Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3503
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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 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 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 1000 cells per cu
mm.<br/>Dosage and
Administration in Children:: The
following dose equivalency scheme should generally provide
equivalent exposure in pediatric and adult patients: 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 disseminatedCandida 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.<br/>Dosage In Patients
With Impaired Renal Function:: Fluconazole
is cleared primarily by renal excretion as unchanged drug. There
is no need to adjust single dose therapy for vaginal candidiasis
because of impaired renal function. 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.)<br/>Administration: Fluconazole
is 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
injection in INTRAVIA plastic containers is 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.<br/>Directions for IV
Use of fluconazole in INTRAVIA 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 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.<br/>To Open: Tear
overwrap down side at 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.<br/>Preparation for
Administration::
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Fluconazole, a
member of a new subclass of synthetic triazole antifungal agents, is
available as a sterile solution for intravenous use in INTRAVIA plastic
container. Fluconazole is
designated chemically as 2,4-difluoro-��,��-bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol with a
molecular 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 in a sodium
chloride diluent. Each mL contains 2 mg of fluconazole and 9 mg of
sodium chloride. Osmolarity is 315 mOsmol/L (calc). The pH is 5.5 (4.0
to 8.0). Injection volumes of 100 mL and 200 mL are packaged in INTRAVIA
plastic containers. The flexible
container is manufactured from a specially designed multilayer plastic
(PL 2408). Solutions in contact with the plastic container leach out
certain chemical components from the plastic in very small amounts;
however, biological testing was supportive of the safety of the plastic
container materials. The flexible container has a foil overwrap. Water
can permeate the plastic into the overwrap, but the amount is
insufficient to significantly affect the premixed solution.
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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.<br/>Pharmacokinetics
and Metabolism: The
pharmacokinetic properties of fluconazole are similar following
administration by the intravenous or oral routes. In normal
volunteers, the bioavailability of orally administered
fluconazole is over 90% compared with intravenous
administration. Bioequivalence was established between the 100
mg tablet and both suspension strengths when administered as a
single 200 mg dose. Peak plasma
concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of
approximately 30 hours (range: 20 to 50 hours) after oral
administration. In fasted
normal volunteers, administration of a single oral 400 mg dose
of fluconazole leads to a mean Cmax of 6.72 mcg/mL (range: 4.12
to 8.08 mcg/mL) and after single oral doses of 50 to 400 mg,
fluconazole plasma concentrations and AUC (area under the plasma
concentration-time curve) are dose proportional. 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 to
plasma concentrations at both 4 and 24 hours post dose. In
patients with fungal meningitis, fluconazole concentrations in
the CSF are approximately 80% of the corresponding plasma
concentrations. 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.<br/>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.<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. 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 fluconazole and 50 mg
hydrochlorothiazide for 10 days in 13 normal volunteers resulted
in a significant increase in fluconazole AUC and Cmax compared
to fluconazole given alone. There was a mean��SD increase in
fluconazole AUC and Cmax of 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. 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%).
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. 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%). 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 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. 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. Rifabutin: There have been
published reports that an interaction exists when fluconazole is
administered concomitantly with rifabutin, leading to increased
serum levels of rifabutin. Tacrolimus: There have been
published reports that an interaction exists when fluconazole is
administered concomitantly with tacrolimus, leading to increased
serum levels of tacrolimus. Cisapride: A preliminary
report from a placebo-controlled, randomized multiple-dose study
in subjects given fluconazole 200 mg daily and cisapride 20 mg
four times daily starting after 7 days of fluconazole dosing
found that fluconazole significantly increased the AUC and Cmax
of cisapride both after single (AUC 102% and Cmax 92% increases)
and multiple (AUC 192% and Cmax 153% increases) dosing of
cisapride. Fluconazole significantly increased the QTc interval
in subjects receiving cisapride 20 mg four times daily for 5
days.<br/>Microbiology: Fluconazole
exhibits in vitro
activity against Cryptococcus
neoformans and Candida spp. Fungistatic activity has also been
demonstrated in normal and immunocompromised animal models for
systemic and intracranial fungal infections due to Cryptococcus neoformans and
for systemic infections due to Candida albicans. In common
with other azole antifungal agents, most fungi show a higher
apparent sensitivity to fluconazole in vivo than in
vitro. Fluconazole administered orally and/or
intravenously was active in a variety of animal models of fungal
infection using standard laboratory strains of fungi. Activity
has been demonstrated against fungal infections caused byAspergillus flavus
and Aspergillus fumigatus
in normal mice. Fluconazole has also been shown to be active in
animal models of endemic mycoses, including one model ofBlastomyces
dermatitidis pulmonary infections in normal mice; one
model of Coccidioides
immitis intracranial infections innormal mice; and
several models of Histoplasma
capsulatum pulmonary infection in normal and
immunosuppressed mice. The clinical significance of results
obtained in these studies is unknown. Concurrent
administration of fluconazole and amphotericin B in infected
normal and immunosuppressed mice showed the following results: a
small additive antifungal effect in systemic infection withC. albicans, no
interaction in intracranial infection with Cr. neoformans, and antagonism
of the two drugs in systemic infection with Asp. fumigatus. The clinical
significance of results obtained in these studies is unknown. There have
been reports of cases of superinfection with Candida species other thanC. albicans, which
are often inherently not susceptible to fluconazole (e.g.,Candida krusei). Such
cases may require alternative antifungal therapy.
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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 INTRAVIA plastic
containers containing volumes of 100 mL or 200 mL affording doses of 200
mg and 400 mg of fluconazole, respectively. Fluconazole
Injections in INTRAVIA Plastic Containers:<br/>Storage: Store
between 77��F (25��C) and 41��F (5��C). Brief exposure up to 104��F
(40��C) does not adversely affect the product. Protect from
freezing. Avoid excessive heat. Baxter Healthcare
Corporation Deerfield,
IL 60015 USA Printed in
USA 07-19-42-943 Issued March 2004 Maalox' is
a registered trademark of Aventis Pharmaceuticals Products Inc. BAXTER and
INTRAVIA are trademarks of Baxter International Inc.
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Drug Interactions: (SeeCLINICAL
PHARMACOLOGY: Drug Interaction Studies andCONTRAINDICATIONS.) 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 Coumarin-type anticoagulants Phenytoin Cyclosporine Rifampin Theophylline Terfenadine Cisapride Astemizole Rifabutin Tacrolimus 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. 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. (SeeCLINICAL
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. (SeeCLINICAL
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 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. 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.
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. (SeeCLINICAL
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.) 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. (SeeCLINICAL
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 incidenceof 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) andin 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:<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.
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There has been one
reported case of overdosage with fluconazole. A 42-year-old patient
infected with human immunodeficiency virus developed hallucinations and
exhibited paranoid behavior after reportedly ingesting 8200 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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Fluconazole
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| dailymed-instance:fullName |
Fluconazole (Injection, Solution)
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| dailymed-instance:adverseRe... |
In Patients
Receiving Multiple Doses for 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
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%. The
following adverse events have occurred under conditions where a
causal association is probable: Hepatobiliary: In combined
clinical trials and marketing experience, there have been rare
cases of serious hepatic reactions during treatment with
fluconazole. 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. Immunologic: In rare cases,
anaphylaxis has been reported. The
following adverse events have occurred under conditions where a
causal association is uncertain: Central Nervous System:
Seizures. Dermatologic: Exfoliative skin
disorders including Stevens-Johnson syndrome and toxic epidermal
necrolysis , alopecia. Hematopoietic and Lymphatic:
Leukopenia, including neutropenia and agranulocytosis,
thrombocytopenia. Metabolic:
Hypercholesterolemia, hypertriglyceridemia,
hypokalemia.<br/>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 dueto
laboratory test abnormalities. The majority of treatment-related
laboratory abnormalities were elevations of transaminases or
alkaline phosphatase.
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Fluconazole
injection 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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