Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3110
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Fluconazole (Injection, Solution)
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Dosage and Administration
in Adults: SINCE ORAL ABSORPTION IS RAPID
AND ALMOST COMPLETE, THE DAILY DOSE OF FLUCONAZOLE IS THE SAME FOR ORAL (TABLETSAND SUSPENSION) AND INTRAVENOUS ADMINISTRATION. In general, a loading dose
of twice the daily dose is recommended on the first day of therapy to result
in plasma concentrations close to steady-state by the second day of therapy. The
daily dose of fluconazole for the treatment of infections other than vaginal
candidiasis should be based on the infecting organism and the patient's
response to therapy. Treatment should be continued until clinical parameters
or laboratory tests indicate that active fungal infection has subsided. An
inadequate period of treatment may lead to recurrence of active infection.
Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal
candidiasis usually require maintenance therapy to prevent relapse. Oropharyngeal candidiasis: The recommended dosage
of fluconazole for oropharyngeal candidiasis is 200 mg on the first day, followed
by 100 mg once daily. Clinical evidence of oropharyngeal candidiasis generally
resolves within several days, but treatment should be continued for at least
2 weeks to decrease the likelihood of relapse. Esophageal candidiasis: The recommended dosage
of fluconazole for esophageal candidiasis is 200 mg on the first day, followed
by 100 mg once daily. Doses up to 400 mg/day may be used, based on medical
judgment of the patient's response to therapy. Patients with esophageal
candidiasis should be treated for a minimum of three weeks and for at least
two weeks following resolution of symptoms. Systemic Candida infections: For systemic Candida infections including candidemia, disseminated
candidiasis, and pneumonia, optimal therapeutic dosage and duration of therapy
have not been established. In open, noncomparative studies of small numbers
of patients, doses of up to 400 mg daily have been used. Urinary tract infections and peritonitis: For
the treatment of Candida urinary tract
infections and peritonitis, daily doses of 50 to 200 mg have been used in
open, noncomparative studies of small numbers of patients. Cryptococcal meningitis: The recommended dosage
for treatment of acute cryptococcal meningitis is 400 mg on the first day,
followed by 200 mg once daily. A dosage of 400 mg once daily may be used,
based on medical judgment of the patient's response to therapy. The
recommended duration of treatment for initial therapy of cryptococcal meningitis
is 10 to 12 weeks after the cerebrospinal fluid becomes culture negative.
The recommended dosage of fluconazole for suppression of relapse of cryptococcal
meningitis in patients with AIDS is 200 mg once daily. Prophylaxis in patients undergoing bone marrow transplantation: The recommended fluconazole daily dosage for the prevention of
candidiasis of patients undergoing bone marrow transplantation is 400 mg,
once daily. Patients who are anticipated to have severe granulocytopenia (less
than 500 neutrophils per cu mm) should start fluconazole prophylaxis several
days before the anticipated onset of neutropenia, and continue for 7 days
after the neutrophil count rises above 1,000 cells per cu mm. Dosage and Administration in Children: The
following dose equivalency scheme should generally provide equivalent exposure
in pediatric and adult patients: *Some older children may have clearances similar to that
of adults. Absolute doses exceeding 600 mg/day are not recommended. Experience
with fluconazole in neonates is limited to pharmacokinetic studies in premature
newborns. (See CLINICAL PHARMACOLOGY.)
Based on the prolonged half-life seen in premature newborns (gestational age
26 to 29 weeks), these children, in the first two weeks of life, should receive
the same dosage (mg/kg) as in older children, but administered every 72 hours.
After the first two weeks, these children should be dosed once daily. No information
regarding fluconazole pharmacokinetics in full-term newborns is available. Oropharyngeal candidiasis: The recommended dosage
of fluconazole for oropharyngeal candidiasis in children is 6 mg/kg on the
first day, followed by 3 mg/kg once daily. Treatment should be administered
for at least 2 weeks to decrease the likelihood of relapse. Esophageal candidiasis: For the treatment of
esophageal candidiasis, the recommended dosage of fluconazole in children
is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up to 12
mg/kg/day may be used based on medical judgment of the patient's response
to therapy. Patients with esophageal candidiasis should be treated for a minimum
of three weeks and for at least 2 weeks following the resolution of symptoms. Systemic Candida infections: For the treatment
of candidemia and disseminated Candida infections,
daily doses of 6 to 12 mg/kg/day have been used in an open, noncomparative
study of a small number of children. Cryptococcal
meningitis: For the treatment of acute cryptococcal meningitis,
the recommended dosage is 12 mg/kg on the first day, followed by 6 mg/kg once
daily. A dosage of 12 mg/kg once daily may be used, based on medical judgment
of the patient's response to therapy. The recommended duration of treatment
for initial therapy of cryptococcal meningitis is 10 to 12 weeks after the
cerebrospinal fluid becomes culture negative. For suppression of relapse of
cryptococcal meningitis in children with AIDS, the recommended dose of fluconazole
is 6 mg/kg once daily. Dosage
In Patients With Impaired Renal Function: Fluconazole
is cleared primarily by renal excretion as unchanged drug. In patients with
impaired renal function who will receive multiple doses of fluconazole, an
initial loading dose of 50 to 400 mg should be given. After the loading dose,
the daily dose (according to indication) should be based on the following
table: These are suggested dose adjustments based on pharmacokinetics
following administration of multiple doses. Further adjustment may be needed
depending upon clinical condition. When serum creatinine
is the only measure of renal function available, the following formula (based
on sex, weight, and age of the patient) should be used to estimate the creatinine
clearance in adults: Although the pharmacokinetics of fluconazole has not been
studied in children with renal insufficiency, dosage reduction in children
with renal insufficiency should parallel that recommended for adults. The
following formula may be used to estimate creatinine clearance in children: (Where K=0.55 for children older than 1 year and 0.45 for
infants.) Administration Fluconazole
injection may be administered by intravenous infusion. Fluconazole injection
has been used safely for up to fourteen days of intravenous therapy. The intravenous
infusion of fluconazole should be administered at a maximum rate of approximately
200 mg/hour, given as a continuous infusion. Fluconazole
injections in flexible plastic containers are intended only for intravenous
administration using sterile equipment. Parenteral drug
products should be inspected visually for particulate matter and discoloration
prior to administration whenever solution and container permit. Do
not use if the solution is cloudy or precipitated or if the seal is not intact. Directions for IV Use of Fluconazole in Flexible Plastic
Containers Do not remove unit from overwrap
until ready for use. The overwrap is a moisture barrier. The inner bag maintains
the sterility of the product. CAUTION: Do not use flexible plastic containers in series connections.
Such use could result in air embolism due to residual air being drawn from
the primary container before administration of the fluid from the secondary
container is completed. To
Open Tear outer wrap at notch slit and remove
solution container. Some opacity of the plastic due to moisture absorption
during the sterilization process may be observed. This is normal and does
not affect the solution quality or safety. The opacity will diminish gradually.
After removing overwrap, check for minute leaks by squeezing inner bag firmly.
If leaks are found, discard solution as sterility may be impaired. DO
NOT ADD SUPPLEMENTARY MEDICATION. Preparation
for Administration: (Use
Aseptic Technique) WARNING: Do not use flexible container
in series connections.
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Fluconazole, the first of a new subclass of synthetic triazole
antifungal agents, is available as a sterile solution for intravenous use
in flexible plastic containers. Fluconazole is designated
chemically as 2,4-difluoro-��,��-bis(1H-1,2,4-triazol-1-ylmethyl)
benzyl alcohol with a chemical formula of CHFNO
and molecular weight 306.3. The structural formula is: Fluconazole
is a white crystalline solid which is slightly soluble in water and saline. Fluconazole
injection is an iso-osmotic, sterile, nonpyrogenic solution of fluconazole
in a sodium chloride or dextrose diluent. Each mL contains 2 mg of fluconazole
and 9 mg of sodium chloride or 56 mg of dextrose, hydrous. The pH ranges from
4.0 to 8.0 in the sodium chloride diluent and from 3.5 to 6.5 in the dextrose
diluent. Injection volumes of 100 mL and 200 mL are packaged in flexible plastic
containers. The flexible plastic container is fabricated
from a specially formulated polyvinylchloride. The amount of water that can
permeate from inside the container into the overwrap is insufficient to affect
the solution significantly. Solutions in contact with the plastic container
can leach out certain of its chemical components in very small amounts; however,
biological testing was supportive of the safety of the plastic container materials.
Exposure to temperatures above 25��C (77��F) during transport and
storage will lead to minor losses in moisture content. Higher temperatures
lead to greater losses. It is unlikely that these minor losses will lead to
clinically significant changes within the expiration period.
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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
(C) in fasted normal volunteers occur between 1 and 2 hours
with a terminal plasma elimination half-life of approximately 30 hours (range:
20 to 50 hours) after oral administration. In fasted
normal volunteers, administration of a single oral 400 mg dose of fluconazole
leads to a mean Cof 6.72 mcg/mL (range: 4.12 to 8.08 mcg/mL)
and after single oral doses of 50 to 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 Cof 2.61 mcg/mL (range: 1.57 to 3.65 mcg/mL). Steady-state
concentrations are reached within 5 to 10 days following oral doses of 50
to 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 to 12%). Following
either single- or multiple-oral doses for up to 14 days, fluconazole penetrates
into all body fluids studied (see table below). 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 toplasma 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. *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: 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. Pharmacokinetics in Elderly A
pharmacokinetic study was conducted in 22 subjects, 65 years of age or older
receiving a single 50 mg oral dose of fluconazole. Ten of these patients were
concomitantly receiving diuretics. The Cwas 1.54 mcg/mL and
occurred at 1.3 hours post dose. The mean AUC was 76.4+ 20.3 mcg���h/mL,
and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter
values are higher than analogous values reported for normal young male volunteers.
Coadministration of diuretics did not significantly alter AUC or C.
In addition, creatinine clearance (74 mL/min), the percent of drug recovered
unchanged in urine (0-24 hr, 22%) and the fluconazole renal clearance estimates
(0.124 mL/min/kg) for the elderly were generally lower than those of younger
volunteers. Thus, the alteration of fluconazole disposition in the elderly
appears to be related to reduced renal function characteristic of this group.
A plot of each subject's terminal elimination half-life versus creatinine
clearance compared with the predicted half-life���creatinine clearance
curve derived from normal subjects and subjects with varying degrees of renal
insufficiency indicated that 21 of 22 subjects fell within the 95% confidence
limit of the predicted half-life���creatinine clearance curves. These
results are consistent with the hypothesis that higher values for the pharmacokinetic
parameters observed in the elderly subjects compared with normal young male
volunteers are due to the decreased kidney function that is expected in the
elderly.<br/>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%). In a
second study, twenty-five normal females received daily doses of both 200
mg 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. A
third study evaluated the potential interaction of once weekly dosing of fluconazole
300 mg to 21 normal females taking an oral contraceptive containing ethinyl
estradiol and norethindrone. In this placebo-controlled, double-blind, randomized,
two-way crossover study carried out over three cycles of oral contraceptive
treatment, fluconazole dosing resulted in small increases in the mean AUCs
of ethinyl estradiol and norethindrone compared to similar placebo dosing.
The mean AUCs of ethinyl estradiol and norethindrone increased by 24% (95%
C.I. range 18-31%) and 13% (95% C.I. range 8-18%), respectively relative to
placebo. Fluconazole treatment did not cause a decrease in the ethinyl estradiol
AUC of any individual subject in this study compared to placebo dosing. The
individual AUC individual values of norethindrone decreased very slightly
(<5%) in 3 of the 21 subjects after fluconazole treatment. 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 C. There
was a mean��SD decrease in fluconazole AUC of 13%��11% (range:���3.4 to���31%) and Cdecreased 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 fluconazole and 50 mg hydrochlorothiazide for 10 days in 13 normal
volunteers resulted in a significant increase in fluconazole AUC and Ccompared
to fluconazole given alone. There was a mean��SD increase in fluconazole
AUC and Cof 45%��31% (range: 19 to 114%) and 43%��31% (range: 19 to 122%), respectively. These changes are attributed 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 administered 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 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 Cwere 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, C, C(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 Cincreased 60%��48% (range:���5 to 133%). The Cincreased 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, C, and half-life
with a corresponding decrease in clearance. The mean��SD theophylline
AUC increased 21%��16% (range:���5 to 48%). The Cincreased
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. (See PRECAUTIONS.) 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 day 15 with
the concomitant administration of fluconazole. There was no change in cardiac
repolarization as measured by Holter QTc intervals. Another study at a 400-mg
and 800-mg daily dose of fluconazole demonstrated that fluconazole taken in
doses of 400 mg per day or greater significantly increases plasma levels of
terfenadine when taken concomitantly. (See CONTRAINDICATIONS and PRECAUTIONS.) 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. (SeePRECAUTIONS.) Tolbutamide: In 13 normal male volunteers, there was significant increase in
tolbutamide (500 mg single dose) AUC and Cfollowing the administration
of fluconazole. There was a mean��SD increase in tolbutamide AUC of
26%��9% (range: 12 to 39%). Tolbutamide Cincreased 11%��9% (range:���6 to 27%). (See PRECAUTIONS.) Glipizide: The AUC and Cof glipizide (2.5 mg single dose)
were significantly increased following the administration of fluconazole in
13 normal male volunteers. There was a mean��SD increase in AUC of 49%��13% (range: 27 to 73%) and an increase in Cof 19%��23% (range:���11 to 79%). (See PRECAUTIONS.) Glyburide: The AUC and Cof 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 Cincreased 19%��19% (range:���23 to 62%). Five subjects required oral glucose following
the ingestion of glyburide after 7 days of fluconazole administration. (See PRECAUTIONS.) Rifabutin: There have been published reports that an interaction exists when
fluconazole is administered concomitantly with rifabutin, leading to increased
serum levels of rifabutin. (See PRECAUTIONS.) Tacrolimus: There have been published reports
that an interaction exists when fluconazole is administered concomitantly
with tacrolimus, leading to increased serum levels of tacrolimus. (See PRECAUTIONS.) Cisapride:A placebo-controlled, randomized, multiple-dose study examined
the potential interaction of fluconazole with cisapride. Two groups of 10
normal subjects were administered fluconazole 200 mg daily or placebo. Cisapride
20 mg four times daily was started after 7 days of fluconazole or placebo
dosing. Following a single dose of fluconazole, there was a 101% increase
in the cisapride AUC and a 91% increase in the cisapride C.
Following multiple doses of fluconazole, there was a 192% increase in the
cisapride AUC and a 154% increase in the cisapride C. Fluconazole
significantly increased the QTc interval in subjects receiving cisapride 20
mg four times daily for 5 days. (See CONTRAINDICATIONS and PRECAUTIONS.) Midazolam: The effect of fluconazole on the
pharmacokinetics and pharmacodynamics of midazolam was examined in a randomized,
cross-over study in 12 volunteers. In the study, subjects ingested placebo
or 400 mg fluconazole on Day 1 followed by 200 mg daily from Day 2 to Day
6. In addition, a 7.5 mg dose of midazolam was orally ingested on the first
day, 0.05 mg/kg was administered intravenously on the fourth day, and 7.5
mg orally on the sixth day. Fluconazole reduced the clearance of IV midazolam
by 51%. On the first day of dosing, fluconazole increased the midazolam AUC
and Cby 259% and 150%, respectively. On the sixth day of dosing,
fluconazole increased the midazolam AUC and Cby 259% and 74%,
respectively. The psychomotor effects of midazolam were significantly increased
after oral administration of midazolam but not significantly affected following
intravenous midazolam. A second randomized, double-dummy,
placebo-controlled, cross-over study in three phases was performed to determine
the effect of route of administration of fluconazole on the interaction between
fluconazole and midazolam. In each phase the subjects were given oral fluconazole
400 mg and intravenous saline; oral placebo and intravenous fluconazole 400
mg; and oral placebo and IV saline. An oral dose of 7.5 mg of midazolam was
ingested after fluconazole/placebo. The AUC and Cof midazolam
were significantly higher after oral than IV administration of fluconazole.
Oral fluconazole increased the midazolam AUC and Cby 272% and
129%, respectively. IV fluconazole increased the midazolam AUC and Cby
244% and 79%, respectively. Both oral and IV fluconazole increased the pharmacodynamic
effects of midazolam. (See PRECAUTIONS.) Azithromycin: An open-label, randomized, three-way
crossover study in 18 healthy subjects assessed the effect of a single 800
mg oral dose of fluconazole on the pharmacokinetics of a single 1200 mg oral
dose of azithromycin as well as the effects of azithromycin on the pharmacokinetics
of fluconazole. There was no significant pharmacokinetic interaction between
fluconazole and azithromycin.
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Fluconazole is contraindicated in patients who
have shown hypersensitivity to fluconazole or to any of its excipients. There
is no information regarding cross-hypersensitivity between fluconazole and
other azole antifungal agents. Caution should be used in prescribing fluconazole
to patients with hypersensitivity to other azoles. Coadministration of terfenadine
is contraindicated in patients receiving fluconazole at multiple doses of
400 mg or higher based upon results of a multiple dose interaction study.
Coadministration of cisapride is contraindicated in patients receiving fluconazole.
(See CLINICAL PHARMACOLOGY: Drug Interaction Studies and PRECAUTIONS .)
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Fluconazole Injections: Fluconazole injections for intravenous
infusion administration are formulated as sterile iso-osmotic solutions containing
2 mg/mL of fluconazole. They are supplied in flexible plastic containers containing
volumes of 100 mL or 200 mL affording doses of 200 mg and 400 mg of fluconazole,
respectively. Fluconazole injections in flexible plastic containers areavailable
in both sodium chloride and dextrose diluents. Fluconazole
Injections in Flexible Plastic Containers are supplied in the following: Storage: Store at 20
to 25��C (68 to 77��F). [See USP Controlled Room Temperature.] Protect
from freezing.
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General: Some azoles, including fluconazole, have been associated
with prolongation of the QT interval on the electrocardiogram. During post-marketing
surveillance, there have been rare cases of QT prolongation and torsade de
pointes in patients taking fluconazole. Most of these reports involved seriously
ill patients with multiple confounding risk factors, such as structural heart
disease, electrolyte abnormalities and concomitant medications that may have
been contributory. Fluconazole should be administered
with caution to patients with these potentially proarrhythmic conditions.<br/>Drug Interactions:: (See CLINICAL PHARMACOLOGY: Drug
Interaction Studies and CONTRAINDICATIONS.) 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. (See CLINICAL PHARMACOLOGY: Drug Interaction
Studies.) Coumarin-type
anticoagulants: Prothrombin time may be increased in patients receiving
concomitant fluconazole and coumarin-type anticoagulants. In post-marketing
experience, as with other azole antifungals, bleeding events (bruising, epistaxis,
gastrointestinal bleeding, hematuria, and melena) have been reported in association
with increases in prothrombin time in patients receiving fluconazole concurrently
with warfarin. Careful monitoring of prothrombin time in patients receiving
fluconazole and coumarin-type anticoagulants is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Phenytoin: Fluconazole increases the plasma
concentrations of phenytoin. Careful monitoring of phenytoin concentrations
in patients receiving fluconazole and phenytoin is recommended. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) 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.
(See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) 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.
(See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Theophylline: Fluconazole increases the serum concentrations of theophylline.
Careful monitoring of serum theophylline concentrations in patients receiving
fluconazole and theophylline is recommended. (See CLINICAL
PHARMACOLOGY: Drug Interaction Studies.) Terfenadine: Because of the occurrence of serious
cardiac dysrhythmias secondary to prolongation of the QTc interval in patients
receiving azole antifungals in conjunction with terfenadine, interaction studies
have been performed. One study at a 200-mg daily dose of fluconazole failed
to demonstrate a prolongation in QTc interval. Another study ata 400-mg and
800-mg daily dose of fluconazole demonstrated that fluconazole taken in doses
of 400 mg per day or greater significantly increases plasma levels of terfenadine
when taken concomitantly. The combined use of fluconazole at doses of 400
mg or greater with terfenadine is contraindicated. (See CONTRAINDICATIONS and CLINICAL PHARMACOLOGY: Drug Interaction
Studies.) The coadministration of fluconazole at doses lower than
400 mg/day with terfenadine should be carefully monitored. Cisapride: There have been reports of cardiac
events, including torsade de pointes in patients to whom fluconazole and cisapride
were coadministered. A controlled study found that concomitant fluconazole
200 mg once daily and cisapride 20 mg four times a day yielded a significant
increase in cisapride plasma levels and prolongation of QTc interval. The
combined use of fluconazole with cisapride is contraindicated. (See CONTRAINDICATIONS and CLINICAL
PHARMACOLOGY: Drug Interaction Studies.) Astemizole: The use of fluconazole in patients
concurrently taking astemizole or other drugs metabolized by the cytochrome
P450 system may be associated with elevations in serum levels of these drugs.
In the absence of definitive information, caution should be used when coadministering
fluconazole. Patients should be carefully monitored. Rifabutin: There have been reports of uveitis
in patients to whom fluconazole and rifabutin were coadministered. Patients
receiving rifabutin and fluconazole concomitantly should be carefully monitored.
(See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) Tacrolimus: There have been reports of nephrotoxicity in patients to whom
fluconazole and tacrolimus were coadministered. Patients receiving tacrolimus
and fluconazole concomitantly should be carefully monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies .) Short-acting Benzodiazepines: Following oral
administration of midazolam, fluconazole resulted in substantial increases
in midazolam concentrations and psychomotor effects. This effect on midazolam
appears to be more pronounced following oral administration of fluconazole
than with fluconazole administered intravenously. If short-acting benzodiazepines,
which are metabolized by the cytochrome P450 system, are concomitantly administered
with fluconazole, consideration should be given to decreasing the benzodiazepine
dosage, and the patients should be appropriately monitored. (See CLINICAL PHARMACOLOGY: Drug Interaction Studies.) 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 CLINICAL PHARMACOLOGY: Drug Interaction Studies.)
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 the CLINICAL PHARMACOLOGY section
have not been conducted, but such interactions may occur.<br/>Carcinogenesis, Mutagenesis and Impairment of Fertility: Fluconazole showed no evidence of carcinogenic potential
in mice and rats treated orally for 24 months at doses of 2.5, 5 or 10 mg/kg/day
(approximately 2 to 7 times the recommended human dose). Male rats treated
with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas. Fluconazole,
with or without metabolic activation, was negative in tests for mutagenicity
in 4 strains of S. typhimurium, and
in the mouse lymphoma L5178Y system. Cytogenetic studies in
vivo (murine bone marrow cells, following oral administration of
fluconazole) and in vitro (human lymphocytes
exposed to fluconazole at 1000 mcg/mL) showed no evidence of chromosomal mutations. Fluconazole
did not affect the fertility of male or female rats treated orally with daily
doses of 5, 10 or 20 mg/kg or with parenteral doses of 5, 25 or 75 mg/kg,
although the onset of parturition was slightly delayed at 20 mg/kg PO. In
an intravenous perinatal study in rats at 5, 20 and 40 mg/kg, dystocia and
prolongation of parturition were observed in a few dams at 20 mg/kg (approximately
5 to 15 times the recommended human dose) and 40 mg/kg, but not at 5 mg/kg.
The disturbances in parturition were reflected by a slight increase in the
number of still-born pups and decrease of neonatal survival at these dose
levels. The effects on parturition in rats are consistent with the species
specific estrogen-lowering property produced by high doses of fluconazole.
Such a hormone change has not been observed in women treated with fluconazole.
(See CLINICAL PHARMACOLOGY.)<br/>Pregnancy:<br/>Teratogenic Effects.: Pregnancy Category C: Fluconazole
was administered orally to pregnant rabbits during organogenesis in two studies,
at 5, 10 and 20 mg/kg and at 5, 25 and 75 mg/kg, respectively. Maternal weight
gain was impaired at all dose levels, and abortions occurred at 75 mg/kg (approximately
20 to 60 times the recommended human dose); no adverse fetal effects were
detected. In several studies in which pregnant rats were treated orally with
fluconazole during organogenesis, maternal weight gain was impaired and placental
weights were increased at 25 mg/kg. There were no fetal effects at 5 or 10
mg/kg; increases in fetal anatomical variants (super-numerary ribs, renal
pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg
and higher doses. At doses ranging from 80 mg/kg (approximately 20 to 60 times
the recommended human dose) to 320 mg/kg embryolethality in rats was increased
and fetal abnormalities included wavy ribs, cleft palate and abnormal cranio-facial
ossification. These effects are consistent with the inhibition of estrogen
synthesis in rats and may be a result of known effects of lowered estrogen
on pregnancy, organogenesis and parturition. There are
no adequate and well controlled studies in pregnant women. There have been
reports of multiple congenital abnormalities in infants whose mothers were
being treated for 3 or more months with high dose (400 to 800 mg/day) fluconazole
therapy for coccidioidomycosis (an unindicated use). The relationship between
fluconazole use and these events is unclear. Fluconazole should be used in
pregnancy only if the potential benefit justifies the possible risk to the
fetus.<br/>Nursing Mothers: Fluconazole is secreted in human milk at concentrations similar
to plasma. Therefore, the use of fluconazole in nursing mothers is not recommended.<br/>Pediatric Use: An open-label, randomized, controlled trial has shown fluconazole
to be effective in the treatment of oropharyngeal candidiasis in children
6 months to 13 years of age. (See CLINICAL STUDIES.) The use of fluconazole in children with
cryptococcal meningitis, Candida esophagitis,
or systemic Candida infections is supported
by the efficacy shown for these indications in adults and by the results from
several small noncomparative pediatric clinical studies. In addition, pharmacokinetic
studies in children (See CLINICAL PHARMACOLOGY)
have established a dose proportionality between children and adults. (See DOSAGE AND ADMINISTRATION.) In
a noncomparative study of children with serious systemic fungal infections,
most of which were candidemia, the effectiveness of fluconazole was similar
to that reported for the treatment of candidemia in adults. Of 17 subjects
with culture-confirmed candidemia, 11 of 14 (79%) with baseline symptoms (3
were asymptomatic) had a clinical cure; 13/15 (87%) of evaluable patients
had a mycologic cure at the end of treatment but two of these patients relapsed
at 10 and 18 days, respectively, following cessation of therapy. The
efficacy of fluconazole for the suppression of cryptococcal meningitis was
successful in 4 of 5 children treated in a compassionate-use study of fluconazole
for the treatment of life-threatening or serious mycosis. There is no information
regarding the efficacy of fluconazole for primary treatment of cryptococcal
meningitis in children. The safety profile of fluconazole
in children has been studied in 577 children ages 1 day to 17 years who received
doses ranging from 1 to 15 mg/kg/day for 1 to 1,616 days. (See ADVERSE
REACTIONS .) Efficacy of fluconazole has not
been established in infants less than 6 months of age. (See CLINICAL
PHARMACOLOGY.) A small number of patients (29) ranging in age from
1 day to 6 months have been treated safely with fluconazole.<br/>Geriatric Use: In non-AIDS patients, side effects possibly related to fluconazole
treatment were reported in fewer patients aged 65 and older (9%, n=339) than
for younger patients (14%, n=2240). However, there was no consistent difference
between the older and younger patients with respect to individual side effects.
Of the most frequently reported (>1%) side effects, rash, vomiting and diarrhea
occurred in greater proportions of older patients. Similar proportions of
older patients (2.4%) and younger patients (1.5%) discontinued fluconazole
therapy because of side effects. In post-marketing experience, spontaneous
reports of anemia and acute renal failure were more frequent among patients
65 years of age or older than in those between 12 and 65 years of age. Because
of the voluntary nature of the reports and the natural increase in the incidence
of anemia and renal failure in the elderly, it is however not possible to
establish a casual relationship to drug exposure. Controlled
clinical trials of fluconazole did not include sufficient numbers of patients
aged 65 and older to evaluate whether they respond differently from younger
patients in each indication. Other reported clinical experience has not identified
differences in responses between the elderly and younger patients. Fluconazole
is primarily cleared by renal excretion as unchanged drug. Because elderly
patients are more likely to have decreased renal function, care should be
taken to adjust dose based on creatinine clearance. It may be useful to monitor
renal function. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
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dailymed-instance:overdosag... |
There have been reports of overdosage with fluconazole. A
42-year-old patient infected with human immunodeficiency virus developed hallucinations
and exhibited paranoid behavior after reportedly ingesting 8,200 mg of fluconazole.
The patient was admitted to the hospital, and his condition resolved within
48 hours. In the event of overdose, symptomatic treatment
(with supportive measures and gastric lavage if clinically indicated) should
be instituted. Fluconazole is largely excreted in urine.
A three-hour hemodialysis session decreases plasma levels by approximately
50%. In mice and rats receiving very high doses of
fluconazole, clinical effects in both species included decreased motility
and respiration, ptosis, lacrimation, salivation, urinary incontinence, loss
of righting reflex and cyanosis; death was sometimes preceded by clonic convulsions.
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dailymed-instance:genericMe... |
Fluconazole
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dailymed-instance:fullName |
Fluconazole (Injection, Solution)
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dailymed-instance:adverseRe... |
In Patients Receiving Multiple
Doses for Other Infections: Sixteen percent
of over 4,000 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 4,048 patients receiving fluconazole 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%. 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. Post-Marketing Experience In
addition, the following adverse events have occurred during post-marketing
experience. Immunologic:In rare cases, anaphylaxis (including angioedema, face edema and
pruritus) has been reported. Cardiovascular:QT prolongation, torsade de pointes. (See PRECAUTIONS.) Central Nervous System: Seizures, dizziness. Dermatologic: Exfoliative skin disorders including
Stevens-Johnson syndrome and toxic epidermal necrolysis (see WARNINGS), alopecia. Hematopoietic
and Lymphatic: Leukopenia, including neutropenia and agranulocytosis,
thrombocytopenia. Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia. Gastrointestinal: Dyspepsia, vomiting. Other Senses: Taste perversion. Adverse Reactions in Children: In
Phase II/III 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 in 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.
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dailymed-instance:warning |
(1) Hepatic injury: Fluconazole
has been associated with rare cases of serious hepatic toxicity, including
fatalities primarily in patients with serious underlying medical conditions.
In cases of fluconazole-associated hepatotoxicity, no obvious relationship
to total daily dose, duration of therapy, sex or age of the patient has been
observed. Fluconazole hepatotoxicity has usually, but not always, been reversible
on discontinuation of therapy. Patients who develop abnormal liver function
tests during fluconazole therapy should be monitored for the development of
more severe hepatic injury. Fluconazole should be discontinued if clinical
signs and symptoms consistent with liver disease develop that may be attributable
to fluconazole. (2) Anaphylaxis: In rare cases,
anaphylaxis has been reported. (3) Dermatologic:
Patients have rarely developed exfoliative skin disorders during treatment
with fluconazole. In patients with serious underlying diseases (predominantly
AIDS and malignancy), these have rarely resulted in a fatal outcome. Patients
who develop rashes during treatment with fluconazole should be monitored closely
and the drug discontinued if lesions progress.
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dailymed-instance:indicatio... |
Fluconazole is indicated for the treatment of: Prophylaxis: Fluconazole is also indicated to decrease the
incidence of candidiasis in patients undergoing bone marrow transplantation
who receive cytotoxic chemotherapy and/or radiation therapy. Specimens
for fungal culture and other relevant laboratory studies (serology, histopathology)
should be obtained prior to therapy to isolate and identify causative organisms.
Therapy may be instituted before the results of the cultures and other laboratory
studies are known; however, once these results become available, anti-infective
therapy should be adjusted accordingly.
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dailymed-instance:name |
Fluconazole
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