DESCRIPTION: 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 µg/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 µg/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-ß-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 µg/mL, 27.7 µg/mL, and 83.9 µg/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 µg/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 µg/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 µg/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 enters the fungal cell via cytosine permease; thus, flucytosine is metabolized

to 5-fluorouracil within fungal organisms. The 5-fluorouracil is extensively incorporated

into fungal RNA and inhibits synthesis of both DNA and RNA. The result is unbalanced

growth and death of the fungal organism. Antifungal synergism between Ancobon and

polyene antibiotics, particularly amphotericin B, has been reported.

Actions: Flucytosine has in vitro and in vivo activity against Candida and Cryptococcus.

The exact mode of action against these fungi is not known. Ancobon is not metabolized

significantly when given orally to man.

Susceptibility: Cryptococcus: Most strains initially isolated from clinical material have

shown flucytosine minimal inhibitory concentrations (MIC’s) ranging from .46 to 7.8

µg/mL. Any isolate with an MIC greater than 12.5 µg/mL is considered resistant. In vitro

resistance has developed in originally susceptible strains during therapy. It is

recommended that clinical cultures for susceptibility testing be taken initially and at

weekly intervals during therapy. The initial culture should be reserved as a reference in

susceptibility testing of subsequent isolates.

Candida: As high as 40% to 50% of the pretreatment clinical isolates of Candida have

been reported to be resistant to flucytosine. It is recommended that susceptibility studies

be performed as early as possible and be repeated during therapy. An MIC value greater

than 100 µg/mL is considered resistant.

Interference with in vitro activity of flucytosine occurs in complex or semisynthetic

media. In order to rely upon the recommended in vitro interpretations of susceptibility, it

is essential that the broth medium and the testing procedure used be that described by

Shadomy.1

INDICATIONS AND USAGE: Ancobon is indicated only in the treatment of serious

infections caused by susceptible strains of Candida and/or Cryptococcus.

Candida: Septicemia, endocarditis and urinary system infections have been effectively

treated with flucytosine. Limited trials in pulmonary infections justify the use of

flucytosine.

Cryptococcus: Meningitis and pulmonary infections have been treated effectively.

Studies in septicemias and urinary tract infections are limited, but good responses have

been reported.

With the exception of urinary tract infection, Ancobon should be used in combination

with amphotericin B for the treatment of systemic candidiasis and cryptococcosis because

of rapid emergence of resistance to Ancobon in Candida and Cryptococcus isolates in

patients receving Ancobon alone.