conazole and other drugs. English-language data sources included human subjects' com-
puterized databases and published indexes. Case reports and studies demonstrate de-
creased dosage requirements of cyclosporine sodium, methylprednisolone sodium succinate,
and possibly anticoagulants and phenytoin after ketoconazole or fluconazole administration, sug-
gesting hepatic enzyme inhibition. Increased dosage requirements of ketoconazole are necessary
after rifampin administration, suggesting rifampin's induction of hepatic microsomal enzymes. Pos-
sibly a similar effect may occur with concomitant fluconazole and rifampin. The effect of ketocon-
azole administration on prednisolone sodium phosphate and theophylline warrants further study.
Fluconazole, a more selective agent for fungal P-450, seems to be of less concern regarding the
potential for drug interactions than ketoconazole. (Arch Intern Med. 1993;153:1970-1976)
The azole antifungal agents are used in the Select drugs may interact with one azole
treatment of a variety of fungal infec¬ antifungal but not affect the other azole an-
tions.1"4 Two azole antifungals, ketocona¬ tifungal. This is possibly due to the fol¬
zole and fluconazole, will likely be taken lowing: (1) different ring structures of the
with other medications. Therefore, the po¬ imidazoles and triazoles, (2) pharmaco-
tential for azole antifungal-related interac¬ kinetic and pharmacologie differences be¬
tions with other medications exists. tween ketoconazole and fluconazole, (3)
The main mechanism postulated for different binding affinities to hepatic mi-
the interactions that may occur between crosomal enzymes between ketoconazole
ketoconazole or fluconazole and other drugs and fluconazole, and (4) hydrophilicity of
is altered enzymatic activity of hepatic mi- fluconazole.1"5 This article will review stud¬
crosomal enzymes via the P-450 system. ies and case reports of interactions be¬
Select subsets of the hepatic mixed- tween ketoconazole or fluconazole and other
function oxidase system appear to be in¬ drugs. The literature contains limited well-
hibited or enhanced. The extent to which designed studies on interactions for keto¬
the azole antifungals or other agents acti¬ conazole or fluconazole and other agents.
vate or inhibit the hepatic enzymes may
be dependent on the dose administered and RIFAMPIN
the duration of treatment. Other proposed
theories are as follows: (1) change in vol¬ Brass et al6 observed a patient receiving ke¬
ume of distribution (Vd), (2) alteration in
toconazole who was treated with isoniazid
protein binding, and (3) competition for and rifampin for tuberculosis. The patient
an excretion pathway.3"5 was studied after a single 200-mg dose of

ketoconazole, after administration of a sin¬

From the Department of Pharmacy Services, University Hospitals of Cleveland (Ohio) gle 600-mg dose of rifampin 1 hour be¬
(Dr A. Baciewicz), and the Department of Surgery, Division of Cardiothoracic Surgery, fore ketoconazole, and 5 months after con¬
Wayne State University, Detroit, Mich (Dr F. Baciewicz). current daily administration of 200 mg of

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 ketoconazole, 300 mg of isoniazid,
and 600 mg of rifampin. The area
under the curve (AUC) for ketocon¬
azole decreased by 47% after the sin¬
gle rifampin dose and 88% after 5
months of concurrent isoniazid and
rifampin therapy. A 10-fold de¬
crease in the peak serum ketocona¬
zole concentration was observed when
all three drugs were given concom-
itantly. Drouhet and Dupont7 noted
a decrease in serum ketoconazole lev¬
els in two patients receiving rifampin-
ketoconazole.
Engelhard et al8 assessed the in¬
teraction of rifampin, isoniazid, and
ketoconazole, 5 or 10 mg/kg per day,
in a child. When the antituberculo-
sis drug therapy was discontinued af¬
ter 9 months, an accelerated re¬
sponse to ketoconazole was noted.
Three months later the cervical
lymphadenopathy reappeared; the bi¬
opsy specimen revealed necrotizing
caseating granulomas. The patient was
again given rifampin and isoniazid,
and ketoconazole therapy was
stopped. Serum ketoconazole levels
decreased by 70% or more when the
patient received rifampin or iso¬
niazid. Whether the antimicrobials
were given concurrently or 12 hours
apart had no effect on the interac¬
tion. Serum concentrations of rifampin
were undetectable when given with
isoniazid and ketoconazole. Rifampin
concentrations decreased by approx¬
imately half when given with keto¬
conazole only.
Two cases reported poor clini¬
cal response to esophageal candidi-
asis and a Blastomyces dermatiüdis bone
infection in patients with tubercu¬
losis treated concomitantly with ke¬
toconazole and isoniazid, rifampin,
ethambutol hydrochloride, and pyra-
zinamide. Serum ketoconazole con¬
centrations were low or undetect¬
able, while rifampin concentrations
varied, depending on whether
rifampin administered concom¬
was
itantly or separated by 12 hours from
ketoconazole.9'10
Meunier11 studied the effects of
ketoconazole, 600 mg, and rifampin,
600 mg, for several days in 10 healthy
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volunteers. The author reported a de¬
crease in the expected ketoconazole
serum concentration with concur¬
rent administration of rifampin.
Doble et al12 assessed the com¬
bination of 600 mg of rifampin and
200 mg of ketoconazole in six male
volunteers. Rifampin's peak plasma
concentration (Cmax) and AUC were
unchanged when given with keto¬
conazole. However, ketoconazole's
Cmax and AUC decreased by 65% and
81%, respectively, when taken si¬
multaneously with rifampin. The neg¬
ligible effect on rifampin concentra¬
tions is different from other reports.5,7"9
No reasons were postulated for these
differences.
Eighteen healthy male volun¬
teers received a single, oral, 200-mg
dose of fluconazole on days 1 and
22.1314 After a week washout, 10 vol¬
unteers received rifampin, 600 mg/d,
and eight received placebo for 20 days
(days 8 to 27). Concomitant admin¬
istration of fluconazole and rifampin
resulted in a 22% and 23% decrease
in fluconazole's half-life and AUC, re¬
spectively.1314 Fluconazole's effect on
rifampin was not studied.
Coker et al15 described three pa¬
tients with cryptococcal meningitis
treated with fluconazole, 400 mg/d.
Treatment with rifampin, isoniazid,
ethambutol hydrochloride, and pyra-
zinamide was initiated when tuber¬
culosis was suspected. Clinical relapse
of cryptococcal meningitis occurred
1 to 5 months after beginning anti-
tuberculosis therapy and a rifampin-
fluconazole interaction was suspected.
Caution is suggested when ke¬
toconazole is given with rifampin or
isoniazid. Clinical response, serum
ketoconazole concentrations, and se¬
rum antituberculosis concentrations
should be monitored if possible when
these agents are given concomi-
tantly. To minimize the effect of ke¬
toconazole on rifampin serum lev¬
els, administration of the two drugs
should be 12 hours apart. Unsuc¬
cessful management of these inter¬
actions may result in therapeutic fail¬
ure of both the antifungal and
antituberculosis treatments. Flucon-
azole probably can be coadminis-
tered with rifampin, but the dose of
fluconazole may need to be in¬
creased. Ketoconazole is primarily he-
patically metabolized and would be
more likely to interact with rifampin
than fluconazole, which is primarily
excreted unchanged in the urine.1"4
CYCLOSPORINE
Two cases reported renal transplant
patients who had increased cyclo-
sporine concentrations and serum cre-
atinine levels within 1 week of con¬
comitant administration of oral cy-
closporine, 12 mg/kg per day or 320
mg/d, and oral ketoconazole, 400 or
600 mg/d. The cyclosporine concen¬
trations and serum creatinine con¬
centrations continued to increase de¬
spite decreasing cyclosporine doses.
After discontinuing ketoconazole ther¬
apy, the cyclosporine concentration
and serum creatinine concentration
returned to baseline over several
weeks.1617 Similar cases of a cyclo¬
sporine and ketoconazole interac¬
tion have been reported in bone
marrow transplant (BMT)
recipients.18"21
Charles et al22 noted a tripling
of trough whole blood cyclosporine
concentration by radioimmunoas-
say when ketoconazole, 400 mg/d,
was added to the patient's mainte¬
nance cyclosporine dose of 325 mg,
orally, twice daily. Reduction of the
cyclosporine dose to 125 mg, orally,
twice daily and discontinuing keto¬
conazole therapy caused cyclo¬
sporine concentrations to return to
baseline values by 1 week. Addition¬
ally, serum creatinine, alkaline phos-
phatase, and bilirubin values dou¬
bled during this time. These
measurements returned to baseline
values when cyclosporine and keto¬
conazole therapy was discontinued.
To our knowledge, this is the first
reported case of adverse liver func¬
tion results.
Articles have reported short-
term (up to 20 days)16"23 and long-
term (1 to 4 years)24'25 treatment with
cyclosporine-ketoconazole in renal,
 BMT, and heart transplant recipi¬
ents.Some heart transplantation re¬
ports suggest that oral cyclosporine
may require substantial reduction to
35 to 100 mg/d to maintain thera¬
peutic cyclosporine concentrations
and reduce potential nephrotoxic re¬
actions when oral ketoconazole, 100
to 400 mg/d, is concomitantly ad¬
ministered.23"25 Some investigators also
recommend a 50% to 75% ketocon¬
azole dose reduction.24 Butman et al25
noted significant reductions at 1 year
in serum cholesterol level and mean
and diastolic systemic arterial pres¬
sure in patients receiving both cy¬
closporine and ketoconazole.
Similar cyclosporine dosage re¬
ductions (66 mg/d average, 70% to
88% range) have been described
among 36 patients who had under¬
gone renal transplants followed up
for 4 to 22 months when ketocon¬
azole, 200 mg/d, was added to their
medication regimen. Mean trough
whole blood cyclosporine levels (high-
performance liquid chromatogra-
phy) remain similar before ketocon¬
azole therapy and after 1 year of
combination therapy. Renal and he¬
patic function were unchanged after
starting ketoconazole therapy.2627 Gen¬
erally, this combination may bene¬
ficially reduce cyclosporine toxicity
and organ transplantation cost by us¬
ing lower cyclosporine doses.
Two articles described either an
increase in cyclosporine concentra¬
tions or serum creatinine concentra¬
tion when oral fluconazole, 100 mg/d,
was added cyclosporine therapy
to
(100 or mg/d) in diabetic pa¬
400
tients who had undergone renal trans¬
plants.2829 Torregrosa et al30 ob¬
served three patients who had
undergone renal transplants who re¬
quired at least a 50% reduction in
cyclosporine dosing to maintain ther¬
apeutic cyclosporine concentrations
(radioimmunoassay) when flucona¬
zole, 200 mg/d, was added to their
medication regimen.
Canafax et al31-32 studied 16 pa¬
tients who had undergone renal trans¬
plantations receiving a constant cy¬
closporine dose in a double-blind,
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placebo-controlled manner. Two
groups of eight patients received ei¬
ther placebo or oral fluconazole, 200
mg/d, for 14 days. Results from 12
patients showed a 114% increase in
trough whole blood cyclosporine lev¬
els (high-performance liquid chro-
matography) in patients receiving flu¬
conazole with no change in the group
receiving placebo. Mean cyclo¬
sporine clearance decreased by an av¬
erage of 55% in the patients receiv¬
ing fluconazole with no change in the
patients receiving placebo.
Different results have been noted
in other articles.13,33'34 Lazar and Wil-
ner13 reported 10 BMT recipients who
were receiving stable doses of cy¬
closporine and fluconazole, 100 mg
either as a single dose or for 14 days
of therapy. No statistically signifi¬
cant changes in plasma cyclospo¬
rine levels were detected after single
or multiple doses of fluconazole.
The effect of a single 100-mg
oral fluconazole dose and a 14-day
course of oral fluconazole, 100 mg/d,
on plasma concentrations and kinet¬
ics of cyclosporine was studied in 10
stable BMT recipients.33,34 The mean
cyclosporine dose was 205 mg/d. Cy¬
closporine mean plasma trough and
peak levels (radioimmunoassay) and
AUC were increased after single or
multiple doses of fluconazole but no
statistical difference was noted. Se¬
rum creatinine concentration in¬
creased slightly or moderately (20%)
in six patients or one patient, respec¬
tively. The authors attributed these
variations to cyclosporine nephro-
toxirity alone. Four patients had slight
to moderate increases in liver in¬
dexes that could possibly be attrib¬
uted to concomitant medications, dis¬
eases, or fluconazole. The authors also
studied the cyclosporine-flucona-
zole interaction in 20 patients re¬
ceiving oral fluconazole, 200 mg/d,
over 100 days prophylactically for fun¬
gal infections.34 No differences in cy¬
closporine doses and levels com¬
pared with a historical control group
were observed. Different results may
exist among studies due to either the
low fluconazole dose used in the BMT
recipients or the use of historical con¬
trols, which can be unreliable in
experiments.
Monitoring of patients' cyclo¬
sporine concentrations, renal func¬
tion, and liver function is essential
when patients are receiving concom¬
itant ketoconazole or fluconazole and
cyclosporine. Ketoconazole's effect on
cyclosporine is usually seen in 2 to
4 days and may persist until 3 weeks
after ketoconazole therapy is discon¬
tinued. Decreased cyclosporine dos¬
ages may be required when ketocon¬
azole or higher doses of fluconazole
are administered concomitantly with
cyclosporine. Cyclosporine concen¬
trations probably will increase due
to an azole-associated change in the
hepatic metabolism, altered protein
binding, or competition for an ex¬
cretion pathway. Usual cyclo¬
sporine dosages will be required when
ketoconazole or fluconazole therapy
is discontinued. If feasible, an alter¬
native antifungal should be used. Cur¬
rently, some physicians are prescrib¬
ing cyclosporine and ketoconazole
concomitantly to reduce cyclo¬
sporine dosages while also reducing
cyclosporine toxicity and cost.
CORTICOSTEROIDS
Glynn et al35 studied six normal sub¬
jects who received methylpredniso-
lone sodium succinate, 20 mg intra¬
venously (IV), alone and after receiving
oral ketoconazole, 200 mg/d, for 6
days. Ketoconazole decreased the
clearance of methylprednisolone-
and steady state Vd by 60% and 32%,
respectively. Ketoconazole given con¬
currently with methylprednisolone
further reduced the 24-hour Corti¬
sol AUC and morning cortisol con¬
centrations beyond that produced by
methylprednisolone alone.
Kandrotas et al36 observed the
effects of methylprednisolone and ke¬
toconazole on endogenous cortisol in
eight normal subjects. Methylpred¬
nisolone sodium succinate IV was
given alone as 15 mg or 30 mg. Ke¬
toconazole, 200 mg/d, given orally
for 1 week reduced the clearance of
 methylprednisolone by 46%. The au¬
thors noted that the additional en¬
dogenous cortisol suppressive effect
from methylprednisolone and keto¬
conazole was minor as the cortisol
AUC ratio change was modest and
the adrenal suppression duration was
not extended. They recommended a
50% lower methylprednisolone dose
during concomitant ketoconazole
therapy to generate equivalent AUC
for cortisol and methylprednisone.
Zürcher et al37 investigated the
influence of oral ketoconazole so¬
dium phosphate, 200 mg/d, for 6 to
7 days on the kinetics of oral pred-
nisone, 0.8 mg/kg, and IV pred-
nisolone, 0.8 mg/kg, in 10 healthy
volunteers. The ratio of urinary 6ß-
OH-cortisol/17-OH-corticosteroids
declined by more than 50% and the
urinary excretion of 6ß-OH-
prednisolone decreased between
threefold and sixfold in all subjects.
The clearance of IV prednisolone given
concurrently with ketoconazole was
decreased by 27%. The decrease of
6ß-hydroxylase was associated with
both impaired metabolic and renal
clearances of total and unbound pred¬
nisolone. Ketoconazole inhibited 6ß-
hydroxylase and increased the body's
exposure to active unbound pred¬
nisolone. No pharmacodynamic ef¬
fect on adrenal suppression was noted.
Ludwig et al38 demonstrated no
significant effect on prednisolone
pharmacokinetics or cortisol sup¬
pression in four healthy volunteers.
Subjects were given a single oral dose
of prednisone, 20 mg, alone or after
oral ketoconazole, 200 mg/d, for 5
days and ketoconazole and pred¬
nisone on day 6. Ketoconazole's ad¬
ministration decreased predniso-
lone's clearance by 8%.
Yamashita et al39 assessed the ef¬
fects of ketoconazole on the phar¬
macokinetics and pharmacodynam-
ics of 20 mg IV of prednisolone
sodium phosphate (equivalent pred¬
nisolone, 14.8 mg). Six healthy vol¬
unteers were studied receiving pred¬
nisolone IV alone and after receiving
ketoconazole, 200 mg, orally for 6
days. Ketoconazole did not signifi-
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cantly change the clearance, Vd,
plasma protein binding, or pharma-
codynamics of prednisolone. Differ¬
ences between study results could be
due to different dosages adminis¬
tered, different assays used, or sub¬
ject's age.
The prednisolone-ketocona-
zole interaction seems to be of little
clinical significance compared with
the methylprednisolone-ketocona-
zole interaction. The difference could
be due to glucocorticoids being me¬
tabolized by different enzymatic path¬
ways; ketoconazole may selectively
inhibit certain subsets of hepatic ox-
idative metabolic enzymes. Patients
receiving methylprednisolone and ke¬
toconazole concurrently probably will
require a reduction in methylpred¬
nisolone dosage. Ketoconazole has no
pharmacokinetic or pharmacody-
namic effect on single low doses of
prednisolone. To our knowledge, no
studies have assessed fluconazole
and corticosteroids administered
concomitantly.
THEOPHYLLINE
Brown et aP studied the effect of oral
ketoconazole, 400 mg, 1 hour prior
to and 72 hours after a single dose
of IV aminophylline, 3.8 mg/kg, over
5 minutes in six healthy nonsmok¬
ing subjects. The single dose of ke¬
toconazole 1 hour prior to IV ami¬
nophylline had no effect on
theophylline kinetics. Seventy-two
hours after a single ketoconazole dose,
theophylline's Vd increased by
44%. Four of six subjects were re-
studied after taking oral ketocona¬
zole, 400 mg, for 5 days. The¬
ophylline's clearance was un¬
changed, but the Vd increased by
approximately 44%.
Heusner et al40 examined the ef¬
fect of ketoconazole on the pharrna-
cokinetics of theophylline in 10
healthy nonsmoking men. Each sub¬
ject received IV aminophylline, 6 mg/
kg, over 20 minutes before and after
7 days of oral ketoconazole, 200 mg/d.
No difference in half-life or clear¬
ance could be demonstrated for the-
ophylline before or after ketocona¬
zole administration.
Murphy et al41 observed a 50%
decrease in an asthmatic patient's the¬
ophylline concentration when oral ke¬
toconazole, 200 mg/d, was admin¬
istered concomitantly with slow-
release theophylline, 800 mg/d. Peak
expiratory flow rate also decreased
after ketoconazole ingestion. The au¬
thors confirmed the interaction in two
other patients.
Concurrent administration of
theophylline and ketoconazole may
manifest a potential drug interac¬
tion. Monitoring of serum theophyl¬
line concentrations, pulmonary func¬
tion, and hepatic function is suggested.
To our knowledge, no studies have
assessed fluconazole and theophyl¬
line coadministration.
GASTROINTESTINAL DRUGS
Several articles6,13,42"46 indicate that
agents or disease states that raise the
gastric pH can interfere with the ab¬
sorption of ketoconazole. Van Der
Meer et al42 studied the administra¬
tion of cimetidine IV form only, 400
mg, sodium bicarbonate, 0.5 g, and
ketoconazole, 200 mg, in three healthy
male volunteers. The Cmaxs for keto¬
conazole were as follows: 4.5 mg/
L—ketoconazole alone; 1.2 mg/L—
cimetidine and ketoconazole; 6.8 mg/
L—cimetidine, ketoconazole, and
hydrochloric acid solution; and 0.3
mg/L—cimetidine, ketoconazole, and
sodium bicarbonate. Cimetidine and
antacids appear to interfere with the
absorption of oral ketoconazole. Ant¬
acids, if needed, should be given 2
hours after ketoconazole.
Brass et al6 studied four pa¬
tients after simultaneous administra¬
tion of ketoconazole, 200 mg, and
antacid (Maalox), 30 mL, on empty
stomachs after an overnight fast. Al¬
though individual patients showed
decreased AUC or Cmax, the differ¬
ences were not statistically signifi¬
cant.This variable effect probably rep¬
resents the nonuniform neutralization
of stomach acids by antacids.
Lelawongs et al43 investigated the
 effect of food and gastric acidity on
the bioavailability of ketoconazole, 200
mg, in 12 volunteers using a six-
treatment randomized, Latin-square
crossover design. Treatments in¬
cluded ketoconazole with the fol¬
lowing: after a fast; with a standard¬
ized high-fat meal; with a standardized
high-carbohydrate meal; after pre-
treatment with 680-mg glutamic acid
hydrochloride capsules; in a simu¬
lated achlorhydric state induced with
cimetidine, 300 mg, and sodium bi¬
carbonate, 2 g; and administration
with glutamic acid hydrochloride in
a simulated achlorhydric state. After
a single 200-mg ketoconazole tab¬
let, ketoconazole's Cmax was 4.37 mg/L
at 1.21 hours. Mean peak plasma ke¬
toconazole concentrations of 4.42 and
3.01 (jLghmL were reached at 2.33
and 2.38 hours after administration
of a high-fat and high-carbohydrate
meal, respectively. A significant dif¬
ference was noted in the Cmax be¬
tween the fasting state and the achlor-
hydria model (4.37 vs 0.32 mg/L).
The mean AUC for the fasting state
was 15.25 |xg-hmL compared with
the achlorhydria model 1.29 |xghmL,
with the difference being signifi¬
cant. In the group administered
glutamic acid hydrochloride in the
simulated achlorhydria model, the
mean AUC increased significantly to
3.30 |xghmLfrom 1.29 LLghmLin
the achlorhydric state, alone. The C^
was also significantly increased (1.46
vs 0.32 mg/L). The use of glutamic
acid hydrochloride capsules may ef¬
fectively and conveniently enhance
ketoconazole's absorption in achlor¬
hydric patients. Ketoconazole's bio¬
availability is most complete in the
fasting state.
Drew et al44 described a 39-
year-old woman with chronic mu-
cocutaneous candidiasis, pernicious
anemia (documented achlorhydria on
several occasions), and recurrent uri¬
nary tract infections. Variable re¬
sponses and exacerbations were ob¬
served during 6 years of suppressive
therapy with ketoconazole. After 1
month of ketoconazole, either 400
mg/d or 600 mg/d, with 180 mL of
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carbonated cola, the serum ketocon-
azole concentration 4 hours after the
dose was undetectable. Ketocona-
zole therapy was discontinued and
fluconazole therapy was started. The
patient's fluconazole serum level was
3.1 u.ghmL (range, 1.90 to 2.85
|i,g-h-mL—volunteers) 2 hours after
the seventh dose of fluconazole, 100
mg/d. Substantial reductions in dys-
phagia, oral mucosal lesions, and
vaginitis occurred after 2 months.
LAZAR
AND Wilner13
noted an effect of ci-
metidine on the ab¬
sorption of flucona¬
zole. A single 100-mg
dose of fluconazole was adminis¬
tered to six healthy male volunteers.
After a week washout, each subject
received cimetidine, 400 mg, orally
followed 2 hours later by flucona¬
zole, 100 mg. Concomitant admin¬
istration of cimetidine with flucon¬
azole caused a 13% and a 21%
decrease in the AUC and Cmax of flu¬
conazole, respectively.
Thorpe et al45 studied 14 healthy
male subjects who received a single
oral 100-mg fluconazole dose alone
or fluconazole, 100 mg, following 20
mL of a combination of aluminum hy¬
droxide, 1800 mg, and magnesium hy¬
droxide, 1200 mg (Maalox Forte), in
a two-way crossover study. There was
no statistically significant difference
between fluconazole's AUC, Cm^, time
to peak plasma concentration (Tmax),
or elimination ratein fasted volunteers
with orwithout antacid.
Blum et al46 studied the effects
of cimetidine-induced increase in gas¬
tric pH on the relative bioavailability
of fluconazole and ketoconazole. Us¬
ing a randomized, four-way crossover
study, 24 healthy male volunteers re¬
ceived oral fluconazole, 200 mg, and
oral ketoconazole, 400 mg, with and
without cimetidine hydrochloride. At
30 and 60 minutes before the anti-
fungal dose, two 300-mg IV cimeti¬
dine hydrochloride doses were admin¬
istered. During the first 5 hours of the
study, three supplemental 100-mg ci-
metidine bolus doses were adminis¬
tered if the gastric pH fell below 6.
The antifungal was given 1 hour af¬
ter the initial cimetidine infusion. The
mean AUC and mean Cmax of keto¬
conazole were reduced 95% and 93%,
respectively, by cimetidine. Flucon¬
azole was not affected by cimetidine-
induced elevations in gastric pH. In
clinical practice, a gastric pH greater
than 6 is probably rarely achieved.
Patients with achlorhydria or
those who are receiving histamine2
antagonists should not receive con¬
comitant ketoconazole, as the absorp¬
tion of ketoconazole depends on gas¬
tric pH for dissolution.47 Fluconazole's
disposition appears unaffected by con¬
comitant cimetidine therapy.
Piscitelli et al48 compared the ef¬
fects of sucralfate and ranitidine hy¬
drochloride administration on the ab¬
sorption of a 400-mg ketoconazole dose.
Six healthy male volunteers were ran¬
domized in a three-way crossover to
receive ketoconazole alone (treatment
1), 1.0 g of sucralfate with ketocon¬
azole (treatment 2), or ranitidine hy¬
drochloride, 150 mg, orally 2 hours
prior to ketoconazole (treatment 3).
During treatment 3, if the gastric pH
is less than 6 within 4 hours of ke¬
toconazole administration, a maximum
of two ranitidine hydrochloride 50-mg
IV doses could be given. The mean
AUC of ketoconazole decreased by 20%
and 95%, respectively, for treatment
2 and treatment 3. The decreased bio-
availability of ketoconazole observed
with ranitidine was due to a decrease
in the dissolution of ketoconazole at
a gastric pH greater than 5. The de¬
crease observed with sucralfate is due
to delayed ketoconazole absorption
by sucralfate, as evidenced by a 95%
increase in T^, from ketoconazole alone.
To our knowledge, no studies have
assessed fluconazole and ranitidine
administered concomitantly.
Carver et al49 investigated the ef¬
fect of ketoconazole and sucralfate
administered simultaneously or 2
hours apart. Twelve healthy male vol¬
unteers received ketoconazole, 400
mg orally, 10 minutes after and con¬
currently with 680 mg of glutamic
 acid in three treatments separated by
1 week: ketoconazole alone (treat¬
ment 1), ketoconazole concomi-
tantly with sucralfate, 1.0 g orally
(treatment 2), and ketoconazole 2
hours after administration of sucral¬
fate, 1.0 g orally (treatment 3). The
concurrent administration of keto¬
conazole and sucralfate resulted in
significant decreases in ketocona-
zole's AUC, Cmax, and Tmax. How¬
ever, the interaction varied consid¬
erably between subjects. Ad¬
ministration of sucralfate 2 hours prior
to ketoconazole did not signifi¬
cantly affect ketoconazole's pharma-
cokinetic parameters. To our knowl¬
edge, no studies have assessed the
fluconazole-sucralfate interaction.
The concurrent administration
Ketoconazole or Fluconazole
Drug
Rifampin6"15
Isonlazid68,10
Cyclosporine634
Corticosteroids35"39
of ketoconazole and sucralfate causes
a significant but variable decrease in
ketoconazole's bioavailability. Ad¬
ministration of ketoconazole 2 hours
after sucralfate minimizes the inter¬
action and may be one alternative for
patients requiring concurrent ther¬
apy for acid-peptic disorders as well
as antifungal therapy.
OTHER DRUGS
Potential interactions may exist be¬
tween azole antifungals and other
drugs, including anticoagu¬
lants,6,13,50"52 phenytoin sodium ,6,13,53-56
isoniazid,6,8,10 chlordiazepoxide hy¬
drochloride,5 tolbutamide,13 terfena-
dine,57,58 alcohol,59,60 quinidine sul¬
fate,61 and oral contraceptives.13,62
Drug Interactions: Management
Ketoconazole Fluconazole
Possibly monitor rifampin level Similar
Possibly monitor antifungal level No need to
space drugs
Space drugs by 12 h
Possibly monitor isoniazid level No data
Possibly monitor ketoconazole level
Monitor cyclosporine level Similar
Monitor renal, liver function
CONCLUSIONS
A compilation of potential drug in¬
teractions between ketoconazole or
fluconazole and other drugs is found
in the Table. Cyclosporine, meth-
ylprednisolone, possibly anticoagu¬
lants, and phenytoin may require dos¬
age reduction when given con¬
currently with ketoconazole or flu¬
conazole due to inhibition of he¬
patic microsomal enzymes. In¬
creased ketoconazole dosages and
possibly fluconazole dosages may be
required with concomitant rifampin
administration due to rifampin's po¬
tent induction of hepatic microso¬
mal enzymes. Rifampin dosage may
also require adjustment following
ketoconazole.
Time courses of the interac¬
tions vary with each drug. These in¬
teractions may occur in several days
to a week and may take several weeks
to dissipate after treatment with the
concomitant agent is discontinued.
Patients should be assessed for
signs or symptoms of concurrent re¬
nal, hepatic, or neurotoxic reac¬
tions. Monitoring of readily avail¬
able drug concentrations such
as

MethylprerJnisolone Decrease methylprednisolone dose No data cyclosporine, theophylline, and

sodium succinate phenytoin is recommended to com¬
Prednisolone Minimal effect No data
sodium phosphate
plement clinical judgment and main¬
w
tain therapeutic drug concentra¬
Theophylline Monitor theophylline level No data
Monitor liver function tions. Fluconazole appears to he
Monitor pulmonary function associated with fewer potential drug
Gastrointestinal drugs 6,13,42"*ä interactions than ketoconazole.
Cimetidine Avoid combination No effect
Use other antifungal
Ranitidine Avoid combination No data Accepted for publication February 19,
Use other antifungal 1993.
Antacid Possibly monitor antifungal level No data Reprints not available.
Separate drugs by 2 h
Sucralfate Possibly monitor antifungal level No data
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