SIDE EFFECTS
In Patients Receiving a Single Dose for Vaginal
Candidiasis: During comparative clinical
studies conducted in the United States, 448 patients with
vaginal candidiasis were treated with Diflucan, 150 mg
single dose. The overall incidence of side effects possibly
related to Diflucan was 26%. In 422 patients receiving
active comparative agents, the incidence was 16%. The
most common treatment-related adverse events reported
in the patients who received 150 mg single dose fluconazole
for vaginitis were headache (13%), nausea (7%), and abdominal
pain (6%). Other side effects reported with an incidence
equal to or greater than 1% included diarrhea (3%), dyspepsia
(1%), dizziness (1%), and taste perversion (1%). Most
of the reported side effects were mild to moderate in
severity. Rarely, angioedema and anaphylactic reaction
have been reported in marketing experience.
In Patients Receiving Multiple Doses for
Other Infections: Sixteen percent of over
4000 patients treated with fluconazole in clinical trials
of 7 days or more experienced adverse events. Treatment
was discontinued in 1.5% of patients due to adverse clinical
events and in 1.3% of patients due to laboratory test
abnormalities.
Clinical adverse events were reported more frequently
in HIV infected patients (21%) than in non-HIV infected
patients (13%); however, the patterns in HIV infected
and non-HIV infected patients were similar. The proportions
of patients discontinuing therapy due to clinical adverse
events were similar in the two groups (1.5%).
The following treatment-related clinical adverse events
occurred at an incidence of 1% or greater in 4048 patients
receiving Diflucan for 7 or more days in clinical trials:
nausea 3.7%, headache 1.9%, skin rash 1.8%, vomiting 1.7%,
abdominal pain 1.7%, and diarrhea 1.5%.
The following adverse events have occurred under conditions
where a casual association is probable:
Hepatobiliary: In combined
clinical trials and marketing experience, there have been
rare cases of serious hepatic reactions during treatment
with fluconazole. (See WARNINGS.) The spectrum of these
hepatic reactions has ranged from mild transient elevations
in transaminases to clinical hepatitis, cholestasis and
fulminant hepatic failure, including fatalities. Instances
of fatal hepatic reactions were noted to occur primarily
in patients with serious underlying medical conditions
(predominantly AIDS or malignancy) and often while taking
multiple concomitant medications. Transient hepatic reactions,
including hepatitis and jaundice, have occurred among
patients with no other identifiable risk factors. In each
of these cases, liver function returned to baseline on
discontinuation of fluconazole.
In two comparative trials evaluating the efficacy of
fluconazole for the suppression of relapse of cryptococcal
meningitis, a statistically significant increase was observed
in median AST (SGOT) levels from a baseline value of 30
IU/l to 41 IU/l in one trial and 34 IU/l to 66 IU/l in
the other. The overall rate of serum transaminase elevations
of more than 8 times the upper limit of normal was approximately
1% in fluconazole-treated patients in clinical trials.
These elevations occurred in patients with severe underlying
disease, predominantly AIDS or malignancies, most of whom
were receiving multiple concomitant medications, including
many known to be hepatotoxic. The incidence of abnormally
elevated serum transaminases was greater in patients taking
fluconazole concomitantly with one or more of the following
medications: rifampin, phenytoin, isoniazid, valproic
acid, or oral sulfonylurea hypoglycemic agents.
Immunological: In rare cases,
anaphylaxis has been reported.
The following adverse events have occurred under conditions
where a casual association is uncertain:
Central Nervous System: Seizures.
Dermatologic: Exfoliative skin disorders including Stevens-Johnson
Syndrome and toxic epidermal necroivsis (See WARNINGS,
alopecia).
Hematopoietic and Lymphatic: Leukopenia,
thrombocytopenia.
Metabolic: Hypercholesterolemia,
hypertriglyceridemia, hypokalemia.
Adverse Reactions in Children:
In phase 2/3 clinical trials conducted in the United States
and in Europe, 577 pediatric patients, ages 1 day to 17
years were treated with fluconazole at doses up to 15 mg/kg/day
for up to 1,616 days. Thirteen percent of children experienced
treatment related adverse events. The most commonly reported
events were vomiting (5%), abdominal pain (3%), nausea (2%),
and diarrhea (2%). Treatment was discontinued inn 2.3% of
patients due to adverse clinical events and in 1.4% of patients
due to laboratory test abnormalities. The majority of treatment-related
laboratory abnormalities were elevations of transaminases
or alkaline phosphatase (see TABLE 6).
TABLE 6 Percentage of Patients with Treatment-Related Side
Effects
|
| |
Fluconazole |
Comparative Agents |
| |
(N=577) |
(N=451) |
| With any side effect |
13.0 |
9.3 |
| Vomiting |
5.4 |
5.1 |
| Abdominal pain |
2.8 |
1.6 |
| Nausea |
2.3 |
1.6 |
| Diarrhea |
2.1 |
2.2 |
DRUG INTERACTIONS
See PRECAUTIONS: General.
Clinically or potentially significant drug interactions
between fluconazole and the following agents/classes have
been observed. These are described in greater detail below:
Oral Hypoglycemics: Clinically
significant hypoglycemia may be precipitated by the use
of fluconazole with oral hypoglycemic agents: one fatality
has been reported from hypoglycemia in association with
combined fluconazole and glyburide use. Fluconazole reduces
the metabolism of tolbutamide, glyburide, and glipizide
and increases the plasma concentration of these agents.
When fluconazole is used concomitantly with these or other
sulfonylurea oral hypoglycemic agents, blood glucose concentrations
should be carefully monitored and the dose of the sulfonylurea
should be adjusted as necessary.
Coumarin-Type Anticoagulants:
Prothrombin time may be increased in patients receiving
concomitant fluconazole and coumarin-type anticoagulants.
Careful monitoring of prothrombin time in patients receiving
fluconazole and coumarin-type anticoagulants is recommended.
Phenytoin: Fluconazole increases
the plasma concentrations of phenytoin. Careful monitoring
of phenytoin concentrations in patients receiving fluconazole
and phenytoin is recommended.
Cyclosporine: Fluconazole may
significantly increase cyclosporine levels in renal transplant
patients with or without renal impairment. Careful monitoring
of cyclosporine concentrations and serum creatinine is
recommended in patients receiving fluconazole and cyclosporine.
Rifampin: Rifampin enhances
the metabolism of concurrently administered fluconazole.
Depending on clinical circumstances, consideration should
be given to increasing the dose of fluconazole when it
is administered with rifampin.
Theophylline: Fluconazole increases
the serum concentrations of theophylline. Careful monitoring
of serum theophylline concentrations in patients receiving
fluconazole and theophylline is recommended.
Terfenadine: Because of the
occurrence of serious cardiac dysrhythmias in patients
receiving other azole antifungals in conjunction with
terfenadine, an interaction study has been performed (See
Drug Interaction Studies below), and failed to demonstrate
a clinically significant drug interaction. Although these
events have not been observed in patients receiving fluconazole,
the co-administration of fluconazole and terfenadine should
be carefully monitored.
Fluconazole tablets coadministered with ethinyl estradiol-
and levonorgestrel -containing oral contraceptives produced
an overall mean increase in ethinyl estradiol and levonorgestrel
levels; however, in some patients there were decreases
up to 47% and 33% of ethinyl estradiol and levonorgestrel
levels (See Drug Interaction Studies below.) The data
presently available indicate that the decreases in some
individual ethinyl estradiol and levonorgestrel AUC values
with fluconazole treatment are likely the result of random
variation. While there is evidence that fluconazole can
inhibit the metabolism of ethinyl estradiol and levonorgestrel,
there is no evidence that fluconazole is a net inducer
of ethinyl estradiol or levonorgestrel metabolism. The
clinical significance of these effects is presently unknown.
Physicians should be aware that interaction studies with
medications other than those listed in CLINICAL PHARMACOLOGY
have not been conducted, but such interactions may occur.
Drug Interaction Studies
Oral Contraceptives: Oral contraceptives
were administered as a single dose both before and after
the oral administration of fluconazole 50 mg once daily
for 10 days in 10 healthy women. There was no significant
difference in ethinyl estradiol or levonorgestrel AUC
after the administration of 50 mg of fluconazole. The
mean increase in ethinyl estradiol AUC was 6% (range:
-47 to 108%) and levonorgestrel AUC increased 17% (range:
-33 to 141%).
Twenty-five normal females received daily doses of both
200 mg of fluconazole tablets or placebo for two, ten-day
periods. The treatment cycles were one month apart with
all subjects receiving fluconazole during one cycle and
placebo during the other. The order of study treatment
was random. Single doses of an oral contraceptive tablet
containing levonorgestrel and ethinyl estradiol were administered
on the final treatment day (day 10) of both cycles. Following
administration of 200 mg of fluconazole, the mean percentage
increase of AUC for levonorgestrel compared to placebo
was 25% (range: -12 to 82%) and the mean percentage increase
for ethinyl estradiol compared to placebo was 38% (range:
-11 to 101%). Both of these increases were statistically
significantly different from placebo.
Cimetidine: Fluconazole 100
mg was administered as a single oral dose alone and two
hours after a single dose of cimetidine 400 mg to six
healthy male volunteers. After the administration of cimetidine,
there was a significant decrease in fluconazole AUC and
Cmax. There was a mean ± SD decrease in fluconazole
AUC of 13% ± 11% (range: -3.4 to -31%) and Cmax
decreased 19% ± 14% (range: -5 to -40%). However,
the administration of cimetidine 600 mg to 900 mg intravenously
over a four hour period (from one hour before to 3 hours
after a single oral dose of fluconazole 200 mg) did not
affect the bioavailability or pharmacokinetics of fluconazole
in 24 healthy male volunteers.
Antacid: Administration of
Maalox (20 ml) to 14 normal male volunteers immediately
prior to a single dose of fluconazole 100 mg had no effect
on the absorption or elimination of fluconazole.
Hydrochlorothiazide: Concomitant
oral administration of 100 mg Diflucan and 50 mg hydrochlorothiazide
for 10 days in 13 normal volunteers resulted in a significant
increase in fluconazole AUC and Cmax compared to Diflucan
given alone. There was a mean ± SD increase in
fluconazole AUC and Cmax 45% ± 31% (range: 19 to
114%) and 43% ± 31% (range: 19 to 122%), respectively.
These changes are attributable to a mean ± SD reduction
in renal clearance of 30% ± 12% (range: -10 to
-50%).
Rifampin: Administration of
a single oral 200 mg dose of fluconazole after 15 days
of rifampin administration as 600 mg daily in eight healthy
male volunteers resulted in a significant decrease in
fluconazole AUC and a significant increase in apparent
oral clearance of fluconazole. There was a mean ±
SD reduction in fluconazole AUC of 23% ± 9% (range:
- 13 to -42%). Apparent oral clearance of fluconazole
increased 32% ± 17% (range: 16 to 72%). Fluconazole
half-life decreased from 33.4 ± 4.4 hours to 26.8
± 3.9 hours. (See PRECAUTIONS.)
Warfarin: There was a significant
increase in prothrombin time response (area under the
prothrombin time-time curve) following a single dose of
warfarin (15 mg) administered to 13 normal male volunteers
following oral fluconazole 200 mg administered daily for
14 days as compared to the administration of warfarin
alone. There was a mean ± SD increase in the prothrombin
time response (area under the prothrombin time-time curve)
of 7% ± 4% (range: -2 to 13%). (See PRECAUTIONS.)
Mean is based on data from 12 subjects as one of 13 subjects
experienced a 2-fold increase in his prothrombin time
response.
Phenytoin: Phenytoin AUC was
determined after 4 days of phenytoin dosing (200 mg daily,
orally for 3 days followed by 250 mg intravenously for
one dose) both with and without the administration of
fluconazole (oral fluconazole 200 mg daily for 16 days)
in 10 normal male volunteers. There was a significant
increase in phenytoin AUC. The mean ± SD increase
in phenytoin AUC was 88% ± 68% (range: 16 to 247%).
The absolute magnitude of this interaction is unknown
because of the intrinsically nonlinear disposition of
phenytoin. (See PRECAUTIONS.)
Cyclosporine: Cyclosporine
AUC and Cmax were determined before and after the administration
of fluconazole 200 mg daily for 14 days in eight renal
transplant patients who had been on cyclosporine therapy
for at least 6 months and on a stable cyclosporine dose
for at least 6 weeks. There was a significant increase
in cyclosporine AUC, Cmax, Cmin (24 hour concentration),
and a significant reduction in apparent oral clearance
following the administration of fluconazole. The mean
± SD increase in AUC was 92% ± 43% (range:
18 to 147%). The Cmax increased 60% ± 48% (range:
-5 to 133%). The Cmin increased 157% ± 96% (range:
33 to 360%). The apparent oral clearance decreased 45%
± 15% (range: -15 to -60%). (See PRECAUTIONS.)
Zidovudine: Plasma zidovudine
concentrations were determined on two occasions (before
and following fluconazole 200 mg daily for 15 days) in
13 volunteers with AIDS or ARC who were on a stable zidovudine
dose for at least two weeks. There was a significant increase
in zidovudine AUC following the administration of fluconazole.
The mean ± SD increase in AUC was 20% ±
32% (range: -27 to 104%). The metabolite, GZDV to parent
drug ratio significantly decreased after the administration
of fluconazole, from 7.6 ± 3.6 to 5.7 ±
2.2.
Theophylline: The pharmacokinetics
of theophylline were determined from a single intravenous
dose of aminophylline (6 mg/kg) before and after the oral
administration of fluconazole 200 mg daily for 14 days
in 16 normal male volunteers. There were significant increases
in theophylline AUC, Cmax, and half-life with a corresponding
decrease in clearance. The mean ± SD theophylline
AUC increased 21% ± 16% (range: -5 to 48%). The
Cmax increased 13% ± 17% (range: -13 to 40%). Theophylline
clearance decreased 16% ± 11% (range: -32 to 5%).
The half-life of theophylline increased from 6.6 ±
1.7 hours to 7.9 ± 1.5 hours.
Terfenadine: Six healthy volunteers
received terfenadine 60 mg bid for 15 days. Fluconazole
200 mg was administered daily from days 9 through 15.
Fluconazole did not affect terfenadine plasma concentrations.
Terfenadine acid metabolite AUC increased 36% ±
36% (range: 7 to 102%) from day 8 to 15 with the concomitant
administration of fluconazole. There was no change in
cardiac repolarization as a measure by Holter QTc intervals.
Oral Hypoglycemics: The effects
of fluconazole on the pharmacokinetics of the sulfonylurea
oral hypoglycemic agents tolbutamide, glipizide, and glyburide
were evaluated in three placebo- controlled studies in
normal volunteers. All subjects received the sulfonylurea
alone as a single dose and again as a single dose following
the administration of fluconazole 100 mg daily for 7 days.
In these three studies 22/46 (47.8%) of fluconazole treated
patients and 9/22 (40.1%) of placebo treated patients
experienced symptoms consistent with hypoglycemia. (See
PRECAUTIONS.)
Tolbutamide: In 13 normal male
volunteers, there was significant increase in tolbutamide
(500 mg single dose) AUC and Cmax following the administration
of fluconazole. There was a mean ± SD increase
in tolbutamide AUC of 26% ± 9% (range: 12 to 39%).
Tolbutamide Cmax increased 11% ± 9% (range: -6
to 27%). (See PRECAUTIONS.)
Glipizide: The AUC and Cmax
of glipizide (2.5 mg single dose) were significantly increased
following the administration of fluconazole in 13 normal
male volunteers. There was mean ± SD increase in
AUC of 49% ± 13% (range: 27 to 73%) and an increase
in Cmax of 19% ± 23% (range: -11 to 79%). (See
PRECAUTIONS.)
Glyburide: The AUC and Cmax
of glyburide (5 mg single dose) were significantly increased
following the administration of fluconazole in 20 normal
male volunteers. There was a mean ± SD increase
in AUC of 44% ± 29% (range: -13 to 115%) and Cmax
increased 19% ± 19% (range: -23 to 62%). Five subjects
required oral glucose following the ingestion of glyburide
after 7 days of fluconazole administration. (See PRECAUTIONS.)
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