Product Description.:
Logo and 10, logo and 10
capsule , gray yellow , oblong oblong
Opaque
Ancobon (flucytosine), an antifungal agent, is available as 250-mg and
500-mg capsules for oral administration. Each capsule also contains corn starch, lactose
and talc. Gelatin capsule shells contain parabens (butyl, methyl, propyl) and sodium
propionate, with the following dye systems: 250-mg capsules ? black iron oxide, FD&C
Blue No. 1, FD&C Yellow No. 6, D&C Yellow No. 10 and titanium dioxide 500-mg
capsules ? black iron oxide and titanium dioxide. Chemically, flucytosine is 5-
fluorocytosine, a fluorinated pyrimidine which is related to fluorouracil and floxuridine.
It is a white to off-white crystalline powder with a molecular weight of 129.09 and the
following structural formula:
CLINICAL PHARMACOLOGY: Flucytosine is rapidly and virtually completely
absorbed following oral administration. Bioavailability estimated by comparing the area
under the curve of serum concentrations after oral and intravenous administration showed
78% to 89% absorption of the oral dose. Peak blood concentrations of 30 to 40 ?g/mL
were reached within 2 hours of administration of a 2-gm oral dose to normal subjects.
The mean blood concentrations were approximately 70 to 80 ?g/mL 1 to 2 hours after a
dose in patients with normal renal function who received a 6-week regimen of flucytosine
(150 mg/kg/day given in divided doses every 6 hours) in combination with amphotericin
B. The half-life in the majority of normal subjects ranged between 2.4 and 4.8 hours.
Flucytosine is excreted via the kidneys by means of glomerular filtration without
significant tubular reabsorption. More than 90% of the total radioactivity after oral
administration was recovered in the urine as intact drug. Flucytosine is deaminated
(probably by gut bacteria) to 5-fluorouracil. The area under the curve (AUC) ratio of 5-
fluorouracil to flucytosine is 4%. Approximately 1% of the dose is present in the urine as
the α-fluoro-?-ureido-propionic acid metabolite. A small portion of the dose is excreted
in the feces.
The half-life of flucytosine is prolonged in patients with renal insufficiency the average
WARNING
Use with extreme caution in patients with impaired renal function. Close
monitoring of hematologic, renal and hepatic status of all patients is essential.
These instructions should be thoroughly reviewed before administration of
Ancobon.
half-life in nephrectomized or anuric patients was 85 hours (range: 29.9 to 250 hours). A
linear correlation was found between the elimination rate constant of flucytosine and
creatinine clearance.
In vitro studies have shown that 2.9% to 4% of flucytosine is protein-bound over the
range of therapeutic concentrations found in the blood. Flucytosine readily penetrates the
blood-brain barrier, achieving clinically significant concentrations in cerebrospinal fluid.
Studies in pregnant rats have shown that flucytosine injected intraperitoneally crosses the
placental barrier (see PRECAUTIONS).
Pharmacokinetics in Pediatric Patients: Limited data are available regarding the
pharmacokinetics of Ancobon administered to neonatal patients being treated for
systemic candidiasis. After five days of continuous therapy, median peak levels in infants
were 19.6 ?g/mL, 27.7 ?g/mL, and 83.9 ?g/mL at doses of 25 mg/kg (N=3), 50 mg/kg
(N=4), and 100 mg/kg (N=3), respectively. Mean time to peak serum levels was of 2.5 +
1.3 hours, similar to that observed in adult patients. A good deal of interindividual
variability was noted, which did not correlate with gestational age. Some patients had
serum levels > 100 ?g/mL, suggesting a need for drug level monitoring during therapy.
In another study, serum concentrations were determined during flucytosine therapy in
two patients (total assays performed =10). Median serum flucytosine concentrations at
steady state were calculated to be 57 + 10 ?g/mL (doses of 50 to 125 mg/kg/day,
normalized to 25 mg/kg per dose for comparison). In three infants receiving flucytosine
25 mg/kg/day (four divided doses), a median flucytosine half-life of 7.4 hours was
observed, approximately double that seen in adult patients. The concentration of
flucytosine in the cerebrospinal fluid of one infant was 43 ?g/mL 3 hours after a 25 mg
oral dose, and ranged from 20 to 67 mg/L in another neonate receiving oral doses of 120
to 150 mg/kg/day.
Microbiology: Flucytosine has in vitro and in vivo activity against Candida and
Cryptococcus. Although the exact mode of action is unknown, it has been proposed that
flucytosine acts directly on fungal organisms by competitive inhibition of purine and
pyrimidine uptake and indirectly by intracellular metabolism to 5-fluorouracil.
Flucytosine ente