FLUCONAZOLE
DESCRIPTION:
(FLUCONAZOLE TABLETS)
(FLUCONAZOLE INJECTION--FOR INTRAVENOUS INFUSION ONLY)
(FLUCONAZOLE FOR ORAL SUSPENSION)
DIFLUCAN(R) (fluconazole), the first of a new subclass of synthetic triazole
antifungal agents, is available as tablets for oral administration, as a powder
for oral suspension and as a sterile solution for intravenous use in glass and
in Viaflex(R) Plus plastic containers.
Fluconazole is designated chemically as 2,4-difluoro-alpha,alpha1-bis(1H-1,2,4-
triazol- 1-ylmethyl) benzyl alcohol with an empirical formula of C13H12F2N6O and
molecular weight 306.3.
Fluconazole is a white crystalline solid which is slightly soluble in water and
saline.
DIFLUCAN tablets contain 50, 100, 150, or 200 mg of fluconazole and the
following inactive ingredients: microcrystalline cellulose, dibasic calcium
phosphate anhydrous, povidone, croscarmellose sodium, FD&C Red No. 40 aluminum
lake dye, and magnesium stearate.
DIFLUCAN for oral suspension contains 350 mg or 1400 mg of fluconazole and the
following inactive ingredients: sucrose, sodium citrate dihydrate, citric acid
anhydrous, sodium benzoate, titanium dioxide, colloidal silicon dioxide, xanthan
gum and natural orange flavor. After reconstitution with 24 mL of distilled pure
water or Purified Water (USP), each mL of reconstituted suspension contains 10
mg or 40 mg of fluconazole.
DIFLUCAN 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.
ACTIONS/CLINICAL PHARMACOLOGY:
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 (Cmax) in fasted normal volunteers occur between 1
and 2 hours with a terminal plasma elimination half-life of approximately 30
hours (range 20-50 hours) after oral administration.
In fasted normal volunteers, administration of a single oral 400 mg dose of
DIFLUCAN (fluconazole) leads to a mean Cmax of 6.72 mcgm/mL (range: 4.12 to 8.08
mcgm/mL) and after single oral doses of 50-400 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 DIFLUCAN (fluconazole) to ten
lactating women resulted in a mean Cmax of 2.61 mcgm/mL (range: 1.57 to 3.65
mcgm/mL).
Steady-state concentrations are reached within 5-10 days following oral doses of
50-400 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 (11-12%). 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.
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.
RATIO OF FLUCONAZOLE
TISSUE (FLUID)/PLASMA
TISSUE OR FLUID CONCENTRATION*
-----------------------------------------------------------------------------------------------------------------------------
Cerebrospinal fluid** .5-.9
Saliva 1
Sputum 1
Blister fluid 1
Urine 10
Normal skin 10
Nails 1
Blister skin 2
Vaginal tissue 1
Vaginal fluid 0.4-0.7
-----------------------------------------------------------------------------------------------------------------------------
* 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 DIFLUCAN 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, DIFLUCAN 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:
Age Dose Clearance Half-life Cmax Vdss
udied (mg/kg) (mL/min/kg) (Hours) (mcgm/mL) (L/kg)
-----------------------------------------------------------------------------------------------------------------------------------
9 Months- Single-Oral 0.40 (38%) 25.0 2.9 (22%) --
13 years 2 mg/kg N=14 N=16
----------------------------------------------------------------------------------------------------------------------------------
9 Months- Single-Oral 0.51 (60%) 19.5 9.8 (20%) --
13 years 8 mg/kg N=15 N=15
----------------------------------------------------------------------------------------------------------------------------------
5-15 years Multiple 0.49 (40%) 17.4 5.5 (25%) 0.722 (36%)
i.v.
2 mg/kg N=4 N=5 N=4
----------------------------------------------------------------------------------------------------------------------------------
5-15 years Multiple 0.59 (64%) 15.2 11.4 (44%) 0.729 (33%)
i.v.
4 mg/kg N=5 N=6 N=5
---------------------------------------------------------------------------------------------------------------------------------
5-15 years Multiple 0.66 (31%) 17.6 14.1 (22%) 1.069 (37%)
i.v.
8 mg/kg N=7 N=8 N=7
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.
DRUG INTERACTION STUDIES
Oral Contraceptives: Oral contraceptives were administered as a single dose both
before and after the oral administration of DIFLUCAN 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 DIFLUCAN.
The mean increase in ethinyl estradiol AUC was 6% (range: -47 to 108%) and
levonorgestrel AUC increased 17% (range: -33 to 141%).
Twenty-five normal females received daily doses of both 200 mg of DIFLUCAN
tablets or placebo for two, ten-day periods. The treatment cycles were one month
apart with all subjects receiving DIFLUCAN 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 DIFLUCAN, 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: DIFLUCAN 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 DIFLUCAN 200 mg) did not affect the bioavailability or pharmacokinetics
of fluconazole in 24 healthy male volunteers.
Antacid: Administration of Maalox(R) (20 mL) to 14 normal male volunteers
immediately prior to a single dose of DIFLUCAN 100 mg had no effect on the
absorption or elimination of fluconazole.
Hydrochlorothiazide: Concomitant oral administration of 100 mg DIFLUCAN and 50
mg hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a
significant increase in fluconazole AUC and Cmax compared to DIFLUCAN given
alone. There was a mean SD increase in fluconazole AUC and Cmax 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 DIFLUCAN 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 DIFLUCAN 200 mg
administered daily for 14 days as compared to the administration of warfarin
alone. There was a mean SD increase in the prothrombin time response (area
under the prothrombin time- time curve) of 7% 4% (range: -2 to 13%). (See
PRECAUTIONS.) Mean is based on data from 12 subjects as one of 13 subjects
experienced a 2-fold increase in his prothrombin time response.
Phenytoin: Phenytoin AUC was determined after 4 days of phenytoin dosing (200 mg
daily, orally for 3 days followed by 250 mg intravenously for one dose) both
with and without the administration of fluconazole (oral DIFLUCAN 200 mg daily
for 16 days) in 10 normal male volunteers. There was a significant increase in
phenytoin AUC. The mean SD increase in phenytoin AUC was 88% 68% (range:
16 to 247%). The absolute magnitude of this interaction is unknown because of
the intrinsically nonlinear disposition of phenytoin. (See PRECAUTIONS.)
Cyclosporine: Cyclosporine AUC and Cmax were determined before and after the
administration of fluconazole 200 mg daily for 14 days in eight renal transplant
patients who had been on cyclosporine therapy for at least 6 months and on a
stable cyclosporine dose for at least 6 weeks. There was a significant increase
in cyclosporine AUC, Cmax, Cmin (24 hour concentration), and a significant
reduction in apparent oral clearance following the administration of
fluconazole. The mean SD increase in AUC was 92% 43% (range: 18 to
147%). The Cmax increased 60% 48% (range: -5 to 133%). The Cmin increased
157% 96% (range: 33 to 360%). The apparent oral clearance decreased 45%
15% (range: -15 to -60%). (See PRECAUTIONS.)
Zidovudine: Plasma zidovudine concentrations were determined on two occasions
(before and following fluconazole 200 mg daily for 15 days) in 13 volunteers
with AIDS or ARC who were on a stable zidovudine dose for at least two weeks.
There was a significant increase in zidovudine AUC following the administration
of fluconazole. The mean SD increase in AUC was 20% 32% (range: -27 to
104%). The metabolite, GZDV, to parent drug ratio significantly decreased after
the administration of fluconazole, from 7.6 3.6 to 5.7 2.2.
Theophylline: The pharmacokinetics of theophylline were determined from a single
intravenous dose of aminophylline (6 mg/kg) before and after the oral
administration of fluconazole 200 mg daily for 14 days in 16 normal male
volunteers. There were significant increases in theophylline AUC, Cmax, and
half-life with a corresponding decrease in clearance. The mean SD
theophylline AUC increased 21% 16% (range: -5 to 48%). The Cmax increased
13% 17% (range: -13 to 40%). Theophylline clearance decreased 16% 11%
(range: -32 to 5%). The half-life of theophylline increased from 6.6 1.7
hours to 7.9 1.5 hours.
Terfenadine: Six healthy volunteers received terfenadine 60 mg BID for 15 days.
Fluconazole 200 mg was administered daily from days 9 through 15. Fluconazole
did not affect terfenadine plasma concentrations. Terfenadine acid metabolite
AUC increased 36% 36% (range: 7 to 102%) from day 8 to day 15 with the
concomitant administration of fluconazole. There was no change in cardiac
repolarization as measured by Holter QTc intervals. (See PRECAUTIONS.)
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 DIFLUCAN 100 mg daily for 7 days. In these
three studies 22/46 (47.8%) of DIFLUCAN treated patients and 9/22 (40.1%) of
placebo treated patients experienced symptoms consistent with hypoglycemia. (See
PRECAUTIONS.)
Tolbutamide: In 13 normal male volunteers, there was significant increase in
tolbutamide (500 mg single dose) AUC and Cmax following the administration of
fluconazole. There was a mean SD increase in tolbutamide AUC of 26% 9%
(range: 12 to 39%). Tolbutamide Cmax increased 11% 9% (range: -6 to 27%).
(See PRECAUTIONS.)
Glipizide: The AUC and Cmax of glipizide (2.5 mg single dose) were significantly
increased following the administration of fluconazole in 13 normal male
volunteers. There was a mean SD increase in AUC of 49% 13% (range: 27 to
73%) and an increase in Cmax of 19% 23% (range: -11 to 79%). (See
PRECAUTIONS.)
Glyburide: The AUC and Cmax of glyburide (5 mg single dose) were significantly
increased following the administration of fluconazole in 20 normal male
volunteers. There was a mean SD increase in AUC of 44% 29% (range: -13
to 115%) and Cmax increased 19% 19% (range: -23 to 62%). Five subjects
required oral glucose following the ingestion of glyburide after 7 days of
fluconazole administration. (See PRECAUTIONS.)
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 by Aspergillus Flavus and
Aspergillus Fumigatus in normal mice. Fluconazole has also been shown to be
active in animal models of endemic mycoses, including one model of Blastomyces
Dermatitidis pulmonary infections in normal mice; one model of Coccidioides
Immitis intracranial infections in normal 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.
Oral fluconazole has been shown to be active in an animal model of vaginal
candidiasis.
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 with C. 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
than C. Albicans, which are often inherently not susceptible to DIFLUCAN (e.g.,
Candida Krusei). Such cases may require alternative antifungal therapy.
INDICATIONS AND USAGE:
DIFLUCAN (fluconazole) is indicated for the treatment of:
1. Vaginal Candidiasis (vaginal yeast infections due to Candida).
2. Oropharyngeal and esophageal candidiasis. In open noncomparative studies of
relatively small numbers of patients, DIFLUCAN was also effective for the
treatment of Candida urinary tract infections, peritonitis, and systemic Candida
infections including candidemia, disseminated candidiasis, and pneumonia.
3. Cryptococcal meningitis. Before prescribing DIFLUCAN (fluconazole) for AIDS
patients with cryptococcal meningitis, please see CLINICAL STUDIES section.
Studies comparing DIFLUCAN to amphotericin B in non-HIV infected patients have
not been conducted.
Prophylaxis. DIFLUCAN 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.
CLINICAL STUDIES:
Cryptococcal Meningitis: In a multicenter study comparing DIFLUCAN (200 mg/day)
to amphotericin B (0.3 mg/kg/day) for treatment of cryptococcal meningitis in
patients with AIDS, a multivariate analysis revealed three pretreatment factors
that predicted death during the course of therapy: abnormal mental status,
cerebrospinal fluid cryptococcal antigen titer greater than 1:1024, and
cerebrospinal fluid white blood cell count of less than 20 cells/mm(cube).
Mortality among high risk patients was 33% and 40% for amphotericin B and
DIFLUCAN patients, respectively (p=0.58), with overall deaths 14% (9 of 63
subjects) and 18% (24 of 131 subjects) for the 2 arms of the study (p=0.48).
Optimal doses and regimens for patients with acute cryptococcal meningitis and
at high risk for treatment failure remain to be determined. (Saag, Et Al. N Engl
J Med 1992; 326:83-9)
Vaginal Candidiasis: Two adequate and well- controlled studies were conducted in
the U.S. using the 150 mg tablet. In both, the results of the fluconazole
regimen were comparable to the control regimen (clotrimazole or miconazole
intravaginally for 7 days) both clinically and statistically at the one month
post-treatment evaluation.
The therapeutic cure rate, defined as a complete resolution of signs and
symptoms of vaginal candidiasis (clinical cure), along with a negative KOH
examination and negative culture for Candida (microbiologic eradication), was
55% in both the fluconazole group and the vaginal products group.
FLUCONAZOLE PO VAGINAL PRODUCT
150 MG TABLET QHS X 7 DAYS
Enrolled 448 422
Evaluable at
Late Follow-up 347 (77%) 327 (77%)
Clinical cure 239/347 (69%) 235/327 (72%)
Mycologic erad. 213/347 (61%) 196/327 (60%)
Therapeutic cure 190/347 (55%) 179/327 (55%)
Approximately three-fourths of the enrolled patients had acute vaginitis (<4
episodes/12 months) and achieved 80% clinical cure, 67% mycologic eradication
and 59% therapeutic cure when treated with a 150 mg DIFLUCAN tablet administered
orally. These rates were comparable to control products. The remaining one-
fourth of enrolled patients had recurrent vaginitis (>/=4 episodes/12 months)
and achieved 57% clinical cure, 47% mycologic eradication and 40% therapeutic
cure. The numbers are too small to make meaningful clinical or statistical
comparisons with vaginal products in the treatment of patients with recurrent
vaginitis.
Substantially more gastrointestinal events were reported in the fluconazole
group compared to the vaginal product group. Most of the events were mild to
moderate. Because fluconazole was given as a single dose, no discontinuations
occurred.
VAGINAL
PARAMETER FLUCONAZOLE PO PRODUCTS
Evaluable patients 448 422
With any adverse event 141 (31%) 112 (27%)
Nervous System 90 (20%) 69 (16%)
Gastrointestinal 73 (16%) 18 ( 4%)
With drug-related event 117 (26%) 67 (16%)
Nervous System 61 (14%) 29 ( 7%)
Headache 58 (13%) 28 ( 7%)
Gastrointestinal 68 (15%) 13 ( 3%)
Abdominal pain 25 ( 6%) 7 ( 2%)
Nausea 30 ( 7%) 3 ( 1%)
Diarrhea 12 ( 3%) 2 (<1%)
Application site event 0 ( 0%) 19 ( 5%)
Taste Perversion 6 ( 1%) 0 ( 0%)
PEDIATRIC STUDIES
Oropharyngeal Candidiasis: An open-label, comparative study of the efficacy and
safety of DIFLUCAN (2-3 mg/kg/day) and oral nystatin (400,000 I.U. 4 times
daily) in immunocompromised children with oropharyngeal candidiasis was
conducted. Clinical and mycological response rates were higher in the children
treated with fluconazole.
Clinical cure at the end of treatment was reported for 86% of fluconazole
treated patients compared to 46% of nystatin treated patients. Mycologically,
76% of fluconazole treated patients had the infecting organism eradicated
compared to 11% for nystatin treated patients.
FLUCONAZOLE NYSTATIN
Enrolled 96 90
Clinical Cure 76/88 (86%) 36/78 (46%)
Mycological eradication* 55/72 (76%) 6/54 (11%)
* Subjects without follow-up cultures for any reason were considered
nonevaluable for mycological response.
The proportion of patients with clinical relapse 2 weeks after the end of
treatment was 14% for subjects receiving DIFLUCAN and 16% for subjects receiving
nystatin. At 4 weeks after the end of treatment the percentages of patients with
clinical relapse were 22% for DIFLUCAN and 23% for nystatin.
CONTRAINDICATIONS:
DIFLUCAN (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 DIFLUCAN to patients
with hypersensitivity to other azoles. Coadministration of terfenadine is
contraindicated in patients receiving DIFLUCAN (fluconazole) at multiple doses
of 400 mg or higher based upon results of a multiple dose interaction study.
(See PRECAUTIONS.)
WARNINGS:
(1) HEPATIC INJURY: DIFLUCAN HAS BEEN ASSOCIATED WITH RARE CASES OF SERIOUS
HEPATIC TOXICITY, INCLUDING FATALITIES PRIMARILY IN PATIENTS WITH SERIOUS
UNDERLYING MEDICAL CONDITIONS. IN CASES OF DIFLUCAN ASSOCIATED HEPATOTOXICITY,
NO OBVIOUS RELATIONSHIP TO TOTAL DAILY DOSE, DURATION OF THERAPY, SEX OR AGE OF
THE PATIENT HAS BEEN OBSERVED. DIFLUCAN HEPATOTOXICITY HAS USUALLY, BUT NOT
ALWAYS, BEEN REVERSIBLE ON DISCONTINUATION OF THERAPY. PATIENTS WHO DEVELOP
ABNORMAL LIVER FUNCTION TESTS DURING DIFLUCAN THERAPY SHOULD BE MONITORED FOR
THE DEVELOPMENT OF MORE SEVERE HEPATIC INJURY. DIFLUCAN SHOULD BE DISCONTINUED
IF CLINICAL SIGNS AND SYMPTOMS CONSISTENT WITH LIVER DISEASE DEVELOP THAT MAY BE
ATTRIBUTABLE TO DIFLUCAN.
(2) Anaphylaxis: In rare cases, anaphylaxis has been reported.
(3) Dermatologic: Patients have rarely developed exfoliative skin disorders
during treatment with DIFLUCAN. 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 DIFLUCAN should be
monitored closely and the drug discontinued if lesions progress.
(4) Cisapride: There have been reports of cardiac events including torsade de
pointes in patients receiving concomitant administration of fluconazole with
cisapride. Patients should be carefully monitored if fluconazole is to be
coadministered with cisapride. (See PRECAUTIONS.)
PRECAUTIONS:
GENERAL: SINGLE DOSE:
The convenience and efficacy of the single dose oral tablet of fluconazole
regimen for the treatment of vaginal yeast infections should be weighed against
the acceptability of a higher incidence of drug related adverse events with
DIFLUCAN (26%) versus intravaginal agents (16%) in U.S. comparative clinical
studies. (See ADVERSE REACTIONS and CLINICAL STUDIES.)
DRUG INTERACTIONS: (See CLINICAL PHARMACOLOGY and PRECAUTIONS--General)
Clinically or potentially significant drug interactions between DIFLUCAN 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
Oral Hypoglycemics: Clinically significant hypoglycemia may be precipitated by
the use of DIFLUCAN with oral hypoglycemic agents; one fatality has been
reported from hypoglycemia in association with combined DIFLUCAN and glyburide
use. DIFLUCAN reduces the metabolism of tolbutamide, glyburide, and glipizide
and increases the plasma concentration of these agents. When DIFLUCAN is used
concomitantly with these or other sulfonylurea oral hypoglycemic agents, blood
glucose concentrations should be carefully monitored and the dose of the
sulfonylurea should be adjusted as necessary.
Coumarin-type Anticoagulants: Prothrombin time may be increased in patients
receiving concomitant DIFLUCAN and coumarin-type anticoagulants. Careful
monitoring of prothrombin time in patients receiving DIFLUCAN and coumarin- type
anticoagulants is recommended.
Phenytoin: DIFLUCAN increases the plasma concentrations of phenytoin. Careful
monitoring of phenytoin concentrations in patients receiving DIFLUCAN and
phenytoin is recommended.
Cyclosporine: DIFLUCAN 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 DIFLUCAN and cyclosporine.
Rifampin: Rifampin enhances the metabolism of concurrently administered
DIFLUCAN. Depending on clinical circumstances, consideration should be given to
increasing the dose of DIFLUCAN when it is administered with rifampin.
Theophylline: DIFLUCAN increases the serum concentrations of theophylline.
Careful monitoring of serum theophylline concentrations in patients receiving
DIFLUCAN and theophylline is recommended.
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 DIFLUCAN 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, DRUG INTERACTION STUDIES.) The
coadministration of fluconazole at doses lower than 400 mg/day with terfenadine
should be carefully monitored.
Cisapride And Astemizole: There have been reports of cardiac events including
torsade de pointes in patients to whom fluconazole and cisapride were
coadministered. The use of fluconazole in patients concurrently taking
cisapride, 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.
Fluconazole tablets coadministered with ethinyl estradiol- and levonorgestrel-
containing oral contraceptives produced an overall mean increase in ethinyl
estradiol and levonorgestrel levels; however, in some patients there were
decreases up to 47% and 33% of ethinyl estradiol and levonorgestrel levels. (See
Drug Interaction Studies.) 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 ACTIONS/CLINICAL PHARMACOLOGY section have not been
conducted, but such interactions may occur.
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
2-7X 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 mcgm/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 p.o.
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 5-15X 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
ACTIONS/CLINICAL PHARMACOLOGY.)
PREGNANCY
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 20-60X 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 (supernumerary ribs, renal pelvis dilation) and
delays in ossification were observed at 25 and 50mg/kg and higher doses. At
doses ranging from 80 mg/kg (approximately 20-60X 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 (400-800 mg/day) fluconazole
therapy for coccidioidomycosis (an unindicated use). The relationship between
fluconazole use and these events is unclear. DIFLUCAN should be used in
pregnancy only if the potential benefit justifies the possible risk to the
fetus.
NURSING MOTHERS
Fluconazole is secreted in human milk at concentrations similar to plasma.
Therefore, the use of DIFLUCAN in nursing mothers is not recommended.
PEDIATRIC USE
An open-label, randomized, controlled trial has shown DIFLUCAN to be effective
in the treatment of oropharyngeal candidiasis in children 6 months to 13 years
of age. (See CLINICAL STUDIES.)
The use of DIFLUCAN 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 ACTIONS/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 DIFLUCAN 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 DIFLUCAN 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 DIFLUCAN 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 DIFLUCAN has not been established in infants less than 6 months of
age. (See ACTIONS/CLINICAL PHARMACOLOGY.) A small number of patients (29)
ranging in age from 1 day to 6 months have been treated safely with DIFLUCAN.
DRUG INTERACTIONS:
(See ACTIONS/CLINICAL PHARMACOLOGY and PRECAUTIONS--General)
Clinically or potentially significant drug interactions between DIFLUCAN 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
Oral Hypoglycemics: Clinically significant hypoglycemia may be precipitated by
the use of DIFLUCAN with oral hypoglycemic agents; one fatality has been
reported from hypoglycemia in association with combined DIFLUCAN and glyburide
use. DIFLUCAN reduces the metabolism of tolbutamide, glyburide, and glipizide
and increases the plasma concentration of these agents. When DIFLUCAN is used
concomitantly with these or other sulfonylurea oral hypoglycemic agents, blood
glucose concentrations should be carefully monitored and the dose of the
sulfonylurea should be adjusted as necessary.
Coumarin-type Anticoagulants: Prothrombin time may be increased in patients
receiving concomitant DIFLUCAN and coumarin-type anticoagulants. Careful
monitoring of prothrombin time in patients receiving DIFLUCAN and coumarin- type
anticoagulants is recommended.
Phenytoin: DIFLUCAN increases the plasma concentrations of phenytoin. Careful
monitoring of phenytoin concentrations in patients receiving DIFLUCAN and
phenytoin is recommended.
Cyclosporine: DIFLUCAN 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 DIFLUCAN and cyclosporine.
Rifampin: Rifampin enhances the metabolism of concurrently administered
DIFLUCAN. Depending on clinical circumstances, consideration should be given to
increasing the dose of DIFLUCAN when it is administered with rifampin.
Theophylline: DIFLUCAN increases the serum concentrations of theophylline.
Careful monitoring of serum theophylline concentrations in patients receiving
DIFLUCAN and theophylline is recommended.
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 DIFLUCAN 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, DRUG INTERACTION STUDIES.) The
coadministration of fluconazole at doses lower than 400 mg/day with terfenadine
should be carefully monitored.
Cisapride And Astemizole: There have been reports of cardiac events including
torsade de pointes in patients to whom fluconazole and cisapride were
coadministered. The use of fluconazole in patients concurrently taking
cisapride, 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.
Fluconazole tablets coadministered with ethinyl estradiol- and levonorgestrel-
containing oral contraceptives produced an overall mean increase in ethinyl
estradiol and levonorgestrel levels; however, in some patients there were
decreases up to 47% and 33% of ethinyl estradiol and levonorgestrel levels. (See
Drug Interaction Studies.) 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 ACTIONS/CLINICAL PHARMACOLOGY section have not been
conducted, but such interactions may occur.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
IN PATIENTS RECEIVING A SINGLE DOSE FOR VAGINAL CANDIDIASIS:
During comparative clinical studies conducted in the United States, 448 patients
with vaginal candidiasis were treated with DIFLUCAN, 150 mg single dose. The
overall incidence of side effects possibly related to DIFLUCAN was 26%. In 422
patients receiving active comparative agents, the incidence was 16%. The most
common treatment- related adverse events reported in the patients who received
150 mg single dose fluconazole for vaginitis were headache (13%), nausea (7%),
and abdominal pain (6%). Other side effects reported with an incidence equal to
or greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and
taste perversion (1%). Most of the reported side effects were mild to moderate
in severity. Rarely, angioedema and anaphylactic reaction have been reported in
marketing experience.
IN PATIENTS RECEIVING MULTIPLE DOSES FOR OTHER INFECTIONS:
Sixteen percent of over 4000 patients treated with DIFLUCAN (fluconazole) in
clinical trials of 7 days or more experienced adverse events. Treatment was
discontinued in 1.5% of patients due to adverse clinical events and in 1.3% of
patients due to laboratory test abnormalities.
Clinical adverse events were reported more frequently in HIV infected patients
(21%) than in non-HIV infected patients (13%); however, the patterns in HIV
infected and non-HIV infected patients were similar. The proportions of patients
discontinuing therapy due to clinical adverse events were similar in the two
groups. (1.5%).
The following treatment-related clinical adverse events occurred at an incidence
of 1% or greater in 4048 patients receiving DIFLUCAN for 7 or more days in
clinical trials: nausea 3.7%, headache 1.9%, skin rash 1.8%, vomiting 1.7%,
abdominal pain 1.7%, and diarrhea 1.5%.
The following adverse events have occurred under conditions where a causal
association is probable:
Hepatobiliary: In combined clinical trials and marketing experience, there have
been rare cases of serious hepatic reactions during treatment with DIFLUCAN.
(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 DIFLUCAN.
In two comparative trials evaluating the efficacy of DIFLUCAN 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
DIFLUCAN 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 (see WARNINGS), alopecia.
Hematopoietic and Lymphatic: leukopenia, including neutropenia and
agranulocytosis, thrombocytopenia.
Metabolic: hypercholesterolemia, hypertriglyceridemia, hypokalemia.
ADVERSE REACTIONS IN CHILDREN:
In Phase 2/3 clinical trials conducted in the United States and in Europe, 577
pediatric patients, ages 1 day to 17 years were treated with DIFLUCAN 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 phosphate.
PERCENTAGE OF PATIENTS
WITH TREATMENT-RELATED SIDE EFFECTS
COMPARATIVE
FLUCONAZOLE AGENTS
(N=577) (N=451)
With any side effect 13.0 9.3
Vomiting 5.4 5.1
Abdominal pain 2.8 1.6
Nausea 2.3 1.6
Diarrhea 2.1 2.2
OVERDOSAGE:
There has been one reported case of overdosage with DIFLUCAN (fluconazole). A
42-year-old patient infected with human immunodeficiency virus developed
hallucinations and exhibited paranoid behavior after reportedly ingesting 8200
mg of DIFLUCAN. 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.
DOSAGE AND ADMINISTRATION:
DOSAGE AND ADMINISTRATION IN ADULTS:
SINGLE DOSE
Vaginal Candidiasis: The recommended dosage of DIFLUCAN for vaginal candidiasis
is 150 mg as a single oral dose.
To prevent repeated infection 150 mg once mthly for 4-12 mths.Some pts may require more frequent dosage.
MULTIPLE DOSE
SINCE ORAL ABSORPTION IS RAPID AND ALMOST COMPLETE, THE DAILY DOSE OF DIFLUCAN
(FLUCONAZOLE) IS THE SAME FOR ORAL (TABLETS AND 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 DIFLUCAN 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 DIFLUCAN 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 DIFLUCAN 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 Infection And Peritonitis: For the treatment of Candida urinary
tract infections and peritonitis, daily doses of 50-200 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 10-12 weeks after the
cerebrospinal fluid becomes culture negative. The recommended dosage of DIFLUCAN
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
DIFLUCAN 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 DIFLUCAN 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.
DOSAGE AND ADMINISTRATION IN CHILDREN:
The following dose equivalency scheme should generally provide equivalent
exposure in pediatric and adult patients:
Pediatric Patients Adults
3 mg/kg 100 mg
6 mg/kg 200 mg
12* mg/kg 400 mg
*Some older children may have clearances similar to that of adults.
Absolute doses exceeding 600 mg/day are not recommended.
Experience with DIFLUCAN in neonates is limited to pharmacokinetic studies in
premature newborns. (See ACTIONS/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
DIFLUCAN pharmacokinetics in full-term newborns is available.
Oropharyngeal Candidiasis: The recommended dosage of DIFLUCAN 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 DIFLUCAN 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 6-12 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 10-12 weeks after the cerebrospinal fluid
becomes culture negative. For suppression of relapse of cryptococcal meningitis
in children with AIDS, the recommended dose of DIFLUCAN is 6 mg/kg once daily.
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 DIFLUCAN, 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:
CREATININE CLEARANCE PERCENT OF
(ML/MIN) RECOMMENDED DOSE
---------------------------------------------- ------------------------------------------
>50 100%
=50 (no dialysis) 50%
Regular dialysis 100% after each dialysis
These are suggested dose adjustments based on pharmacokinetics following
administration of multiple doses. Further adjustments 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:
Males: Weight (kg) X (140-age)
------------------------------------------------
72 X serum creatinine (mg/100 mL)
Females: 0.85 X above value
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:
linear length or height (cm)
K X --------------------------------------------
serum creatinine (mg/100 mL)
(Where K=0.55 for children older than 1 year and 0.45 for infants.)
ADMINISTRATION
DIFLUCAN may be administered either orally or by intravenous infusion. DIFLUCAN
injection has been used safely for up to fourteen days of intravenous therapy.
The intravenous infusion of DIFLUCAN should be administered at a maximum rate of
approximately 200 mg/hour, given as a continuous infusion.
DIFLUCAN injections in glass and Viaflex(R) Plus 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 MIXING THE ORAL SUSPENSION
Prepare a suspension at time of dispensing as follows: tap bottle until all the
powder flows freely. To reconstitute, add 24 mL of distilled water or Purified
Water (USP) to fluconazole bottle and shake vigorously to suspend powder. Each
bottle will deliver 35 mL of suspension. The concentrations of the reconstituted
suspensions are as follows:
FLUCONAZOLE CONCENTRATION OF
CONTENT RECONSTITUTED
PER BOTTLE SUSPENSION
350 mg 10 mg/mL
1400 mg 40 mg/mL
Note: Shake oral suspension well before using. Store reconstituted suspension
between 86 deg F (30 deg C) and 41 deg F (5 deg C) and discard unused portion
after 2 weeks. Protect from freezing.
DIRECTIONS FOR IV USE OF DIFLUCAN IN VIAFLEX(R) PLUS 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.
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 the inner bag firmly. If leaks are found, discard solution as
sterility may be impaired.
DO NOT ADD SUPPLEMENTARY MEDICATION.
PREPARATION FOR ADMINISTRATION:
1. Suspend container from eyelet support.
2. Remove plastic protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.